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Basic Pharmacokinetics PHA 443

Course Content available @ http://pharmacy.creighton.edu

Schedule Spring 1999


Week of Text Content Comments
Chapters
March 15 1 –2 Introduction,
Basic Math Skills
March 22 3 Pharmacological
Response
March 29 4–5 IV Bolus, End of Material
IV Infusion for Exam # 1
April 5 Exam #1 40% To Be Scheduled

April 12 7–8 Oral Dosing,


Bioavailability
April 19 9 Clearance

April 26 10 Dosage
Regimens
May 3 Exam #2 60% To Be Scheduled

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Teaching Philosophy

Teaching is the number one priority of my Creighton mission. This is why I went to graduate school. This
is what I wanted to do all of my life. After I had graduated from pharmacy school and been a practicing
pharmacist, I applied to and was accepted into pharmacy graduate school and medical school. I chose the
former, without hesitation and without a second thought.

Availability

My students come first. I am available to students at any time. I do not have office hours. Instead, I have
a two-week running schedule on my door which tells the student when I am not available through previous
commitments. A student may see me whenever I’m available in the office or sign up for a future
appointment on that schedule if I’m not available. When in my office, the student has my entire attention
even to the point of ignoring phone calls. I have voice mail and can return calls but a student ignored is lost
forever. Obviously, this process is only a problem when more than one student needs attention at the same
time. Thus the need for future appointments.

My vision - what I do.

When asked, “What do you do?” I am reminded of a story in which the prince of a nation came upon a
construction site whereupon he asked several people what they were doing. They answered according to
their job description: “I’m cutting stone.” or “I’m mixing mortar.” The prince happened on an old stone
carver cutting a gargoyle. He asked, “What are you doing?” To which the old stone cutter replied, ”I’m
building a cathedral!” Well, I’m building competent health professionals. I teach them Creighton values. I
teach them teamwork. I teach them to be self motivated. I teach them to be self learners. We discuss
ethics; the professional, intellectual, social aspects of what it means to be a health professional graduate of
Creighton University. I tell my students that I used to teach Pharmacokinetics and Pharmacy Calculations.
Now, I use this same course content to teach Creighton values and to build competent health professionals.
It took ten years and major trauma to recognize who I am and prioritize what I do. This is what I do.!
Every morning, I get up and think, “I get to go to school today.” It’s exciting! When we talk in class about
careers, I tell the students that they will have a professional life of about 40 years. For five days a week,
fifty weeks a year, they will go to work. It had better be what they want to do! It had better be fun!

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Teaching Style – Excerpted from Presentation to American Association of
Colleges of Pharmacy – July 1997

Evolution of style - Where did it come from?

I have over the years attempted to emulate several different styles of pedagogy in an attempt to be a better
teacher. Most of us have been trained to do research, but have we been trained to teach? Most of us teach
as we were taught. Whether that is good or bad, it’s the best we can do because it's all we know how to do.
We use the tools that we learned to pass on the skills that we learned to the next generation of health
professionals. Many of us, (Pharmacy professors) come to the AACP meeting and attend the Teacher's
Seminar. We spend one day a year attempting to perfect our craft. I say craft, for craft, it really is. It
really is a learned skill and it doesn't come on conferral of a degree. We don't know how to teach content
just because we know content. I have searched for a better way to do this. What I have found,
interestingly, comes from coaching techniques as well as pedagogical literature. Several years ago, I took
courses to become an ACEP (American Coaching Effectiveness Program) certified Judo coach. Most
states recognize this program in lieu of a teaching certificate. After taking this course, I felt that the
techniques utilized in the psycho-motor domain should have counterparts in the cognitive domain and I
began to search the literature as well as attending workshops on pedagogy. I began to apply what I learned
with a gradual improvement of the outcomes of my teaching as evidenced by an improvement of overall
performance by the students and improvement of student perceptions of what was being taught as
evidenced by my teaching evaluations and student letters. A major breakthrough in my teaching style came
as a result of a one week workshop hosted by AACP in the use of case studies in teaching. What I saw was
the basics of group dynamics and the beginnings of the process described below. This seminar
significantly altered my teaching style from a professor-centered, passive-learning lecture format to an
student-centered, active-learning problem solving format.

Student Centered, Active Learning Process

What I will describe is a student-centered, active learning process applied to teaching a basic science
course. Results of this process over multi-year longitudinal retrospective study with respect to student
perceptions and performance are evaluated.

Objective: Describe (II) the role of objectives in evaluation process

I submit that we make competent health professionals. We don't have a guild system of apprenticeship to
accomplish this, like pharmacy of a hundred and fifty years ago nor do we have a completely didactic
system, but a combination of both with a didactic system designed to impart the scientific background and
basis for the rotational “apprenticeship” experience. If, in fact, our job is to make competent health
professionals, it would be reasonable to define a competent health professional. The profession of
Pharmacy has determined that there are minimum, entry level abilities or competencies necessary for
pharmacists. It is important to understand that these are not the result of some faculty member who sits in
his ivory tower saying what he thinks is important, these are what pharmacists do. These have been
promulgated as a set competency statements. The NABPLEX competency statements are one such set.
These competency statements should be the basis for the NABLPEX part of the state board exam as well as
some of the pharmacy curriculum. They are a subset of the Creighton outcomes statements which have
been promulgated by and for the faculty. These competency statements are broken down into five general
areas and further subdivided into specific activities. These should be considered goals of the educational

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process, these measurable competencies. From these, should come the course objectives, broken down as
finely as necessary to give the student the tools to do the competencies. These objectives should consist of
three parts, information necessary to do something, (Given....), an action verb (student does something)
with a level of difficulty (Bloom's taxonomy of higher educational objectives), and what is it that is to be
done. For example:

Connect course objectives to desired outcomes

Competence statement 2.00.00 Assessing prescriptions / medication orders and the drugs used in
dispensing them.

Specific activity 2.02.00 The candidate shall assess the physicochemical equivalency or non-equivalency of
multi-source drugs

Course objectives for Bioavailability:


i. Given sufficient data to compare an oral product with another oral product or an IV product, the student
will estimate (III) the bioavailability (compare AUCs) and judge (VI) professional acceptance of the product
with regard to bioequivalence (evaluate (VI) AUC, Tp, and Cpmax).

ii. The student will write (V) a professional consult using the above calculations.

Connect course exams to course objectives.

It follows, then, that the practice problems and the examinations or course evaluations should be
measurement of how well the student mastered the course objectives and nothing else. If it's not an
objective, it shouldn't be graded. Conversely, if you think that it should be graded, then it should be an
objective. The exam questions and problem sets should be linked to the course objectives and the course
objectives should be linked to the competency statements. Chaining this process back one more step, it
should be obvious that the prerequisites necessary to complete the objectives also can be determined by this
process and clearly stated.

The concept is reasonably straight forward:

1. tell them what you expect from them in detail,


2. give them practice at doing it, and
3. have them show you that they can do it.

My accountability to stick to the objectives.

I add a fourth part: If I don't follow the above three parts and put a question on an exam which doesn't meet
the requirements, the class votes and if it is agreed that the question did not meet the requirements, it is
thrown out. Note: not that it was hard, not that you got it wrong, not that you didn't think that it should be
on the exam, but did I tell them that they needed to know how to do it?; was it an objective?; and were
there practice problems? Not all possibilities can be explored in problem sets, but general problem solving
procedures can be taught. In ten years of student suffrage, not one question has ever been voted out. I do
not believe that teaching is the hauling out of voluminous amounts of facts to be sorted out and prioritized
by the neophyte student, nor is it the spoon-feeding of predigested pabulum.

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Clearly, tell the students what they are to do.

Objective: Compare (III) various levels of expectations

The expectations that you should have for the student performance would be in three arenas:

Expectations for the course


1. Level of Complexity - how much do you want them to know? (Table 2)
2. Level of Mastery - how well do you want them to know it? (Table 3)
3. Level of Instructional Demand- what student resources are required? (Table4)

These levels are really a continuum, arbitrarily partitioned into six levels with some landmarks defined. It
should be apparent that the levels should be commensurate with the student's abilities. Students should no
more be expected to perform in a previously unpracticed level than they should be able to swim when
thrown into the water for the first time. They need demonstration, practice, encouragement, practice,
evaluation, practice and then more practice.

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TABLE 2. Level of Complexity (Evans’Taxonomy of Complexity (Modified))
Cognitive Domain Psycho-motor Domain
1 Overview - Highlights of the area
Simple Motor Skills: easy repetitive motions
2 Introduction: Some perspectives and Compound Motor Skills: Multiple motions not
principles necessarily repetitive
3 Perspectives and some essential principles Applied Motor Skills: care and beginnings of
dexterity required
4 Intermediate : Most essential principles and few Involved Motor skills: coordinated, multiple
topics in depth manipulations
5 Advanced: All principles and majority of topics in depth Complex Motor Skills: high degree of dexterity required
6 Most Advanced: Great depth in virtually all subjects Most Complex Motor Skills: strength, endurance,
dexterity needed
TABLE 3. Level of Mastery (Bloom’s Taxonomy of Higher Educational Objectives)
Cognitive Domain Psycho-motor Domain
1 To Know, Recognize information / material Slow and awkward
2 To Comprehend, Recall information / Not as slow with moderate precision and accuracy
material
3 To Apply information, do calculations
Speed, accuracy and precision improving
technical skills but still substandard for entry level
4 To Analyze a body of knowledge identify Methodical and meeting all minimum standards of
relationships precision and accuracy
5 To Synthesize put together information in new ways
Methodical processing declining and finesse
increasing as well as accuracy and precision
6 To evaluate judge the worth of an idea Good speed, with precision
accuracy and finesse
TABLE 4. Level of Instructional Demand (Evans’Taxonomy of Instructional Demand (Modified))
1
Little or no initiative required, virtually no outside class time needed
2 Moderate initiative and concentration, outside class time approaches in-class time
3 Increased level of initiative and concentration required; begin independent learning; outside class time begins
to exceed in-class time
4 Average level of initiative and concentration independent learning required; outside class time about twice in-
class time
5 Substantial initiative, concentration, independent learning as well as outside class time required
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Intense initiative and concentration required, in-class time minimal

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Getting the student to buy into your expectations is critical for his/her success.

Level one in complexity, mastery and demand might be boring to a first year pharmacy student and be
considered a “nothing” course, but if your objective is to simply expose the students to the job
opportunities available to a pharmacist, for example, level one is appropriate. Setting appropriate
expectation levels is essential and making the students aware of the expectations is critical. This latter
process is most difficult. Students have a learning process which has served them well in the first two
years of undergraduate courses. In these courses the mastery level was wrote memorization (Bloom's level
I), a little essay (level II), maybe some application (Level III), and occasionally, very rarely, some analysis
(level IV). They have gotten good grades by cramming the night before the exam, which works well with
level I and decreases in effectiveness as the cognitive expectations increase. Now, in professional school,
the mastery level expectations are Level IV for many of the courses and by the time they are on rotations,
level V. Interestingly, even when these expectations are discussed in detail, the students memorize the fact
that they need to operate at level IV and are quite good at regurgitating the taxonomy, and the definitions (a
Level I cognitive skill), but complain bitterly when asked to perform at that level (do one on an exam.)
“You never showed us how to do that variation!” That’s right. If I had showed them that variation, it
wouldn’t be a Level IV. It would be a Level III.

They are not prepared to operate at these levels. They are, for the most part, devoid of experience in these
levels. They are comfortable being passive learners in which the faculty lecture and they take notes and
memorize the notes for the exam. Getting them to understand that, if they continue on this course of action,
they are doomed to failure is difficult and in many cases takes a “wake up call” of poor performance which
galvanizes them to change behavior. Those that can not, or will not because they cling to old behaviors, are
eliminated. Each year, we lose several bright, young students who can't or won’t make the transition.
Thinking is hard. Thinking is painful. To quote Tom Hanks from “A League of Their Own,” “Of course
it's hard! If it were easy, everybody could do it!”

Why might students fail?

I believe that there could be four reasons for failure:

Student is not intelligent or prepared enough to do his/her job.

In the first reason/excuse, I would offer that our student pool is such that we take the best of the best. At
Creighton School of Pharmacy and Allied Health Professions, we routinely have 9 applicants for every
seat. Our incoming classes GPA is > 3.2 with many having attained a Bachelor’s degree. These folks are
educable. I've found that they are neither stupid nor lazy. Content ignorant, yes, but that is why they are
here and that is fixable. Give them the tools, point them in the right direction, and get out of their way.

Faculty refuses to do his/her job.

In the second reason/excuse, I would also offer that I routinely get students who have failed a comparable
course at other universities in my summer session. These students not only pass, but learn with enthusiasm
and get A's in a course that they hated before. And before you chalk it off to “a nothing course,” take a
look at the exams. One student from another university called me to tell me of her experience upon
returning to her home college. Her instructor asked her how she did and when she told him that she earned
an A, his response was that it must have been an easy course. What does that tell the student about his
opinion of her abilities? She whipped out the final exam and said, “Here, you do it!” His response, upon

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looking at the final was, “Oh, S---! - You've got to be kidding.” This faculty member routinely fails 20% of
the class. I wonder.

Student refuses to do his/her job.

In this third instance, I believe the students have motivation to perform well. They, after all, have chosen
pharmacy as their profession. In most cases, no one holds a gun to their head (although I can remember
two cases in which this was not true. Once, I had a young lady who dearly wanted to be a dancer and her
parents would pay for college only if she would become a pharmacist. She's now a dancer. A second
student didn't want to be a pharmacist but again, parental pressure. He's now a happy, professionally
satisfied pharmacist in Oregon.) If they don't want to work, we have failed to motivate them, interest them,
or show them the relevance of what we teach. In a recalcitrant few whom I am unable to motivate, even
when they complain, they recognize what is happening and complain all the way down to failure. One
student's evaluation stated, “I hated this course. I had to do it all by myself.” Right on! All learning is
active. If the only active part of the course is the night before the exam, how much can you learn,
particularly at the higher mastery levels. It has been said that people remember 10% of what they hear (I
wonder if it's that high if you are the sixth lecture of the day or right after lunch). I submit that they retain
greater than 90% of what they do, actively do, in concert with their peers.

Students experience problem outside their control.

In a few cases, students who perform poorly, do so as a result of some psychological emotional, monetary
or physical problem which must be solved before and meaningful learning can take place.

Whose education is it anyway?

Objective: Assess (IV) differences between traditional passive and active group-based learning

The crux of the matter is responsibility. The main difference, I believe, between active and passive
learning is shifting the responsibility for the education from the professor to the student. In the professor
centered, passive process, it's the professor's responsibility to set and adhere to a time-line. It's his/her
responsibility to “cover” the material. It becomes a game by the student to get the faculty “off-track” so as
not to cover so much for the exam. When the students are successful, the faculty, either covers less or more
often covers the same amount, only faster. The professor assigns readings with the inevitable question, “Is
that going to be on the exam?” If you tell them it is, and it isn't, they'll never read the book again. If it is,
then you're too picky and you didn't explain it in class. Another part of the game is to ask “Is this relevant?
I don’t do this at Walgreen’s”. It's the professor's responsibility to make up the exam and the students'
game to find out what's on the exam and to argue for points after the fact. Its the professor's responsibility
to come to class prepared, give an organized, coherent lecture, and possibly answer questions. It's the
students' responsibility to take (or get from someone who came to class) a few notes which are ignored
until the night before the exam.

When students take responsibility, students win.

In the student-centered, active learning approach, it's the student's responsibility to set and adhere to a time-
line. It's the student's responsibility to cover the material. It's the student's responsibility to come to class
prepared. (You might argue that these have always been student responsibilities. I submit that in this
active learning process, they accept them and run with it and, if they don't, the members of their group
drag them kicking and screaming into compliance.) Last year's class voted for unannounced quizzes

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because they felt that there were members of the class who were not coming to class prepared. It passed
unanimously! They are given the opportunity to the set the exam schedule. From these, the faculty sets
the content and the weights. The student is given the detailed objectives, reading materials, references, and
practice problem sets. They set their own time lines to attain mastery of the objectives. From the
objectives, the faculty create the exams. This obviates the eternal question, “Will this be on the exam?”
What ever they have to do, where ever they have to go to get competent in an objective is their
responsibility. If they have to read the book, if they have to go to the reference material, if they have to
work a hundred problems, so be it. A second year student retold a first year's conversation that she
overheard, in which the first year was complaining that I had given out 90 problems to review by the
following week, to which she replied, “and you had better do them, too.”

This is a competency based educational experience.

Competence must be reached by the end of the course. I personally don't particularly care if that occurs
early or late in the course. If, for example, the class decides on two exams, then in my course, competence
of the first exam material can be shown in a special version of the second exam whereby students who have
failed to show mastery in the obtaining of the pharmacokinetic parameters from data sets must do so in
order to proceed whereas those who have shown mastery at the appropriate level are given those
parameters for their use in developing a dosage regime. If they, then, have gained competence in the first
section material, taking this exam replaces the previously unsatisfactory grade with the grade earned on
this section of the exam. If they haven't gained competence on the first section, they can not do the second
section as answers from the first section are used as input for the second section. This special exam is
required for the students who previously failed to show competence (D or F) and optional for anyone else.

Pharmacy is a lock step curriculum. What that means is that all the students take the core courses at the
same time. The corollary is also true. The whole class is off at the same time. An interesting phenomenon
has arisen in my classes. Second year students are off and in the building when the first year students are in
Pharmacy Calculations. The second year students voluntarily come into the class and work with the P1
groups and don’t need to look at the book to assist the P1s in problem solving! The third year class is off
when the second year class is in Pharmacokinetics and the same thing is happening. Competence is not that
you could do it on an exam but when you can explain it a year later!

To recap:

1. Expectations: tell them what is expected - in detail, with specific objectives and appropriate discussion
of mastery required.
2. Employ skills: Give them resources to complete the objectives (reading materials, references, problem
sets with answers.)
3. Evaluate Mastery: of those specific skills learned and objectives met.

How does a faculty do this? Group Based Learning is the key! In medicine, the era of the mad scientist,
locked up in his tower laboratory discovering the cure for Cancer or some other dreaded disease is gone
forever. Almost all significant scientific advances come as a result of teamwork. Why not teaching?

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Teaching Process - Group Based Problem Solving

Objective: Describe (II) the process of initiation of group based learning

Establishing the Process

In this changing world of health care, pharmacists are being challenged to enhance their clinical and
problem solving skills. Students of pharmacy must develop these skills so that they may help fulfill the
profession's emerging role in pharmaceutical care. At Creighton University students are introduced to
group-based learning in their first professional year in Calculations and in their second year in
Pharmacokinetics in my courses and several faculty are beginning to apply this pedagogy in their courses.
Being able to work in a team, being an active, contributing member of a team is a Creighton value. It is
one of the other than content things that is stressed at Creighton University. The transformation from
traditional, didactic, professor-centered passive learning to student centered active, group based learning is
often dramatic and always traumatic - for both the student and professor! It will not go well for the first
four weeks if the student has never experienced this process. Don't give up. It will be worth every second
of agony that you go through. (I have found ways to shorten the first, troubled stages of group growth.
Constant communication and defining expectations is the key.) The first time I decided to do this, I
consulted with my chairman and told him that I was going to try a new teaching style and to be ready for a
lot of complaints and possibly bad evaluations at the end of the semester. Then I told the class how it was
to go, I held the first introduction, gave over the keys to the kingdom, and promptly when into the
bathroom and threw up! How could I turn over the responsibility for their education to children who are
always looking for the easy way out? Well, I tell you that it succeeded beyond my wildest dreams.
Seriously, it’s not for the faint hearted. It requires major shifting of paradigms on everybody’s part, but it’s
worth it if you don’t give up.

“Toto, I've a feeling we're not in Kansas anymore!” - Dorothy, Wizard of Oz.

Objective: Describe (II) the responsibilities of the various players

Who are the Players?

Facilitator: Person coordinating the course. (Read Professor in other style.) Person who assists the
students upon request. S/he would direct students to references and help them organize and connect up
what they read.

Quality Team Leader (QTL): Student group leader / ombudsman to facilitator from group. (See QTL
Responsibilities at the end of this section on Teaching.)

Group: Collection of four students assigned to work together by the facilitator. Once a level of
performance is reached, they become a team.

Team: A well organized group who can work together outside of class to meet common goals.

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First day of class

Facilitator introduces the course, outlines his expectations (of both the students and the Quality Team
Leader, QTL), hands out course materials and detailed objectives. He outlines the ground rules, which
are: the groups have majority control governing number of exams to be given, exam dates, and if they
want quizzes. Items that are not negotiable are overall course time table, overall course content, number of
questions on exams, weight of exams or exchanging group members. Attendance is not optional - it's
mandatory. The group needs to be together to function.

Students are randomly assigned to groups of four by a deck of cards. Each group is a card value and each
student is a suit. e.g. the Aces are a group and each student is permanently assigned a suit. The students
are given an “icebreaker” exercise to get them to learn more about each other. Each group selects a quality
leader to serve as a direct liaison between the group and facilitator.

The students are expected to read the book and references, come to class prepared and bring the tools
necessary to work the problems; i.e. ruler, log paper, pencils, etc. They meet within their groups, discuss
the required reading, correlate the specific objectives and the reading material and begin working on
problem sets. In addition to the problem sets each individual student is responsible for several library
assignments in which they are required to calculate the pharmacokinetic parameters from the data using the
tools learned in class. The student is then required to communicate in writing the results of such
calculations with a suitable commentary regarding differences and interpretations. Each of the above
sections is designed to bring the student an understanding of the information and the processes
necessary to operate as a competent professional in the area of pharmacokinetic evaluation and
consulting. Consequently, the course evolves from a quantitative, manipulative mathematics course to
a course which stresses communication skills. Consults will be graded not only on content (the proper
dosage regimen for the patient) but also grammar, punctuation, spelling, organization and neatness. The
student may have the best medical information in the world, but if it is poorly executed, it will be
ignored.

Weekly, the students are asked to provide a one minute summary of the topic consisting answering the
following questions:

Weekly Status Report


1. What was the main thrust of the study section?
2. What was clear about the study section? What was done well?
3. What was unclear? How could it be done better?

This provides a running monitor of effectiveness as well as a framework of what to stress in the reference
materials. This feedback is essential to get the mood of the groups and to address major concerns.
Furthermore it serves to provide a continuous quality improvement aspect of the course - it is constantly
evolving and refined each time it's offered. (See Weekly Status Report at the end of this section on
teaching.)

What does the facilitator do?

The facilitator roams around the groups to answer questions, guides groups to resources to clarify concepts
and start them on derivations of equations if needed. After each section, the facilitator will give an
executive summary of the essential material the student needs to process for the exam, if requested. It is a
short lecture (overview) designed to tie in key concepts in order to enable the student to visualize the big
picture - how small pieces fit into the larger whole. An important piece in the scenario is timing. The

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executive summary is not done at the beginning. It is not a lecture. If done before the student reads the
material, it becomes a replacement for reading the material and since it is not designed as such but designed
only to tie together the reading and emphasize salient points, the process fails. In this case, the operative
thought is: “No question is answered before it's asked.” The facilitator must wait until the student gets
stuck and needs to seek assistance. When the same question shows up in several groups, the facilitator
halts the group activity and gives the executive summary. At that point, an interesting phenomenon occurs.
As the facilitator ties things together, students are listening, the facilitator gets positive feedback by facial
expressions and head bobbing and nobody is taking notes! They are ready to hear what you have to say.
They have already created the storage space in their mind. They are not stenographers who blindly take
every word down in hopes of understanding it later. They understand it now!

Facilitator responsibilities include training the QTLs, initiating regular meetings with QTLs, helping
identify and solve problems within groups. He focuses on process, not content during the meetings. He
might intervene to clarify/correct/teach if discussion deviates too much from what is reasonable. He may
also institute changes in the course if a particular issue seems to be a major problem.

The facilitator should only intervene in a group if and only if the following conditions exist: the group is
dysfunctional; clarification, feedback, summarization, or encouragement is needed; the group needs a
formula/tool that the facilitator knows and can suggest where it can be found. Don't just give the answer.
Show them how to find it. OTHERWISE HE IS TO SIT STILL AND BE QUIET!!!!!!

The facilitator attitude must be (and perceived to be) honest, genuine, respectful, humble (here to serve, not
dominate). He must remain patient and detached, always attentive (listens to everything said, and watches
what goes on). Studies body language and gives careful attention to quiet members. He must stay at a
high energy level (groups will tend to set pace with the facilitator). He must communicate on a one-to-one
basis as well as to the whole class. These must perceive that the facilitator is listening! Most students’
perceptions were favorable about the facilitator. Most students recognize that this is not an easy task:
(Student Quotes from evaluations are added in italics.)
“Dr. Makoid is an outstanding educator, he takes a tremendous amount of pride in what he does. His availability to the students
amazes me, I have never seen this.”
“I think you were very fair and extremely generous with your time.”
“I hope to get a C, but whatever my grade turns out to be I am proud of it because I know that I earned it.”
“You made a very difficult subject very easy to understand.”
“My first really relevant course and my best at Creighton so far.”
“I think he is a great teacher. Always answered my questions and encouraged the students to do their best. He also respects the
students as tomorrow’s professionals.”

However, there are some students who get very hostile about this type of learning. For example:
“This is a worthless approach - by the end of the first class I knew if I was going to get anything from it, it would come from self-
teaching.!! (Isn’t this what I was trying to do?)
“We pay him to teach us, not to teach ourselves! Maybe we should of been paid, instead of him.”
“I think this is an easy way for professor’s to get out of teaching!!”

I might suggest that this is definitely not a teaching cop out. It takes considerably more effort than the
traditional didactic process. In the professor-centered, passive-learning lecture format, I would, for a 2
credit course of 100 students, give two lectures of 50 minutes each. In the student-centered, active learning
process the students are broken into four sections of 24 each (six groups of four.) I am with those six
groups for two and a half hours each section plus an extra two hours every week that is an open section for
anyone to come and ask questions. In a session, each group of four has my entire attention for an average
of about 20 to 30 minutes. Some groups who are doing well don’t need the entire time, while other groups
need more than the average. I do, however, sit with each group for every session, listening to the
discussion and giving direction if necessary. I will also offer that active learning is not some weird process
that I thought up. There is over fifty years of competent research in the educational field proving

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conclusively that this method is substantially better for the student with significant improvement of
comprehension as well as retention. This is also apparent in data from this class at Creighton University.

What do the QTLs do? Kizen.

The Quality Team Leaders (QTL) and the facilitator begin meeting on a regularly scheduled date and time.
They meet throughout the semester to resolve group issues and problems. The Japanese term for this is
“Kizen.” It means to continuously improve. What better way to improve than to ask the people involved,
the students, what is a barrier to your learning? Lets remove it. Last year the students voted to have
unannounced quizzes because they felt some members of the teams were not coming prepared to work. (If
I had instituted that, I’d be persona non grata. Go figure.) This year, the students suggested that we meet
in a room with tables rather than desks -- done. They suggested blackboard for the groups would be useful
-- a little harder, but we got it done. Westerners tend to make giant leaps and sit back on their laurels,
whereas the Japanese constantly work, constantly make things better. We want to constantly make the
learning experience better. It’s kind of like the tortoise and the hare and you know who won that race. The
quality team leaders are given instruction and reading materials regarding their responsibilities. It is their
job to make the group work. It is important to note another cultural difference at this point. It is
commonplace for Westerners to place blame when something doesn't work. Eastern philosophy is not the
least bit concerned with blame; the focus is problem solution.

Problem solving, not placing blame, is important.

It shifts from a person problem to a process problem which is completely non-judgmental. The QTL
members bring suggestions which are discussed and voted on by the entire QTL team. If passed, it is
brought before the class and voted. If passed, it is implemented immediately. Personally, I have always
thought that student evaluations at the end of the semester have only served to allow the student to vent
his/her spleen about some thing that didn't go right in the course that the teacher doesn't know about until
it's too late to do anything about it for this class. This process allows the student to remove the barriers
from his/her learning when it will do her/him some good. Students feel that the faculty has listened and are
more responsive to listen to the faculty.

Quality Team Leader's responsibilities are to attend all the quality meetings with the facilitator or make
arrangements to have another of their group take their place if they cannot make it. They are to participate
as a group member as well as ensure that the group is functioning. The quality leader must exchange
information with the facilitator concerning problems encountered within the group so that they can be
addressed and corrected. They are responsible for the timeline between learning the material and exam
dates. They help establish and abide by guidelines given at beginning of course.

Quality Team Leader attributes include an outgoing friendly nature and a willingness to support the process
as well as a sense of personal responsibility to ensure the process is working. They must be able to
communicate verbally within the group and with facilitator and serve as a role model.

What do the students do?

Students are to participate as a group member and teach one quarter of each exam material to their group
members. This forces each member to be an active participant or risk the wrath of their peers. Obviously,
they are to read the material, be prepared to ask and answer questions and help solve the problems. They
are to seek assistance from the facilitator when the group gets stuck.

13
It is interesting to note that some students secretly, resolutely hold on to their paradigm of the professor-
centered, passive-learning process. Upon poor performance in the class, they lash out against the
facilitator, QTL, and the group even after reporting weekly to the QTL that everything is going well, the
group experience is positive and that they have no complaints. I believe that it is simply a sign of
immaturity to seek to place blame for your failures rather than to accept the consequences of your actions.
They will learn that this behavior is counter productive to their goal of becoming a competent health
professional.

“You can observe a lot just by watching” Yogi Berra

14
Teaching Process - Group Growth Stages

Objective: Describe (II) the stages of group growth

Group Dynamics: Learning to work together.

In group-based learning, the members must work out personal differences, find strengths on which to build,
balance commitments of this class against the demands of other classes and work, and learn how to
problem solve. Pharmacy students are competitive by nature, and in traditional didactic learning they have
relied solely on themselves. A major obstacle to overcome is to change their thinking of “me” to thinking
of “us” and to take the responsibility of teaching a portion of the material to their peers. This is an
important step in realizing that someday they may become part of a team in which they must educate other
health-care professionals in order to improve patient care. As the team matures, members gradually learn
to cope with the emotional and group pressures they face. As a result, the group goes through fairly
predictable stages.

Stage 1: Forming

This is a stage of transition from individual to member status - like hesitant swimmers; they stand by the
pool, dabbling their toes in the water. They don't believe that this is for real. They demand a lecturer,
someone to read the book for them and tell them what to do. Their feelings may include excitement,
suspicion, fear, and anxiety about the course ahead. Student comments regarding this stage include:
“In the beginning I was apprehensive, but at the end of the class comfortable.”
“I felt very defensive at the beginning but better now.”
“In the beginning I felt intimidated, at the end of the course I felt like I could be an asset to my group.”

Because there is so much going on to distract member's attention in the beginning, the group accomplishes
little, if anything.

Stage 2: Storming

Storming is probably the most difficult stage for the group and the facilitator. It is as if the group members
jump in the water, and, thinking they are about to drown, start thrashing about. They begin to realize the
class is different and more difficult than they imagined, becoming testy, and blameful. “It's all Dr.
Makoid’s fault. If he would only teach us like he's supposed to, it would be OK!” At this stage they are
impatient about their lack of progress, but too inexperienced to know what to expect or what action the
group should be taking. At this point they resist the need to collaborate with their group and because test
time is rapidly approaching, panic and revert back to their norm - I can do this by myself - and I can wait
until two days before the exam to do it!!!!! This phase unfortunately takes place before the first exam. Do
not give in to the desire to revert back to spoon feeding the poor dears. Remember “Knowledge maketh a
bloody entrance!”

Stage 3: Norming

This stage forms rapidly after the first exam results are posted. During this stage, members reconcile
competing loyalties between themselves and their group and their responsibilities. They accept the group,

15
the ground rules, their roles in the group, and the individuality of fellow members. Emotional conflict is
reduced as previously competitive relationships become more cooperative. Group members begin to settle
down and start helping each other. The change is significant to an observer - they become more relaxed,
enjoy themselves, and begin to work together. As one insightful student wrote, “I wasn’t giving all I could
on the first exam, thinking I could pick it up days before, but I was sadly mistaken. Groups are a good
thing. I don’t think I was fully taking advantage of them, but I hope to improve in that aspect.”

Stage 4: Performing

By this stage, the group has settled its relationship and expectations. The team is now an effective, cohesive
unit. You can tell when the students reach this stage because they get a lot of work done. Complaints are
rarely made. In fact, when asked to give their group mates a percentage score based on their group activity
- everyone unanimously gives their group members a 100%!!! They have moved from passive to active
learning. One student's response to the facilitator's question of “How are you doing?” was “We’re busy.
We’ll call you if we have any questions.” You can tell when you are there. No questions!

At this stage they may also have insights into personal and group processes, and a better understanding of
each other's strengths and weaknesses. For instance, when surveyed, a majority of students stated that their
greatest individual weakness was that they felt they were slow to understand/learn. They perceived that the
group’s major weakness was that they could not meet as much as they wanted to outside of class.
COMMUNICATION
“I know you believe that you understand what I said, but I'm not sure you realize that what you heard is not what I meant”
1. “In the beginning I was apprehensive, but at the end of the class comfortable.”
2. “I wasn’t giving all I could on the first exam, thinking I could pick it up days before, but I was sadly mistaken. Groups are a good
thing. I don’t think I was fully taking advantage of them, but I hope to improve in that aspect.”
3. “I felt very defensive at the beginning but better now.”
4. “I'm busy. I'll call you if I have any questions.”
5. “In the beginning I felt intimidated, at the end of the course I felt like I could be an asset to my group.”
6. “It's all Dr. Makoid’s fault. If he would only teach us like he's supposed to, it would be OK!”
7. “I was very skeptical concerning the teaching method, especially at the beginning.”
8. “Working in groups was definitely beneficial. I think I learned a lot more than I would have learned on my own.”
9. “I felt the course taught me to think more on my own.”
10. “We pay him to teach us! Not us teaching ourselves! Maybe we should have been paid instead of him!”
11. “Working in groups helped me get a better understanding for it because when I talked about it, I found I really knew what I was
doing. I think it was good just the way we did it.”
12. “Our group has hard time going at the same pace. Some members are ready to jump into the problems with no idea about the
concept while others try to read up on it because they don’t understand.”
13. “The group thing needs a lot of work.”

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Barriers to Overcome

1. Physical

A. This method of instruction will not work well in lecture amphitheaters. Even in rooms with separated
desks, this does not work well. Students complain there is not enough desk top space, and they are
distracted by other groups talking. The ideal atmosphere includes a room divided into discrete sections for
each group with a large table and blackboard for each section.

B. In retrospect, a common complaint of spring/fall semester students is that they don’t have enough time
to work together. This method of teaching is not well suited to 50 minute periods. The ideal scenario
seems to be blocks of time - for instance, summer groups seem to coalesce faster because they meet for 3
hours per day. They have time to accomplish problem sets without running out of time.

2. Mental (Refer to Appendix E)

A. Student Attitude - What I call the John Wayne attitude: I can do it all the night before and teacher will
tell me everything I need to know for the test among others.

B. Facilitator Attitude - You just got to believe and exude confidence in this style of learning. If you
don’t, it will crash and burn.

3. Materials

A. Objectives must be and perceived to be clearly stated and detailed. Approximately 95% of students
surveyed agreed that they felt the course objectives were clearly stated. In addition, 98% agreed that the
examinations given reflected the course objectives.

B. Content of the class must be organized in a step-by-step fashion so that the student is always building
his knowledge base.

“Paradigms are significant problems that cannot be solved with the same level of thinking with which we
created them” EINSTEIN

It is possible to facilitate the group growth into stage four if the students are told what to expect about the
process as well as monitored and behavior corrected as it develops.

17
Teaching - Student Perceptions of the Process

Objective: Discuss (III) the student perceptions and corresponding supportive data derived from
group based learning experience

Student perceptions of group-based learning:


“This is the first course that I've been given credit for being able to read.”
“Wonderful feeling to have an understanding rather than memorizing for a course.”
“I feel more driven and challenged.”
“This teaching style makes you think and learn for yourself. This is the real world.”
“I thought the new style of class instruction helped me learn more effectively.”
“I have never felt this good about a class and so confident.”
“Overall it has prepared me to think more on an individual level, which in some cases in the profession you will have to do that.”

What to expect:

Expect variability in the classroom. In traditional didactic lecturing, the classroom remains a static
environment, however in group based learning each class becomes a new adventure in teaching. Each
group progresses at a different rate and has unique characteristics.

Expect that the groups may fail in the beginning and be ready to accept their failure. It is extremely gut-
wrenching to watch this, but a valuable lesson is learned after the exam: “Let's start working together!”

Expect that the groups will no longer need you when they approach Stage 4. It can be very disconcerting
for a facilitator who wants to be needed!

Expect that other faculty may consider group based learning after they come to observe the process.
However, expect also that some may run away as fast as they can!

With respect to the students expect better performance, higher grades, greater retention, improved attitude
toward field, improved attitude toward facilitator.

18
Teaching - Supportive data - Student Performance

Does this process work?

Group work outside class increases prior to the night before exam. This can be readily observed and
substantiated by the fact that the students who do not work within a group environment or groups that do
not meet outside of class time do not perform well on exams. This is supported by student comments and
self-evaluations.
TABLE 5. Supportive data - Exam Scores
Passive Learning Group Active Learning Group
1991 – 1993 1994 - 1996
(n =273) (n = 255)
Exam 1 78.6 85.3
Exam 2 82.2 92.7

On the average, exam means increased one letter grade without any change in content, complexity or
mastery requirements.

“This was the first time that I went to bed at 9:00 P.M. the night before an exam.”

19
Teaching - Supportive Data - Student Perceptions
TABLE 6. Student Perceptions of their performance
Exam 1 Exam 2
Higher 27% 57%
Same 14% 11%
Lower 21% 11%
No Reply 38% 21%

Do the students think it works?

Since most students do not have a comparison between how they would have performed in a traditional
pharmacokinetics course in comparison the group-based course, they have difficulty in perceiving how the
group has affected their grade. There are, however, a few students from other universities who have had
the “opportunity” to experience similar courses differing only in active v passive style. At first, they are
apprehensive and try to do it the passive way. They even tell me that at _____ university, we did it by
passive teaching style (my translation). I tell them that the operative definition of insanity is to do the same
thing over again and expect a different result. I ask them to give this process a chance and to try something
new.

It was interesting to compare IDEA evaluation responses for traditional (passive) students versus group
based (active) students. In both subject matter mastery and the development of general skills, students who
took the traditional course in the summer mirrored group based learning responses. It has long been my
perception that the summer classes performed better than the regular semester. Everything I did was the
same in both classes, so the differences were not something that I did. In 1991 through 1993, I observed
that in the summer, students came to me in groups to answer questions while in the regular semester, they
came singly. Voluntary group learning was the only difference! Thus, in the subsequent tables, Passive
Summer is separated from Passive Semester. It can be seen that Passive Summer Session more closely
resembles the active groups because they, in fact, voluntarily formed active study groups.
TABLE 7. Student Perceptions from IDEA Evaluations Regarding Development of General Skills
1 3 4 5
Strongly 2 Neutral Agree Strongly
Disagree Disagree Agree

Passive Groups Active Groups


Semester Summer Both
Thinking and 4.0 4.3 4.2
Problem Solving
Creative Capacities 2.4 3.5 3.7
Effective 2.0 3.0 3.0
Communication

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TABLE 8. Student Perception from IDEA Evaluations of Questions regarding Subject Matter
Mastery
1 3 4 5
Strongly 2 Neutral Agree Strongly
Disagree Disagree Agree

Passive Groups Active Groups


Semester Summer Both
Factual Knowledge 3.7 4.1 4.0
Principles and theories 3.8 4.1 4.0
Professional Skills and 4.0 4.2 4.1
viewpoints
Discipline’s Methods 3.2 4.0 4.0

Some student perceptions:


“This course required a lot of hard work and thinking. Initially it was frustrating, but after working hard the concepts fell into place
and soon I was surprised at how much I learned. I became self-motivated to work even harder and found the concepts fascinating and
almost fun.”
“Excellent class and instructor. It challenged my level of thinking and problem solving.”
“This course involved a lot of time and effort, which made it very challenging. But in the end, it pays off.”

TABLE 9. Student Perceptions from IDEA Evaluations Regarding Development of Personal Skills
1 3 4 5
Strongly 2 Neutral Agree Strongly
Disagree Disagree Agree

Passive Groups Active Groups


Semester Summer Both
Personal Responsibility 3.3 4.0 4.1

It is not surprising that the students perceive an increase in personal responsibility in group based learning.
When asked if the group experience made them a more responsible and knowledgeable group member,
>95% agreed. In reply to the question of what was your group’s greatest strength, a majority of students
replied that their group worked well together - members were willing to help each other, communication
was good, and they worked hard to accomplish the given objectives. When asked what strengths they
gained through the group experience, the students replied: understanding, confidence, communication
skills, time management, listening to others.
TABLE 10. Student Perceptions from IDEA Evaluations Regarding Student’s Self Rating
1 3 4 5
Strongly 2 Neutral Agree Strongly
Disagree Disagree Agree

Passive Groups Active Groups


Semester Summer Both
Improved Attitude 3.6 4.0 3.9
toward Field

Student comments:
“After taking this Pharmacokinetics course, I have a more confident feeling about going into the pharmacy profession. I feel that I am
competent and secure in deciding what's best for a patient in regards to dosing regimens.”
“Would like to take advanced kinetics class - am very interested in the field.”
“I was not looking forward to taking this course, however, I have gotten more from this class than I ever thought I could have. I
actually enjoyed kinetics, the method in which the course was taught, and then being able to solve the problems. I now have a very
positive attitude toward kinetics and look forward to taking another class.”

21
Teaching - Appendix A - QTL Responsibilities
Congratulations! You have volunteered (or have been coerced) to assume the role of a Quality Team
Leader (QTL). This is a position of leadership within your group and with it comes some added
responsibility. The purpose of this handout is to outline your role as QTL - your duties, and the
expectations I have for you. Do not panic. I realize that for most of you this process is new and different.
Group based learning is rapidly becoming the teaching method of choice for several important reasons -
students understand better and retain longer knowledge that they have actively learned, and they usually
perform at a higher grade level. The main difficulty students have with this type of education is that they
have never been responsible for learning or teaching each other within a group environment. Many
students resist group learning and rebel or they may not know how or where to begin. Another obstacle is
establishing and maintaining a timetable in order to get through the material before the exams. A major
dilemma you face will be focusing the group’s energy and attention to work through concepts and problems
in time for the exams.

QTL Responsibilities:
1. Attend all quality meetings or make arrangements to have another group member take your place if
you cannot make it. This is important to keep lines of communication open between each group and me.
You can voice your group’s concerns, bring suggestions to discuss and vote for changes. You will be
responsible to take back meeting information to your group.

2. You are to participate as a group member - being a QTL does not excuse you from taking on your
share of group responsibility. Set an example to come to class with the required materials and be ready to
work.

3. Be a role model - be willing to support the process. Your fellow group members will take their cues
from you. We all know attitudes can be as infectious as the common cold - Keep yours positive! If you
have concerns or feel yourself down, talk with me.

4. Communicate with me about any problems or concerns within your group. This is not “ratting” on
your peers. Our (mine and yours) major concern is to ensure that the groups are functioning to the best of
their abilities, that they are meshing together, learning the material, and working on the problem sets. If
your group (or a particular member) is not functioning well, everyone loses time and knowledge. My job
as facilitator is to help get the group working - BUT this can only happen if I know that a problem exists.
This information will remain between us and confidential.

5. You will be responsible for creating your group’s timeline for learning each portion of material
before the exam. Your class determines the date and time of exams but the content is not negotiable. You
need to work within your group to establish how much time you need to devote to each portion so that your
group will be done with the material before each section exam. You will have to monitor your group’s
progress and keep them focused. Tell them what is to be covered next, assign problems to members, and
keep moving forward. Not all groups will work at the same speed. What is important that all the
designated material is covered well before the exam - Do not wait to learn it all the last 2 days before the
exam! It won’t happen!

6. You are responsible for turning in a weekly status report. It is important for us to communicate both
verbally and in writing. I need to know how everyone is progressing through the course material and
within the group. If you have any concerns/problems that you feel cannot be addressed in the quality
meetings, write them down on this report.

22
Teaching - Appendix B - QTL Weekly Status Report

GROUP:___________________ LEADER NAME:_____________________

MEMBERS PRESENT:_________________________________________________

MEMBERS ABSENT:__________________________________________________

DATE:__________________ LAB SECTION (circle one) A B

The purpose of this weekly status report is to keep the lines of communication open between you, the QTL
and me, the course facilitator. Honest, open and constructive dialogue (written or verbal) between us will
result in a class which is continuously improving.

GROUP PROCESS - COMMENTS/CONCERNS/SUGGESTIONS:


What can be done to help your group accomplish the course objectives? Please list any suggestions or
constructive changes that you or your group members may have to improve in this area. Is your group
working together? If not, what can we do to make things better?

COURSE CONTENT - COMMENTS/CONCERNS/SUGGESTIONS:


Is the course running smoothly? Are there any problems with course materials or objectives? If yes, list any
changes/suggestions that you or your group members have to make the course better. What area needs
improvement and how do you suggest that it be done?

LIST PROBLEMS WORKED ON/CONCEPTS COVERED:

DID GROUP WORK OUTSIDE OF CLASS THIS WEEK:


if yes, list # of hours______
if no, what can be done to help the group meet outside of class?

23
Teaching - Appendix C - Examples of QTL Communications:
QTL Meeting 1
I. Introductions:
II. Importance of Group Based Learning(GBL): Pharmacy classes currently using some form of GBL
are: OTC, Toxicology, Therapeutics, Pharmacokinetics, Pharmacology, Chemical Basis for Drug Action,
Parenterals and the list keeps growing… .. However, the main difference between the above classes and
this class is that we teach and monitor the group process along with the content. Past experience has found
that in group based learning, the content cannot be mastered if the group process is failing - course
performance is directly tied to group performance. Therefore, it is imperative that you learn principles of
group dynamics along with the course content. These skills will last you a lifetime and work in any group
situation you may find yourself. Remember as a future pharmacist, you will be a member of the health
care team - and it is necessary to work effectively with others (physicians, nurses, lab, x-ray, etc.) to solve
patient problems.
III. Peer assessment: In group based learning, you have an opportunity to observe your peers in a close
problem-solving environment. You will have more detailed insight and knowledge of their work than the
instructor. In order to honestly and effectively evaluate everyone’s performance within the group, peer
assessment is necessary. In your future as a pharmacist, you may be asked to fill out a performance
appraisal on a co-worker. Many pharmacists find this upsetting since they have had no prior experience at
doing this. We must get comfortable with the process of receiving and giving assessment feedback. In this
class, peer assessment will be worth 10% of your final exam grade. You will assess yourself and be
assessed by your peers at midterm and at the end of the course. Only the final peer and self assessment will
count towards your final grade. The mid-term assessment is for practice and your own personal growth.
See attached sample copy.
IV. Group dynamics - problems?
V. Decision making: Any group’s goal should be to reach a decision that best reflects the thinking of all
group members. This is called reaching a consensus. A consensus is finding a proposal acceptable enough
so that all members can support it and no member opposes it. A consensus is neither a unanimous vote - a
consensus may not represent everyone’s first priorities nor a majority vote - (in a majority vote, only the
majority gets something they are happy with; people in the minority get something they don’t want at all).
A consensus requires time, active participation of all group members, skills in communication (such as
listening, conflict resolution, and discussion), creative thinking and open-mindedness.
Rules for Decision by Consensus:
• Look for acceptable alternatives
• State your opinion - it doesn’t matter that others do not share it. Conflict spawns creativity.
• Look for win-win situations
• Remember that difference of opinion is healthy
Aiming for consensus requires a much different strategy than does unanimous or majority vote. To reach a
consensus, the group must let each member voice their concerns/opinions. It may be hard to tell when you
have reached consensus - a good rule of thumb is when no one is completely satisfied, but the decision is
one that you all can live with. Complete unanimity is not the goal - it is rarely achieved, but acceptance is.
VI. Time-lines:
How to deal with “floundering” (a lack of direction):
• Review the timeline within the group. Hopefully by this point you have set dates for exams and know
the topics to be covered for each. Draw the timeline out on paper. Give each member a copy. Assign
problems to individuals and keep track.
• State “Let’s review our timeline and make sure it is clear to everyone.”
• “What do we have to do next?”
• “What do we need to do/ask so we can move on? What is holding us up?”
• Finish up every class by giving everyone duties for the next meeting. There should not be any
confusion at that point as to who is responsible for what.

24
Teaching Appendix D –

MID-SEMESTER PEER/SELF GROUP INTERACTION ASSESSMENT


Please evaluate each member of your calculations group and yourself. Evaluate performance over the first
half of the semester. You are expected to evaluate each member/self honestly. Please record your
evaluation responses below their names. Hand-written comments are encouraged. Turn in this sheet once
you have completed the evaluations. Be assured that your confidentiality will be maintained. You will get
a copy of these results along with any constructive hand-written comments.
Please indicate your response on the score sheet using the following rating guide.
The rating scale:
5 = Student is consistent and provides excellent contributions
4 = Student is generally consistent and provides very good contributions
3 = Student is somewhat consistent and provides satisfactory contributions
2 = Student is somewhat inconsistent and provides unsatisfactory contributions
1 = Student is inconsistent and provides inappropriate contributions (or doesn’t contribute at all)
Your name:_______________________ Section: _________ Group:__________
List group members below next to their suit:
Club:___________________________________
Diamond:________________________________
Heart:__________________________________
Spade:_________________________________
Extra:__________________________________
Supply written comments on back: General Group and Individual Group Members:

Assessment items Club Diamond Heart Spade extra


1. This person actively contributes to group discussions.
2. This person comes prepared for class each week.

3. This person helps to redirect discussions/problem-solving when


the group gets “off track.”
4. This person listens to the opinions and contributions of others.

5. This person exercises mutual respect for others in the group.


6. This person helps keep the group focused on the timeline.

7. This person works well with the other group members.

8. This person does not monopolize group discussions.

9. This person is available outside of class for group work.


10. This person shares their knowledge within the group.

25
Teaching Appendix E - MANAGING DIFFICULT PEOPLE
Just about everyone has felt the pulse-pounding, face-flushing, word-sputtering frustration caused by trying to reason with
difficult people. We find them to be uncooperative, uncompromising, and stubborn. Each encounter with them leaves us
feeling increasingly frustrated and angry. No matter what we do, it isn't effective. While it may seem easier to ignore
difficult people rather than face a confrontation, team morale and productivity greatly decrease when difficult people are
tolerated, even reluctantly. The following five strategies allow you to take control of situations involving difficult people and
build more cohesive teams as a result.
Question: can you find yourself - what type are you?
STRATEGY 1: De-personalize the situation
No matter how challenging, belligerent, or negative the difficult person behaves, do not take it personally. Difficult
people are often acting out their personal problems, and their behavior is a cry for help. You can more easily control your
emotional reactions to them and defuse any anger you feel if you do not take their behavior personally. When you
encounter a difficult person, observe how he or she behaves with others, especially other team members. You will find
that the behavior is consistently difficult. This awareness helps put things in perspective; you can see that you are not to
blame for the difficulty.
STRATEGY 2: Learn to identify difficult personalities
Generally, there are seven types of difficult personalities. As each type is presented, strategies for coaching, motivating,
and communicating with them will be presented. It takes some planning and practice, but as we learn to manage these
difficult types, the effectiveness of the entire team will increase.

ATTACKERS: Attackers are hostile, aggressive, abusive, and intimidating. They need to be right and will charge like
angry bulls if they think they have been challenged or crossed. The best coping strategy is to let them blow off steam and
express their anger in a safe environment. But you can't let them run on. To maintain control, address them by name:
“David, I hear what you are saying. Let's sit down and talk about it.”Getting attackers to sit will have a calming effect on
them; and, once calmed, attackers become more reasonable. Take what attackers say seriously. Hear them out, let them
know you have heard them, and then state your position clearly and avoid the temptation to argue.

EGOTISTS: Egotists are often experts and know more than others on the team about a particular subject. They believe
facts are power; and, since they know the facts, they act in a superior way that often demeans the knowledge of others.
Plan meetings so the egotists on the team speak first and allow time for them to “bask” in their knowledge. This strategy
minimizes their tendency to interrupt later in the meeting. You must be prepared with facts and information, because you
cannot “fake it” with egotists. But you can capitalize on what they know by asking questions. Egotists love to show off and
have their knowledge appreciated. If you approach them from this perspective, their abusive attitudes and behaviors can
be tempered so you can more effectively use their knowledge and expertise to support your efforts.

SNEAKS: Sneaks take potshots. They undercut your authority in devious ways by using sarcasm, which is often
disguised as a joke. Never ignore the sneak's snide comments. That just gives them power to continue Instead, expose
them. When they snipe at someone, be direct and ask them for their opinions or solutions. Force them into the open and
you will weaken their ability to cause problems. Try to turn their attention and comments to the issues, not the
personalities involved. Once they realize you won't put up with their sniping, they will stop.

VICTIMS: Victims see everything negatively. They complain, whine, seem to be powerless, and act defeated. Victims also
shift blame and refuse to take responsibility for situations or decisions, especially unpopular ones. They act as if they are
passing on orders from above and blame the boss for that “dumb” new policy. Such behavior hurts morale and erodes the
support of your team. Since victims often believe no one thinks they are important or takes them seriously, start your
interactions by listening to what they say. Steer them toward the facts, which are usually much less negative than their
interpretations. When you ask for suggestions to improve the situation, maintain control by bringing up the negatives
yourself, then dismiss each logically. Direct their attention to the more positive aspects of the situation.

NEGATORS: Victims seem pale compared to true negators. Negators aren’t just negative, they distrust anyone in power.
They believe that their way is the only right way, and their motto is “I told you so.”Stay positive, but realistic. Delay
discussing solutions, since negators will dismiss every solution as soon as it is spoken. Refuse to argue with them and
stick with the facts. Anticipate any objections they may raise and prepare facts and information to refute them.

SUPERAGREEABLE PEOPLE: While super-agreeable people are easy to like, they are one of the most difficult
personalities to deal with. Super-agreeables are outgoing and friendly; but, because they have such a strong need to be
liked, they frequently become whatever others need them to be at the expense of their own needs and desires. They are
usually terrified of making mistakes. Superagreeable people can’t say “No” and, thus, overcommit themselves and their
staffs. They disappoint and frustrate the very people from whom they so desperately need to receive approval— their
managers, staff, co-workers and, in personal matters, their family and friends. Carefully limit how much you ask of them to
eliminate the disappointments caused by missed deadlines.Teach them to see things in greater perspective to help them
overcome their fear of making mistakes.

26
UNRESPONSIVE PEOPLE: Unresponsive people are the ''clams'' of humankind. They are the most difficult personalities
to deal with. They don't reveal their true motives, and you play a guessing game trying to find out what makes them tick.
They are hard to understand and seemingly impossible to draw out. Yet that is the most effective strategy: draw them out.
Always ask open-ended questions that require more than “Yes” or “No” answers, then wait for them to respond. Typically,
they respond more slowly than other kinds of personalities and rely on others to take over so they can maintain their clam-
like reserves. Even if the silence between you and an unresponsive person grows chasmlike, wait for a response. If they
refuse to open up, agree to meet again later and ask them to think about specific topics you will discuss at that time. This
strategy will eventually draw them out-and, once they begin to trust you, they will become less clamlike.

STRATEGY 3: Characterize the difficult people in your life


No one demonstrates one of these personality traits to the exclusion of all the others. But most difficult people
demonstrate one so strongly, you can predict how they are going to respond. It is that predictability that gives you the
edge in any situation involving them because you can thoroughly prepare and practice how you will respond to their
behavior. And, as with anything else, practice makes perfect.

List the difficult people you work with and identify which personality most closely fits their dominant behaviors. Jot the
techniques for each personality on a 3 x 5 index card and review the cards before meeting with them. Take time to review
the strategies for dealing with a particular personality, and then recall a past unsatisfactory confrontation with him or her.
Imagine how much more successful it would have been if you had used the techniques for dealing with that personality.
Now, visualize your next confrontation with that person and see yourself Using these techniques. Rehearse until you feel
comfortable with the techniques and are well prepared to deal with the person who manifests this difficult personality trait.

STRATEGY 4: Encourage people to change


By becoming skillful in using these techniques, you will not only learn how to handle difficult people, you will be reinforcing
teamwork behaviors. When we ignore difficult people, they don't change. But when we insist they change, when we refuse
to indulge their behaviors, we require them to learn new coping skills. This can strengthen the entire team.

STRATEGY 5: Know when to give up


These strategies work with people who have grating personality traits, but you must be careful when working with people
for whom the strategies don't work. Keep in mind that some people may suffer from more than just difficult personality
traits. Some may have personal problems they cannot leave at home. If the strategies don't work, seek feedback from
someone who can recognize the existence of serious problems that need professional help. Always document facts about
incidents that occur and strategies you try with difficult employees. If leaders cannot control negative behavior, team
members lose respect for them. A highly cohesive team can soon become one with little cohesiveness and lower
productivity.
Dealing with difficult people doesn't have to lead to confrontation. It takes effort, time, and attention to turn a challenging
person into a productive and satisfying one. But when we are successful, our effectiveness and the effectiveness of the
teams we manage will improve and we will create win-win situations for everyone involved.

(Manning, Marilyn Ph.D. and P.A. Haddock. “Managing Difficult People,” SKY, November 1988, pp. 128-135)

27
F I R S T E D I T I O N

Basic Pharmacokinetics

Michael C. Makoid, Ph.D.


Professor of Pharmaceutical Sciences

Creighton University School of Pharmacy

and Allied Health Sciences,

Omaha, Nebraska

Phillip J. Vuchetich, Pharm.D.


Pharmacocybernetics Resident

Creighton University School of Pharmacy

and Allied Health Sciences,

Omaha, Nebraska

Umesh V. Banakar, Ph.D.


President, PharmAssist, Inc.
Indianapolis, IN

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Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/PHA443/pdf/
Copyright 1996-2000 The Virtual University Press

All rights reserved.

ISBN 0-000-000000-0

ABCDEFGHIJ-DO-89

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Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/PHA443/pdf/
Acknowledgement

When I first started teaching, I had the good fortune to work with another new
Ph.D., John Cobby. We struggled through our first five years on the otherside of
the podium together and learned many of the tenents upon which this book is
based, not content but process. First and formost, it was his belief that students are
bright, enthusiastic and hardworking. We should tell them what to do and get out
of their way. We both prepared extensive handouts complete with even more
extensive practice problems so that the student could experience the scientific
method as a detective might solve a murder mystery. The idea was to make learn-
ing pharmaceutical science interesting and fun. Through the years, as the methods
became more refined, student perceptions and performance improved dramatically.

John ultimately abandoned academe to go to work in the “real world” of industry,


clearly their gain and our loss. I approached him some years ago to co-author this
text. He declined believing himself to be too far removed from the cutting edge of
this discipline. That may be true (I doubt it!), but what can not be argued is that he
was a major contributor to this book in his philosophy and class notes. Over the
years, the explainations were rewritten and revised. Many new problems were
added and some were suplanted. These teaching aides have evolved but their ori-
gins are clear. Using the industry standard regarding authorship, which defines an
author as one whose contributions significantly alters the content of the paper, Dr.
Cobby is an author of this book.

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Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/PHA443/pdf/
CHAPTER 1 Introduction

Author: Michael Makoid and John Cobby


Reviewer: Phillip Vuchetich

OBJECTIVES
At the completion of this chapter, the successful student shall be able to:
1. define pharmacokinetics
2. state the overall objectives of the course
3. state the major themes of the course
4. state the course organizational structure with respect to study sections
5. state the objectives of each study section
6. state the examination structure and objectives
7. state student performance expectations
8. state the schedule and timeline

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Introduction

1.1 Basic Pharmacokinetics


What is pharmacokinet- Pharmacokinetics is the mathematics of the time course of Absorption, Distribu-
ics? tion, Metabolism, and Excretion (ADME) of drugs in the body. The biological,
physiological, and physicochemical factors which influence the transfer processes
of drugs in the body also influence the rate and extent of ADME of those drugs in
the body. In many cases, pharmacological action, as well as toxicological action, is
related to plasma concentration of drugs. Consequently, through the study of
pharmacokinetics, the pharmacist will be able to individualize therapy for the
patient.

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Introduction

1.2 Course Objectives:


The Roman numerals refer to the cognitive complexity as described in Bloom’s
Taxonomy of Educational Objectives described elsewhere in this document. At the
completion of this course, the successful student will be able to:
What will you be able to • Calculate (III) patient and drug specific pharmacokinetic parameters from patient data,
do? • Predict (calculate - III) the changes in relevant pharmacokinetic parameters in the patient with
selected diseases,
• Utilize the above parameters to individualize patient therapy (devise a dosage regimen - V),
• Communicate his/her therapy recommendations to another competent health professional (write
a consult - V).

1.2.1 COURSE ARRANGEMENT:


Two courses are described below. The first, a two credit (Creighton University
required) and the second, a three credit (CU optional) version. The two credit
course will consist of major themes one through three and exams one and two,
while the three credit course will add theme four and exam three. The four major
themes are entitled:
How is the course • Study Group 1: Learn the tools used by the discipline. Calculate patient and drug specific phar-
arranged? macokinetic parameters from single dose patient data,
• Study Group 2: Utilize the tools to optimize patient therapy under multiple dose conditions,
• Study group 3: Apply the tools to predict the changes in relevant pharmacokinetic parameters in
the compromised patient patient with selected diseases,
• Study group 4: Apply the tools in specialized drug classes.

Each major theme of the course is further broken down into study sections, each
with their own set of general objectives as shown below:

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Introduction

1.2.2 STUDY GROUP 1: LEARN THE TOOLS USED BY THE DISCIPLINE.


CALCULATE PATIENT AND DRUG SPECIFIC PHARMACOKINETIC
PARAMETERS FROM SINGLE DOSE PATIENT DATA,

A. Basic Mathematical skills objectives:


What will I be required 1. Given a data set containing a pair of variables, the student will properly construct (III) var-
to be able to do? How ious graphs of the data.
will examination ques- 2. Given various graphical representations of data, the student will calculate (III) the slope
tions be written for this and intercept by hand as well as using linear regression.
material? 3. The student shall be able to interpret (V) the meaning of the slope and intercept for the
various types of data sets.
4. The student shall demonstrate (III) the proper procedures of mathematical and algebraic
manipulations.
5. The student shall demonstrate (III) the proper calculus procedures of integration and dif-
ferentiation.
6. The student shall demonstrate (III) the proper use of computers in graphical simulations
and problem solving.
7. Given the assumptions for the model, the student will construct (III) models of the ADME
processes using Laplace Transforms.
8. The student shall develop (V) integrated equations associated with the above models.
9. The student shall generate a pharmacokinetic model based on given information.
10. The student shall interpret a given model mathematically.
11. The student shall predict changes in the final result based on changes in variables through-
out the model.

B. Pharmacological Response objectives:


1. Given patient data of the following types, the student will be able to properly construct
(III) a graph and compute (III) the slope: response (R) vs. concentration (C), response (R)
vs. time (T), concentration (C) vs. time (T)
2. Given any two of the above data sets, the student will be able to compute (III) the slope of
the third.

C. IV one compartment model, plasma and urine objectives:


1. Given patient drug concentration and/or amount vs. time profiles, the student will calcu-
late (III) the relevant pharmacokinetic parameters available ( V d , K, k m , k r , AUC , Clear-
ance, MRT) from IV data.
2. Given the appropriate pharmacokinetic parameters, the student shall simulate (III)
I.V. bolus/infusion dosing for parent compounds
Plasma concentration vs. time profile analysis
Rate vs. time profile analysis
3. Given patient specific pharmacokinetic parameters, the student shall provide professional
communication regarding IV bolus/infusion information
4. The student shall utilize computer aided instruction and simulation
5. Given patient drug concentration and/or amount vs. time profiles, the student will calcu-
late (III) the relevant metabolite (active vs. inactive) pharmacokinetic parameters avail-
able ( V d , K, k m , k r , AUC , Clearance, MRT) from IV data.

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Introduction

D. Biopharmaceutical factor objectives: the student shall be able to discuss:


1. physiology and mechanisms of absorption
2. effects of diffusion, cardiac output / blood perfusion, physical properties of the drug and
body on distribution
3. biotransformation, first pass effect, and clearance
4. renal, biliary, mammary, salivary, other forms of excretion.
5. the effects of physiological changes with age, sex, and disease on the absorption, distribu-
tion, metabolism, and excretion of a drug.

E. Oral one compartment model objectives:


1. Given patient drug concentration and/or amount vs. Time profiles, the student will calcu-
late (III) the relevant pharmacokinetic parameters ( V d , K, k m , k r , k a , AUC , Clearance,
MRT, MAT) available from oral data.

F. Bioavailability objectives:
1. Given sufficient data to compare an oral product with another oral product or an IV prod-
uct, the student will estimate (III) the bioavailability (compare AUCs) and judge (VI) pro-
fessional acceptance of the product with regard to bioequivalence (evaluate (VI) AUC, T p
and ( C p )max ).
2. The student will write (V) a professional consult using the above calculations.

1.2.3 STUDY GROUP 2: UTILIZE THE TOOLS TO OPTIMIZE PATIENT


THERAPY UNDER MULTIPLE DOSE CONDITIONS,

G. Dosage regimens objectives:


1. Given population average patient data, the student will devise (V) dosage regimens which
will maintain plasma concentrations of drug within the therapeutic range.
2. Given specific patient information, the patient will justify (VI) dosage regimen recom-
mendations.
3. Given patient information regarding organ function, the student will devise (V) and justify
(VI) dosage regimen recommendations for the compromised patient.
4. The student will write (V) a professional consult using the above calculations

1.2.4 STUDY GROUP 3: APPLY THE TOOLS TO PREDICT THE CHANGES IN


RELEVANT PHARMACOKINETIC PARAMETERS IN THE
COMPROMISED PATIENT PATIENT WITH SELECTED DISEASES,

H. Clearance objectives:
1. Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compromised
patients.

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Introduction

1.2.5 STUDY GROUP 4: APPLY THE TOOLS IN SPECIALIZED DRUG


CLASSES.

I. Two Compartment Model objectives:


1. Given patient Concentration and/or Amount of Drug vs. Time, profiles the student will
calculate (III) the relevant pharmacokinetic parameters( V d1 , Alpha, A 1 , Beta, B 1 ,
k 10 , k 12 , k 21 , AUC , Clearance, compartmental amount ratios) available from two com-
partment data.
2. Given population average patient data, the student will devise (V) a dosage regimen which
will maintain plasma concentrations of drug within the therapeutic range.
3. Given specific patient information, the patient will justify (VI) the optimal dosage regi-
men.
4. Given patient information regarding organ function, the student will devise (V) and justify
(VI) the optimal dosage regimen for the compromised patient.
5. The student will write (V) a professional consult using the above calculations.

J. Non-linear kinetics objective:


1. Given population average patient data, the student will devise (V) a dosage regimen which
will maintain plasma concentrations of drug within the therapeutic range.
2. Given specific patient information, the patient will justify (VI) the optimal dosage regi-
men.
3. Given patient information regarding organ function, the student will devise (V) and justify
(VI) dosage regimens for the compromised patient.
4. The student will write (V) a professional consult using the above calculations.

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Introduction

1.3 Exams
How are the exams Exams will consist of problems which will be linked directly back to an objective
made? (above) and a library assignment in which you will be asked to evaluate a research
article with the tools available to you by the time of the exam as discussed below.

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Introduction

1.3.1 LIBRARY ASSIGNMENT IN PHARMACOKINETICS

K. Library Assignment Objectives


What do I have to do in 1. Given a suitable primary research article in the area of pharmacokinetics, the student shall
the library? calculate the pharmacokinetic parameters from the data using the tools learned in class
both by hand and utilizing the computer program, PK Solutions.
2. The student shall communicate in writing the results of such calculations with suitable
commentary regarding differences and interpretations.

Format of the “paper”:


How should the paper 1. Tell me what type of paper you have chosen to evaluate:
look?
The problem sets show what data you need for each of these.

First Exam
What content should I IV Bolus Parent compound 50 pts
look for in the paper and IV Bolus Parent metabolite 65 pts
what is its relative
IV Infusion 65 pts
worth?
Pharmacological Response 75 pts
Oral Dosing / Bioavailability 50 pts

Second Exam (Pharm.D. course)


Multiple dosing 50 pts
Clearance and disease 60 pts
Dosage Regimen 75 pts

Third Exam (Masters / Honors course)


Two compartment model 50 pts
Protein Binding and Disease 65 pts
Non-linear kinetics and disease 75 pts

2. Include a Xerox copy of the entire paper. I need to evaluate it, too.

3. Enlarge the graph by successive Xeroxes so that you can accurately evalu-
ate the data.

4. Do analysis of data by hand and by PK Solutions.

5. Compare your work with the author’s (short paragraph).

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Introduction

6. Comment on any differences of parameter calculation or interpretation. See


objectives above (Paragraph).

7. Write an exam question to obtain pharmacokinetic parameters. You know


from the first exam what they should look like.
Why do I need to do this Each of the above sections is designed to bring the student an understanding of the
library assignment? information and the processes necessary to operate as a competent professional in
the area of pharmacokinetic evaluation and consulting. Consequently, the
course will evolve from a quantitative, manipulative mathematics course to a
course which stresses communication skills. Consults will be graded not only on
content (the proper dosage regimen for the patient) but also grammar, punctuation,
spelling, organization and neatness. You may have the best medical information in
the world, but if it is poorly executed, it will be ignored.
Can I cram the night This course will probably be one of the more rigorous ones that you will have
before? experienced in your college career to date. It will be one of the first ones which
attempt to show some clinical relevance. The course can be successfully com-
pleted with your current skills and background. It is not difficult IF (and that is a
big IF) taken slowly, in small bites. Its just like eating an elephant - you can’t do it
all in one sitting. Some of you may try to get it all the night before the exam,
regardless of my admonitions and those of your upper-class friends (ask them!). In
many cases, that has been more than sufficient to get A’s and B’s on exams in pre-
vious courses. Past experience tells many of you that you can do it. I suggest that
the requirements and expectations of a professional school are considerably more
than your undergraduate experience and it most likely will not work in many
courses which require assimilation of the information presented, as is expected in a
professional program.

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Introduction

1.4 Blooms taxonomy for the Hierarchy of Educational Objectives


Blooms taxonomy for the Hierarchy of Educational Objectives describes the
expectations of a course in increasing order of complexity as:
What is cramming good I. To Know: means to memorize (recognize, recall) (Many college courses
for? Lowest level of cog- require only this level of cognitive effort, hence the extensive experience with
nitive skills. “multiple guess” exams).

II. To Comprehend: means to translate; to be able to put information into your


own words. (Essay exams routinely call for this level of effort on the part of the
student).
This is where we begin. III. To Apply: means to be able to use knowledge, rules and principles in an
unfamiliar situation. (This is the lowest level of skill necessary to function at a
technician level).
This is where we need IV. To Analyze: means to be able to critically examine a body of knowledge
to be in school. and to be able to identify the relationships. (This is where a B.S. graduate should
operate. Education obviates the need for teachers.)
This is where we need V. To Synthesize: means to put together information, not necessarily previ-
to be as graduates. ously so organized, in order to get a new piece of information. (This is the begin-
ning level of professional judgment).

VI. To Evaluate: means to be able to judge the worth of an idea, form hypothe-
ses and do problem solving, research, invent new knowledge. (This is the doctoral
level of participation in the area).
Can’t I just do it the A professional routinely operates at level IV and V with occasional forays into
same way that I have level VI. This is where you will operate in this course and in most subsequent
always studied? courses in the professional curriculum. You will note that each of the objectives for
the course contains specific action words followed by the level in the taxonomy at
which you will operate. These are the standard descriptive terms for use in instruc-
tional objectives. You will be asked to do critical thinking, not simply recite or
recognize the right answer. Problems challenge thinking skills and demand the
synthesis of material into concepts. To facilitate this transition we both must work
very hard.

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Introduction

1.5 Course Contract


I Will:
What will the teacher do 1. Provide individualized learning methods: Some students learn by hearing
in this class? Act as a and others by seeing (auditory or visual learners). I have designed the course to
facilitator. accommodate both types of learners. In class, I will provide you with executive
summaries of what you read. I will provide group leaders with detailed reviews of
materials for which they are responsible. I will tell you what I’m going to say, say
it, and then tell you what I said. I will also attempt to write it out and draw appro-
priate graphs, charts and pictures as well as appropriate visual aids in class and
with the homework problems. I will provide you with ample examples of the types
of manipulations that you will be expected to do. I will provide you with ample
problem sets so that you may practice those manipulations. I will provide you
with computer simulations so that you may see these manipulations in action and
begin to get a feel for the numbers and their magnitude. Feedback and interaction
is encouraged. If I am not meeting your perceived needs, you must tell me. Some
students might feel too intimidated to ask questions. To obviate this problem, you
will elect a group team leader, an ombudsman, whose job it will be to carry your
questions, concerns, and comments to me. It is your job and his responsibility to
see that the group interaction facilitates the learning process. This is not to prevent
you coming to see me but offered as another avenue of communication.
Will I learn anything rel- 2. Provide clinical relevance to the practice of pharmacy. This will be stressed
evant in this course? at all times. I will also relate real clinical experiences; virtually all of the problems
come from real patients. Some educators believe examples must fit the theory
exactly. This gives the student a false set of reality parameters. Consequently,
when “the data does not fall on the line” the student rejects relevant information.
You will become familiar with real data, and the problems associated with real
data.
How will I know how I’m 3. Give adequate feedback: Evaluation of your performance will be available
doing? to you at all times. A running evaluation, updated weekly will be on my door for
your review. You may check any thing with me at any time. I expect that you will
see me outside of class time either individually if you need help or in supervised
review sessions. You must see me for assistance if your performance is unsatis-
factory.
What will the teacher be 4. Teach: As an operational definition this means: clarifying what you read,
doing? Engaging you in demonstrating how and why things work as they do, and unifying the material -
an active learning pro- attempting to generate the A - HA! syndrome. The correlate of teach from the stu-
cess.
dent view is learn. Neither is a passive process. I can not open your head and pour
the knowledge in. A saying in education is: “Knowledge maketh a bloody
entrance”. You must expend the effort necessary for you to learn.

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Introduction

What must I do in this 5. Facilitate Learning. You received objectives (above) and a summary for
active learning process? each study section (chapters in this text), of exactly what is expected of you with
You MUST participate in examples in the problem sets at the end of each chapter. We will have ample time
class and in your
assigned groups!!!
during class to field questions generated by the correlated reading and problem
sets, as well as homework assignments. I will not be duplicating any book’s efforts.
Student participation in class is required. You will answer (as well as ask) ques-
tions, do problems in class. You will sound things out and get feedback from me
and your fellow colleagues. Remember - the class is to help you learn. It is not the
sole means of learning, nor am I the source of all knowledge. Its’ only reason for
being is to help you organize and summarize what you learn. It has a relatively
simple plan with multiple examples. From these examples you will develop con-
cepts which will obviate the need for memorizing individual facts (or actually me
entirely). I will assist you in the formation of these concepts. It is patently obvious
that I can not give you every possible example of every type of question that you
will be asked during your professional career. For one thing I don't know what
questions you will be asked nor problems you will encounter. Going from the spe-
cific to the general forms concepts which will allow you to go from the general to
the specific, even if you have never been there before. The total medical knowl-
edge is now doubling at a rate of every 4 years. I can not teach you the content nec-
essary to operate 5 years in the future, let alone 40. You must learn to learn.
Hence, if you plan to become a competent professional, you must operate at least
in Bloom's level V.
How do I get in touch 6. Be available: I do not have office hours. I believe them to be restrictive
with the teacher? from your view point. What I do have is a schedule calandar preparede weeks in
advance of when I am NOT available. You may set an appointment, at least a 1/2
day in advance to guarantee that I see it, any other time. Of course, appointments
are not necessary if I'm in my office, but you take the chance of my not being there
or someone else being there ahead of you if you do not sign up. You may contact
me by e-mail: makoid@creighton.edu, or by phone: 402-280-2952. You may also-
contact my secretary, Dawn Trojanowski in the departmental office or by phone
402-280-2893 to make an appointment.
How can I tell the 7. Be responsive: Each day, you will be asked to provide me with a one
teacher how things are minute summary of the topic consisting answering the following questions:
going?
a. What was the main thrust of the study section (What did you read)?
b. What was clear about the study section? What was done well?
c. What was unclear? How could it be done better?

This will provide me with a running monitor of my effectiveness as well as a


framework of what to stress and what to change.

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Introduction

Do I have any say in the After each exam, in addition to working out the problems, we will decide whether
examination questions? any individual question was not covered by the objectives. Note: Not that it was
tough, not that you got it wrong, not that it didn’t allow you to tell me what you
knew, but did I tell you that I was going to ask you to do it? (Was it covered by the
objectives?)
How are the exams 8) Evaluate your performance fairly and honestly: Quite simply, I’m going to tell
graded? you what I expect that you will do. I will show you how to do it. I will provide you
with practice in doing it. I will provide you with an exam which tests your ability
to do it. The exams, as well as the whole course, will use real data and/or pharma-
cokinetic parameters for real drugs in real patient settings, much like the state
board exams (and hopefully real life). Like both of these situations, all answers are
interconnected. What that means is, if you improperly calculate a parameter which
is needed to make another calculation which is used to make a third, etc. ALL are
wrong. Conversely, if you can’t get a particular calculation by one method or equa-
tion, try another. That’s simply the way it is. You probably wouldn’t get much sym-
pathy if you calculated a dosage regimen properly based on a wrong elimination
rate constant and ended up killing your patient.

You Will:
What do I have to do? 1) Come prepared to participate in class. This is your full time job. If you are
How much work is really working full time, it is usually 40 to 60 hours per week. If you go to college 15 to
expected? 18 credits and prepare/study 2 hours for each credit, you work 45 to 55 hour per
week - you have a full time job. Your commitment is the 45 to 50 hour week not
just the contact hours and a night for each exam. This specifically means for each 1
hour class, I expect no less than 2 hours of preparation on your part. Each of you
will be assigned to a study group. You will work the problems together and teach
each other both in and out of class. We will have group discussion of class as well
as group problem solving. It will be your responsibility that every member of
your group be adequately prepared to answer for the group during recitation. There
will be a grade for group participation. Part of your grade will be based on your
peer evaluation.
Do I have to read the 2) Read the text. When you read, read critically. Do you understand each idea?
text? Each page in the HTML version has an evaluation section. If you get it you will be
asked to be a resource for that page for your peers. If you don’t get it, you will be
directed to your peers to seek help. Come prepared to ask about it in class.
Why do I have to do the 3) Work the problems. Check the answers. These come from old exams, so they
problem sets? are the type that you are likely to see. Work them in your study groups so that
everyone can see your thought processes. Bring them to class if you can not do
them or come and see me privately. Be prepared to show me your attempts at solv-
ing the problem. I will show you how to get started and give direction to your
thought. I will not work the problem for you. You would not learn if I did it for
you. It is crucial that you work the problems. Each has a specific objective. Over-

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Introduction

all, they contribute to your gaining facility in the processes that a pharmacokineti-
cist must know how to do.
Can I just coast 4) Do not delude yourself with respect to your performance. If you received a
through? grade that was less than satisfactory for you, do not simply console yourself by
saying “I knew the stuff, I just made a little error.” Can you get it right consis-
tently? That's when you know the stuff. That is not a laudable goal. That's what a
professional does. There have been several students in the past that “knew that
stuff” right up till the time that they had to repeat the course (and sometimes
beyond).

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Introduction

1.6 Computers in the course


Can I get through with Computer literacy is necessary in this field. Consequently computers will pervade
just paper and pencil? the course. The homework problems (above) are to done both by hand and
checked with the computer. This will help your understanding of pharmacokinetics
in general and that homework objective in particular. Computers are natural
adjunctive tools in the teaching of pharmacokinetics. The are able to simulate the
concentration vs. time profiles and do difficult repetitive calculations which allow
the student to get a broad view of the processes involved.
What are the programs Program that is becomming the industry standard and is currently being used in the
that I will be using? course is PK Solutions. We have a site licence for it and a working copy is in the
computer lab. It is a required text for the course. You will need to learn to use the
software as complete instructions are available with its purchase.

In addition to the above course objectives, there are specific objectives for the use
of computers in the course. They are:
What will I be expected • Simulation. The student will be able to utilize appropriate graphs and histograms used classical
to do with the comput- pharmacokinetics in the course. The student will demonstrate effects of changes in pharmacoki-
ers? netic parameters on the ADME processes and correlated pharmacological / therapeutic
response.
• Graphical Solutions. Many thing become more understandable in graphical form, or at least we
are able to predict what would happen if a trend were to continue.
• Numerical solutions. The computer would accurately and repeatedly calculate convoluted, diffi-
cult equations quickly and easily.

These objectives will be met in a variety of ways. Clearly, the most direct method
is the solution of the problem sets by computer. First, I expect that you would do
the problem by hand, complete with graphs and other supporting calculations fol-
lowed by computer simulation and data analysis. Just how close did you come to
the best fit? Next, a portion of each exam will be a library exercise in which you
will find and evaluate a published article according to the principles that you
learned in class utilizing the computer facilities. How close did you come the
authors numbers? Do you, in fact, even agree with the authors? You will prepare a
short consult in which you describe the patient and what the authors did along with
your support (or non-support) of the authors conclusions.

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Introduction

1.7 Survival Kit

1.7.1 THINGS FOR YOUR SURVIVAL KIT!


x
What do I need to buy 1. You will need a good calculator - One with e and ln x functions. You must
RIGHT NOW? have it ASAP. You will use it in class.

2. You will also need 2 cycle semilog paper and a clear straight edge ruler for
use in class. These are available in the book store or at an office supply store. You
can also downoad a copy of graph paper printer for you own personal use. A copy
is available in the computer lab.

3. You will need access to a pentium computer. The software, PK Solutions,


is pre-loaded in the Criss computer lab. Purchase is required for home use.

4. You will need a 3” D three-ring binder for collecting and maintaining all
the pages in this book as well as your class notes.
What do I need to do in Work in your study groups. You never learn it so well as when you teach it to
and out of class? someone else. Everyone benefits from a well run prepared study group. You are
not in competition with your fellow classmates. If everyone earns an “A”, then
everyone will receive one.
How can I organize this Organize and label your study notes. This is basic survival. This is one strategy
material? that I find works well. I recommend it highly. Good study notes are formatted on
loose-leaf in a three ring binder. The individual pages have a line drawn down
about 1/3 the way in. The notes are taken on the right (2/3) of the page, while
labels go in the left. The labels on the left are often written as questions, which are
answered in the text on the right. Loose leaf binders allow for the incorporation of
reading summaries as well as relevant problems and homework to be organized
with a divider all in one place. You should write intelligently, with proper punctua-
tion and spelling as if you were preparing a consult for a physician. Organization is
the key.

Remember: you may have all the information in the world at your fingertips; be
able to solve the most difficult therapy problem and no one will listen to you if you
can't communicate intelligently. You will be required to communicate in this
course utilizing both written and verbal skills.

Chapters in the book will be organized as above.

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Introduction

1.7.2 WHAT YOU WILL GAIN: (YOUR GOALS)


How is the course to be 1. At the lowest level, a decent grade for a significant course. Specific grades
graded? will be earned by attaining the following points:
• A 900 and above
• B+ 850 to 899
• B 800 to 849
• C+ 750 to 799
• C 700 to 749
• D 600 to 699
• F 599 and below

Points in the course are assigned for various activities:

TABLE 4-1

Exam 1 410
Exam 1 grp/ind 40
Library 1 50-75
Exam 2 410
Exam 2 grp/ind 40
Library 2 50 to 75
Total 1000 to 1050
Group Bonus -50 to +50
Group Total 950 to 1100

You will be require to pass the first exam before you are allowed to take the
second.

2. At the next higher level, I will guarantee that if you comprehend this mate-
rial at level V, you will have no trouble passing any state board anywhere with
regard to pharmacokinetics.

3. You will gain a useful skill that will make you an integral part of the health
care team.
Do I really need a 4 You will learn to learn. There is an old proverb which goes: “Give a man a
teacher to learn? fish and you feed him for a day. Teach a man to fish and you feed him for a life-
time.” The B.S. Degree is designed to eliminate teachers. An educated man is one
who has learned to how to learn, not one who memorized a page in a book. That
is what you need to be a professional. The total medical knowledge is doubling at a
rate of every 3-4 years. That means that you will be out of date shortly after gradu-
ation (if not before) if you simply memorized content and don't learn to learn and
continue to learn throughout your career.

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Introduction

What about cheating? One last piece of information: Neither you nor I will not tolerate any academic
misconduct. Anyone caught will minimally receive an “F” for their efforts and I
will recommend dismissal from the program. The profession has no room for
unprofessional behavior. I will prosecute.

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Introduction

1.8 Tentative Schedule

1.8.1 STUDY GROUP 1: LEARN THE TOOLS USED BY THE DISCIPLINE.


CALCULATE PATIENT AND DRUG SPECIFIC PHARMACOKINETIC
PARAMETERS FROM SINGLE DOSE PATIENT DATA,
A: Introduction
1. Texts
2. Literature
3. Grading Policy
4. Course Philosophy

B: Math review
1. Numbers and exponents
2. Graphs and reaction order
3. Calculus
4. Laplace transform
5. Computer Introduction
6. Computer simulation and problem sets

C: Pharmacokinetic modeling
1. What a model is and what it isn’t.
2. Why we model
3. Philosophy of modeling

D: Pharmacological Response
1. Michaelis - Menton Mass balance equation
2. Interrelationships between Concentration, time and response.

E: I.V. Bolus dosing


1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets

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Introduction

e. Professional communication.
2. Metabolite
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Rate vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
F: I.V. infusion
1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
1. Metabolite
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.

G: Biopharmaceutical factors
1. Absorption
I. Physiology
II. Mechanisms

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Introduction

III. Physiological changes with age, sex, disease


2. Distribution
I. Diffusion
II. Cardiac output / blood perfusion
III. Physical properties of the drug
IV. Physical properties of the body
V. Physiological changes with age, sex, disease
3. Metabolism
I. Biotransformation methods
II. First pass effect
III. Clearance
IV. Physiological changes with age, sex, disease
4. Excretion
I. Renal
II. Biliary
III. Mammary
IV. Salivary
V. Misc.
VI. Physiological changes with age, sex, disease

H: Oral dosing
1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
2. Metabolite
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation

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Introduction

d. Problem sets
e. Professional communication.
I: Bioavailability, Bioequivalence, Drug product selection
1. Relative and Absolute Bioavailability
2. Factors Influencing Bioavailability
3. Methods of Assessing Bioavailability
I. in vivo
II. in vitro
III. Correlation
4. Bioequivalence
5. Bioavailability
6. Drug Product Selection

1.8.2 STUDY GROUP 2: UTILIZE THE TOOLS TO OPTIMIZE PATIENT


THERAPY UNDER MULTIPLE DOSE CONDITIONS,
J: Dosage regimen (Healthy, aged and diseased patients)
1. Multiple dose kinetics
2. Optimization of dosage regimen
3. Computer aided instruction
4. Computer simulation and problem sets
5. Computer aided consultation
6. Professional consultation process

1.8.3 STUDY GROUP 3: APPLY THE TOOLS TO PREDICT THE CHANGES IN


RELEVANT PHARMACOKINETIC PARAMETERS IN THE
COMPROMISED PATIENT PATIENT WITH SELECTED DISEASES,

L. Clearance objectives:
1. Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compromised
patients.

1.8.4 STUDY GROUP 4: APPLY THE TOOLS IN SPECIAL CASES.


K: Multicompartment Modeling
1. Parent compound plasma vs. time profile analysis
2. Multiple dose considerations
3. Computer aided instruction
4. Computer simulation and problem sets

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Introduction

5. Computer aided consultation


6. Professional consultation process
L: Protein Binding (healthy, aged and diseased patients)
1. Mass balance considerations / drug interactions
2. Effects of protein binding on pharmacokinetic parameters
3. Computer aided instruction
4. Computer simulation and problem sets
5. Computer aided consultation
6. Professional consultation process
M: Non - linear (Michaelis - Menton) kinetics
1. Computer aided instruction
2. Computer simulation and problem sets
3. Computer aided consultation
4. Professional consultation process

End of material for Masters / Honors course

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Introduction

1.9 Competency Statements Related To Pharmacokinetics


The profession of pharmacy has determined that there are minimum, entry level
abilities necessary for a pharmacist. These form the Standards of Practice for the
profession of pharmacy, as written by The National Association of Boards of Phar-
macy (who make the NABPLEX, coincidentally). It is important to note that these
abilities are not thought up by some faculty member who sits in his ivory tower
saying what he thinks is important. These are what pharmacists do. They have
been promulgated as competency statements They are also the basis for the state
board exams as well as the basis far your coursework while in the School of Phar-
macy. They are broken down into five general areas:
1.00.00 Interpreting and dispensing prescriptions/ medication orders,

2.00.00 Assessing prescriptions/ medication orders and the drugs used in dispensing them,

3.00.00 Compounding and calculations involved in extemporaneous preparation of prescriptions/ medication


orders,

4.00.00 Monitoring drug therapy,

5.00.00 Counseling patients and health professionals.

For a complete listing of competency statements please refer to the NABPLEX


Candidate’s Review Guide, published by the National Association of Boards of
Pharmacy.

1.9.1 SPECIFIC COMPETENCY STATEMENTS ADDRESSED IN THIS


COURSE
1.00.00 Interpreting and Dispensing Prescriptions/ Medication Orders

1.04.00Given a prescription or medication order, the candidate shall identify or explain the rationale for the
dosage regimen.

1.04.03The candidate shall calculate the dose or rate of administration of a drug when given appropriate data.

2.00.00 Assessing Prescriptions/Medication Orders and the Drugs Used in Dispensing Them

2.01.00 The candidate shall identify, interpret, or explain patient or pharmacokinetic factors that affect either the
efficacy or safety of individual drug therapy.

2.01.01The candidate shall relate the influence of patient factors (e.g., age, weight, sex, occupation, compli-
ance, exercise, stress, placebo effect, vital organ function) to the choice or dosage of drug therapy.

2.01.02 The candidate shall explain or apply biopharmaceutical principles or pharmacokinetic factors (e.g.,
absorption, distribution, metabolism, excretion) as they relate to dosage regimen design or evaluation of experi-
mental or patient data, including the: definition or explanation of biopharmaceutical terminology; recognition of
the effects of patient health status or concurrent drug therapy on bioavailability; determination of pharmacokinetic
parameters or dosing regimens (e.g., loading dose estimations, maintenance dose calculation, elimination half-

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Introduction

life, determinations of clearance, or volume of distribution); or recognition of biosocial factors that affect pharma-
cokinetic parameters (e.g., smoking, alcohol consumption, work environment.

2.03.00 Given appropriate information or data regarding bioavailability, the candidate shall demonstrate proper
judgment to assure safe and effective drug therapy.

2.03.01The candidate shall interpret or utilize in vitro dissolution test results that are used to predict bioequiv-
alence or shall distinguish these from in vivo tests.

2.03.02 The candidate shall differentiate between relative and absolute bioavailability.

2.03.03 The candidate shall interpret area under plasma concentration versus time curves as an assessment
of bioavailability.

2.03.04 The candidate shall explain or interpret the effect of rate of absorbtion on maximum plasma concentra-
tions and times of maximum plasma concentrations after drug administration.

2.04.00 The candidate shall identify, interpret, or evaluate sources of information for clarifying or answering
questions related to prescriptions, medication orders, or health care.

2.04.01 The candidate shall select appropriate books or references containing needed information (e.g.,
bioequivalence, incompatibility, drugs for emergency situations, physicochemical stability).

2.04.02 The candidate shall evaluate the suitability, accuracy, or reliability of information (e.g., pharmacokinetic
characteristics untoward effects, therapeutic efficacy) from literature sources.

4.00.00 Monitoring Drug Therapy

4.01.02 The candidate shall identify, collect, or evaluate patient information that relates to the effectiveness of
drug therapy (e.g., clinical observations, pharmacokinetic data, laboratory test results, sensitivities).

5.00.00 Counseling Patients and Health Professionals

5.01.00 The candidate shall counsel a patient or health professional regarding the indications, benefits, admin-
istration, storage, or untoward effects of prescription medications.

5.01.01 The candidate shall explain the proper procedure for taking or administering the drug (e.g., dosage,
time of day, method or time of administration -- before or after meals, duration of use), or for providing auxiliary
instructions about the medication.

5.01.03 The candidate shall explain cautions regarding food, drugs, chemicals, or nutrients that should be
avoided while particular medications are taken.

5.05.00 The candidate shall advise consumers regarding the selection, proper use, effects, precautions, or
contraindications of OTC products.

5.05.03 The candidate shall explain how a drug is to be taken (e.g., dosage, time of day, frequency, before or
after meals).

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Introduction

1.10 Pharmacokinetic Symbolism


Pharmacokinetics was developed in several locations simultaneously. Because of
this, the symbols used in the literature are not consistent. Provided each symbol is
rigorously defined prior to use, this inconsistency should not prove an insurmount-
able difficulty when assessing the literature. In this book, the symbolism below
will be generally used, though, as an illustration of the variety, some deviation may
be anticipated on occasions.

1.10.1 AMOUNT TERMS (UNIT: MASS)

ARE amount remaining to be eliminated (excreted)

D dose (or maintenance dose)

DL loading dose

Xa amount of drug remaining to be absorbed at any time

X amount of unchanged drug in body at any time

Xm amount of metabolite in body at any time

Xu cumulative amount of unchanged drug excreted into urine up to any time

X mu cumulative amount of metabolite excreted into urine up to any time

X max maximum amount of unchanged drug in body

X min minimum amount of unchanged drug in body

X average amount of unchanged drug in body (also Laplace transform)

X eff minimum amount of unchanged drug in body necessary for pharmacologi-


cal response

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Introduction

1.10.2 CONCENTRATION TERMS (UNITS MASS/VOLUME)

Cb concentration of drug in blood at any time

Cp concentration of drug in plasma at any time

Cm Concentration of metabolite in plasma (or blood) at any time

ss
(Cp ) “average” steady-state concentration of drug in plasma during a dosing
avg
interval

ss
(Cp ) maximum concentration of drug in plasma
max

ss
(Cp ) minimum concentration of drug in plasma
min

Cp average concentration of drug in plasma

KA dissociation constant of drug-protein complex

KM Michaelis-Menton rate constant

KR dissociation constant of drug-receptor complex

MEC minimum effective concentration of drug or metabolite

MTC minimum toxic concentration of drug or metabolite

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Introduction

1.10.3 VOLUME TERMS (UNIT: VOLUME)

Vd apparent volume of unchanged drug distribution in compartment

Vm apparent volume of metabolite distribution in compartment

Vw physiological volume of plasma water

1.10.4 TIME TERMS (UNIT: TIME)

t time since administration of dose

T duration of zero-order input

t' time since cessation of zero-order input

t0 lag time

t mean time during sampling interval

t½ elimination half-life (“biological half-life”)

t 0.5 time for 50% removal

t max time when maximum amount or concentration occurs

t dur duration of effective pharmacological response

τ dosing interval (greek theta)

b time variable used in association with zero-order input

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Introduction

1.10.5 RATE CONSTANT TERMS (UNIT: RECIPROCAL TIME (*), MASS/TIME


(**))

K, ke ,K i , apparent first-order rate constant for elimination, Summation of all the


ways the drug is eliminated (*)

ka apparent first-order rate constant for absorption (*)

k u, k r apparent first-order rate constant for urinary (renal) excretion of unchanged


drug (*)

km apparent first-order rate constant for metabolism of unchanged drug (*)

k mu apparent first-order rate constant for excretion of metabolite (*)

k ij apparent first-order transfer rate constant (*)

k0 zero-order input rate constant (**)

Q zero-order infusion rate constant (**)

R rate constant for decline in pharmacological effect (usual units:%/time)

α hybrid first-order rate constant (*) (greek alpha)

β hybrid first-order rate constant (*) (greek beta)

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Introduction

1.10.6 CLEARANCE TERMS (UNITS: VOLUME/TIME)

Cl total body clearance (TBC)

Cl r renal clearance (RC)

Cl m metabolic clearance (MC)

Cl cr creatinine clearance

Cl H hepatic clearance (HC)

1.10.7 RATE TERMS (UNITS: MASS/TIME (*), MASS/TIME, VOLUME (**),


VOLUME/TIME (***)

dX
------- instantaneous rate of change of amount of unchanged drug (*)
dt

X
---- measured rate of change of amount of unchanged drug (*)
t

RH rate of plasma flow through the liver (***)

Rr rate of plasma flow through the kidney (***)

VM theoretical maximum rate of a process (**)

1.10.8 OTHER TERMS

AUC area under the plasma concentration-time curve (units: time * mass/vol-
ume)

AUMC area under the first moment of the plasma concentration-time curve (units:
2
time ⋅ mass ⁄ volume )

MRT Mean Residence Time (units: time )

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Introduction

MAT Mean Absorption Time (units: time )

MDT Mean Dissolution Time (units: time )

E intensity of pharmacological effect

EH steady-state hepatic extraction ratio

Er steady-state renal extraction ratio

E max maximum intensity of pharmacological effect

F fraction of administered dose ultimately absorbed

FRE fraction remaining to be eliminated (excreted)

H hematocrit (fractional volume of erythrocytes in whole blood)

N number of elimination half-lives in a dosing interval

R accumulation factor

b intercept

f fraction of drug that is free (unbound)

f ss fraction of steady-state

m slope (sometimes specifically for log dose-response plot)

n number of doses

s Laplace operator

[ ] indicates molar concentration

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Introduction

1.10.9 SUBSCRIPTS

0 at time zero

∞ at time infinity

ss during steady-state

t at time t

T at time T

n following dose n

diff difference between extrapolated and observed

int intrinsic

i index (i.e., 1,2,3)

j index (i.e., 1,2,3)

1.10.10 SUPERSCRIPTS

x extrapolated

x° last measured value

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Introduction

1.11 First Lesson in Pharmacokinetics


It should be intuitively obvious to the most casual observer that the relative bio-
availability of 2 simultaneous I.V. bolus doses of a drug is equal to the following:

 1 δ
2
ln  lim  ( [ x ] – [ x ] )! + ---  + ( sin q ) + ( cos q ) =
1 –1 –1 1 cosh p 1 – ( tanh p )
∑ -------------------------------------------------
2 2
- (EQ 4-1)
δ → ∞  δ  n
  2
n=0

given that 100% bioavailability of a single I.V. bolus dose is equal to 1, and both
doses contain an equal mass of active drug.

For the struggling pharmacokinetics student, we would like to show the veracity of
this statement. Of course, it is obvious that; the reverse of the transpose is equal to
the transpose of the inverse in matrix theory. i.e.:

1 –1 –1 1
[x ] = [x ] (EQ 4-2)

Also, it should be obvious that:

0! = 1 (EQ 4-3)

Consequently,

1 –1 –1 1
([x ] – [ x ] )! = 1 (EQ 4-4)

which means that:



 1 δ cosh p 1 – ( tanh p ) -
2
ln  lim  1 + ---  + ( sin q ) + ( cos q ) = ∑ -------------------------------------------------
2 2
 
(EQ 4-5)
δ → ∞ δ  2
n
n=0

By definition,

1 δ
e =  1 + ---
 δ
(EQ 4-6)

and

2
1 = cosh p 1 – ( tanh p ) (EQ 4-7)

Thus:

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Introduction


1
∑ ----
2 2
ln e + ( sin q ) + ( cos q ) = - (EQ 4-8)
n
n=0
2

Also,

1
2 = ∑ ----
2
-
n
(EQ 4-9)

n=0

and

1 = ln e (EQ 4-10)

and
2 2
1 = ( sin q ) + ( cos q ) (EQ 4-11)

So, as we observed in equation 1,

1+1 = 2 (EQ 4-12)

under the stated conditions, two I.V. bolus doses given simultaneously will have
twice as much available drug as a single I.V. bolus dose.

You will agree, however, equation 1-1 is obvious and therefore is more easily
understood by a pharmacokineticist!

Basic Pharmacokinetics REV. 00.1.11 1-34


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CHAPTER 2 Mathematics Review

Author: Michael Makoid, Phillip Vuchetich and John Cobby


Reviewer: Phillip Vuchetich

BASIC MATHEMATICAL SKILLS OBJECTIVES


1. Given a data set containing a pair of variables, the student will properly construct
(III) various graphs of the data.
2. Given various graphical representations of data, the student will calculate (III) the
slope and intercept by hand as well as using linear regression.
3. The student shall be able to interpret (V) the meaning of the slope and intercept
for the various types of data sets.
4. The student shall demonstrate (III) the proper procedures of mathematical and
algebraic manipulations.
5. The student shall demonstrate (III) the proper calculus procedures of integration
and differentiation.
6. The student shall demonstrate (III) the proper use of computers in graphical simu-
lations and problem solving.
7. Given information regarding the drug and the pharmacokinetic assumptions for
the model, the student will construct (III) models and develop (V) equations of the
ADME processes using LaPlace Transforms.
8. The student will interpret (IV) a given model mathematically.
9. The student will predict (IV) changes in the final result based on changes in vari-
ables throughout the model.
10. The student will correlate (V) the graphs of the data with the equations and mod-
els so generated.

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Mathematics Review

2.1 Concepts of Mathematics


Pharmacokinetcs is a challenging field involving the application of mathematical
concepts to real situations involving the absorbtion, distribution, metabolism and
excretion of drugs in the body. In order to be successful with pharmacokinetics, a
certain amount of mathematical knowledge is essential.
This is just a review. This chapter is meant to review the concepts in mathematics essential for under-
Look it over. You should standing kinetics. These concepts are generally taught in other mathematical
be able to do all of these courses from algebra through calculus. For this reason, this chapter is presented as
manipulations.
a review rather than new material. For a more thorough discussion of any particu-
lar concept, refer to a college algebra or calculus text.

Included in this section are discussions of algebraic concepts, integration/differen-


tiation, graphical analysis, linear regression, non-linear regression and the LaPlace
transform. Pk Solutions is the computer program used in this course.
Something new - A critical concept introduced in this chapter is the LaPlace transform. The LaPlace
LaPlace transforms. transform is used to quickly solve (integrate) ordinary, linear differential equa-
Useful tool.
tions. The Scientist by Micromath Scientific Software, Inc.1 is available for work-
ing with the LaPlace transform for problems throughout the book.

1. MicroMath Scientific Software, Inc., P.O. Box 21550, Salt Lake City, UT 84121-0550,

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Mathematics Review

2.2 Mathematical Preparation

2.2.1 ZERO AND INFINITY

Any number multiplied by zero equals zero. Any number multiplied by infinity
( ∞ ) equals infinity. Any number divided by zero is mathematically undefined.
Any number divided by infinity is mathematically undefined.

2.2.2 EXPRESSING LARGE AND SMALL NUMBERS

Large or small numbers can be expressed in a more compact way using indices.
5
How Does Scientific Examples: 316000 becomes 3.16 × 10
Notation Work?
–3
0.00708 becomes 7.08 ×10

In general a number takes the form:

n
A × 10

Where A is a value between 1 and 10, and n is a positive or negative integer

The value of the integer n is the number of places that the decimal point must be
moved to place it immediately to the right of the first non-zero digit. If the decimal
point has to be moved to its left then n is a positive integer; if to its right, n is a
negative integer.

Because this notation (sometimes referred to as “Scientific Notation”) uses indi-


ces, mathematical operations performed on numbers expressed in this way are sub-
ject to all the rules of indices; for these rules see Section 2.2.4.

A shorthand notation (AEn) may be used, especially in scientific papers. This may
n
be interpreted as A × 10 , as in the following example:

4
2.28E4 = 2.28 ×10 = 22800

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Mathematics Review

2.2.3 SIGNIFICANT FIGURES

A significant figure is any digit used to represent a magnitude or quantity in the


place in which it stands. The digit may be zero (0) or any digit between 1 and 9.
For example:

TABLE 2-1 Significant Figures

Number of
Significant Significant
Value Figures Figures
(a) 572 2,5,7 3
(b) 37.10 0,1,3,7 4
(c) 10.65 x 104 0,1,6,5 4
(d) 0.693 3,6,9 3
(e) 0.0025 2,5 2

How do I determine the Examples (c) to (e) illustrate the exceptions to the above general rule. The value 10
number of significant raised to any power, as in example (c), does not contain any significant figures;
figures? hence in the example the four significant figures arise only from the 10.65. If one
or more zeros immediately follow a decimal point, as in example (e), these zeros
simply serve to locate the decimal point and are therefore not significant figures.
The use of a single zero preceding the decimal point, as in examples (d) and (e), is
a commendable practice which also serves to locate the decimal point; this zero is
therefore not a significant figure.
What do significant fig- Significant figures are used to indicate the precision of a value. For instance, a
ures mean? value recorded to three significant figures (e.g., 0.0602) implies that one can reli-
ably predict the value to 1 part in 999. This means that values of 0.0601, 0.0602,
and 0.0603 are measurably different. If these three values cannot be distinguished,
they should all be recorded to only two significant figures (0.060), a precision of 1
part in 99.

After performing calculations, always “round off” your result to the number of sig-
nificant figures that fairly represent its precision. Stating the result to more signifi-
cant figures than you can justify is misleading, at the very least!

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Mathematics Review

2.2.4 RULES OF INDICES


n
What is an index? An index is the power to which a number is raised. Example: A where A is a
number, which may be positive or negative, and n is the index, which may be pos-
itive or negative. Sometimes n is referred to as the exponent, giving rise to the
general term, “Rules of Exponents”. There are three general rules which apply
when indices are used.

(a) Multiplication

A n n+m
=  --- × B
n m n+m n m
A ×A = A A ×B
B

(b) Division

n n n n–m
A-
------ = A
n–m A-
------ = A--- × B
m m  B
A B

(c) Raising to a Power

n m nm
(A ) = A

There are three noteworthy relationships involving indices:

(i) Negative Index

–n 1 –n
A = -----n- As n tends to infinity ( n → ∞ ) then A → 0 .
A

(ii) Fractional Index

1
---
n n
A = A

(iii) Zero Index

0
A = 1

Basic Pharmacokinetics REV. 00.1.6 2-5


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Mathematics Review

2.2.5 LOGARITHMS
What is a logarithm? Some bodily processes, such as the glomerular filtration of drugs by the kidney,
are logarithmic in nature. Logarithms are simply a way of succinctly expressing a
number in scientific notation.

In general terms, if a number (A) is given by

n
A = 10 then log ( A ) = n

where ‘log’ signifies a logarithm to the base 10, and n is the value of the logarithm
of (A).

5
Example: 713000 becomes 7.13 × 10 ,

0.85 0.85 5 ( 5 + 0.85 ) 5.85


and 7.13 = 10 , thus 713000 becomes 10 × 10 = 10 = 10

and log ( 713000 ) = 5.85

Logarithms to the base 10 are known as Common Logarithms. The transformation


of a number (A) to its logarithm (n) is usually made from tables, or on a scientific
calculator; the reverse transformation of a logarithm to a number is made using
anti-logarithmic tables, or on a calculator.
What is the characteris- The number before the decimal point is called the characteristic and tells the place-
tic? the mantissa? ment of the decimal point (to the right if positive and to the left if negative). The
number after the decimal is the mantissa and is the logarithm of the string of num-
bers discounting the decimal place.

2.2.6 NATURAL LOGARITHMS


What is a natural loga- Instead of using 10 as a basis for logarithms, a natural base (e) is used. This natural
rithm? base is a fundamental property of any process, such as the glomerular filtration of a
drug, which proceeds at a rate controlled by the quantity of material yet to undergo
the process, such as drug in the blood. To eight significant figures, the value of the
transcendental function, e, is


1 Where x is an inte-
e = 2.7182818 ... Strictly speaking, e = 1 + ∑ ---x!-
x=1
ger ranging from 1 to infinity ( ∞ ) ,

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Mathematics Review

∑ denotes the summation from x = 1 to x = ∞ , and


x=1

! is the factorial (e.g., 6! = 6x5x4x3x2x1= 720)

n
In general terms, if a number (A) is given by A = e , then by definition,
ln ( A ) = n

Where, ‘ln’ signifies the natural logarithm to the base e , and n is the value of the
natural logarithm of A .

Natural logarithms are sometimes known as Hyperbolic or Naperian Logarithms;


again tables are available and scientific calculators can do this automatically. The
anti-logarithm of a natural logarithm may be found from exponential tables, which
n
give the value of e for various values of n.
How are natural loga- Common and natural logarithms are related as follows:
rithms ln x and common
logarithms log x related? ln ( A ) = 2.303 × log ( A ) , and

log ( A ) = 0.4343 × ln ( A )

Because logarithms are, in reality, indices of either 10 or e , their use and manipu-
lation follow the rules of indices (See Section 2.2.4).

(a) Multiplication:

n m n m n+m
To multiply N × M , where N = e and M = e ; NM = e × e = e .

By definition, ln ( NM ) = n + m ; but

n = ln ( N ) and m = ln ( M ) , hence ln ( NM ) = ln ( N ) + ln ( M )

Thus, to multiply two numbers (N and M) we take the natural logarithms of each,
add them together, and then take the anti-logarithm (the exponent, in this case) of
the sum.

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Mathematics Review

(b) Division

ln  ----- = ln ( N ) – ln ( M )
N
 M

(c) Number Raised to a Power

m
ln ( N ) = m × ln ( N )

There are three noteworthy relationships involving logarithms:

(i) Number Raised to a Negative Power

) = – m × ln ( N ) = m × ln  ----
–m 1
ln ( N
N

–m
As m tends to infinity ( m → ∞ ) , then ln ( N ) → –∞

(ii) Number Raised to a Fractional Power

1
 ---
m
-
1
ln ( m N ) = ln  N  = ---- × ln ( N )
  m

(iii) Logarithm of Unity

ln ( 1 ) = log ( 1 ) = 0

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Mathematics Review

2.2.7 NEGATIVE LOGARITHMS

The number 0.00713 may be expressed as:

–3
7.13 ×10 , or

0.85 –3
10 × 10 , or

– 2.15
10 .

Hence, log ( 0.00713 ) = – 2.15 , which is the result generated by most calculators.

However, another representation of a negative logarithm (generally used by refer-


encing a log table):

log (0.00713) = 3.85

The 3 prior to the decimal point is known as the characteristic of the logarithm; it
can be negative (as in this case) or positive, but is never found in logarithmic
tables. The .85 following the decimal point is known as the mantissa of the loga-
rithm; it is always positive, and is found in logarithmic tables.

In fact 3 is a symbolic way of writing minus 3 (-3) for the characteristic. In every
case the algebraic sum of the characteristic and the mantissa gives the correct
value for the logarithm.

Example: log (0.00713) = 3.85

Add -3 and 0.85

Result is -2.15, which is the value of log ( 0.00713 )

The reason for this symbolism is that only positive mantissa can be read from anti-
logarithmic tables, and hence a positive mantissa must be the end result of any log-
arithmic manipulations. Note that while there are negative logarithms (when N <
1), they do not indicate that number itself is negative; the sign of a number (e.g., -
N) is determined only by inspection following the taking of anti-logarithms.

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2.2.8 USING LOGARITHMIC AND ANTI-LOGARITHMIC TABLES

Though the preferred method to using logarithms is with a calculator or computer,


the understanding of how the number is being manipulated may be important in
understanding the use of logarithms. (See the end of this chapter for Logarithm
tables).

(a) Find the log of (62.54):


1
1. convert 62.54 to scientific notation ---> 62.54 = 6.254 ×10 ;
2. Look up the mantissa for 6254 in a table of logarithms: it is 7962.
1 0.7962 1 1.7962
3. Hence, 6.254 ×10 = 10 × 10 = 10 and log ( 62.54 ) = 1.7962

(b) Find the log of (0.00329)


–3
1. 0.00329 = 3.29 ×10
2. The mantissa for 329 is 5172
3. Hence, log(0.00329) = 3.5172.

Note that in both examples the value of the characteristic is the integer power to
which 10 is raised when the number is written in scientific notation.
How do I multiply using (c) Multiply 62.54 by 0.00329
logarithms?
log (62.54) = 1.7972

log (0.00329) = 3.5172

log (62.54 + log (0.00329) = 1.7962+3.5172 = 1.7962-3+ 0.5172=-0.6866

0.6866=1.3134

(d) We wish to find anti-log (1.3134) Look up the anti-log for the 0.3134 (man-
tissa) in a table: it is 2058.

–1
Antilog (1.3134) = 2.058 ×10

Hence, antilog (1.3134) = 0.2058


How do I divide using log (62.54) - log (0.00329) = 1.796 - 3.5172=1.796 +3 - 0.5172=4.2788
logarithms?
antilog 4.2788 = 19002

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Mathematics Review

2.2.9 DIMENSIONS
What is a unit? There are three fundamental dimensions which are used in various combinations to
express the properties of matter. Each of these dimensions has been assigned a def-
inite basic unit, which acts as a reference standard.

TABLE 2-2 Dimensions

Dimensional
Dimension Symbol Unit Unit Symbol
Length L meter m
Mass M gram g
Time T second sec

How are units made big- In the metric system, which emerged from the French Revolution around 1799,
ger and smaller? there are various prefixes which precede the basic units and any derived units. The
prefixes indicate the factor by which the unit is multiplied. When the index of the
factor is positive the prefixes are Greek and have hard, consonant sounds. In con-
trast, when the index is negative, the prefixes are Latin and have soft, liquid
sounds. (see Table 2-3).
How big is big? Examples: An average adult male patient is assumed to have a mass of 70 kilo-
grams (70 kg). An average adult male patient is assumed to have a height of 180
centimeters (180 cm). A newly minted nickel has a mass of 5.000 g. Doses of
drugs are in the mg (10-3 g) range (occasionally g) never Kg (103 g) or larger. Stu-
dents have told me that the dose that they have calculated for their patient is 108 g
(converting to common system - ~ 100 tons). I doubt it. Get familiar with this sys-
tem. Note that the plural of Kg or cm is Kg or cm; do not add an “s”. In pharmacy
there are two derived units which are commonly used, even though they are
related to basic units. The Liter (L) is the volume measurement and is a cube 10
cm on a side (1L = (10cm)3 = 1000 cm3 ) while the concentration measurement
and has the units of Mass per Volume.
Why should I use units? Whenever the magnitude of a measured property is stated, it is imperative to state
the units of the measurement. Numbers are useless by themselves.

Example: The procainamide concentration range is 4-8 µ g/ml; stating the range
without units may lead to a potentially lethal error in which procainamide is
administered in a sufficient dose to attain a range of 4-8 mg/ml, which is 1000
times too large and would give rise to cardiac arrest.

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Mathematics Review

TABLE 2-3 Scale of Metric system and SI

Name Symbol Multiplication Factor Name Symbol Multiplication Factor


exa- E 18 deci- d –1
10 10
peta- P 15 centi- c –2
10 10
tera- T 12 milli- m –3
10 10
giga- G
10
9 micro- µ 10
–6

mega- M 6 nano- n –9
10 10
kilo- k 3 pico- p –12
10 10
hecto- h 2 femto- f –15
10 10
deca- da 1 atto- a –18
10 10

TABLE 2-4

Dimensional Unit
Dimension Symbol Unit Symbol
Volume V liter l
Concentration C grams/liter g/l

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2.2.10 DIMENSIONAL ANALYSIS


How are units useful? It is a general rule that the net dimensions (and units) on the two sides of any equa-
tion should be equal. If this is not so, the equation is necessarily meaningless.

Consider the following equation which defines the average concentration of a drug
FD
in blood after many repeated doses, ( C b )∞ = -----------
VKτ

Where:
• F is the fraction of the administered dose ultimately absorbed (Dimensions: none),
• D is the mass of the repeated dose (Dimension: M),
• V is the apparent volume of distribution of the drug (Dimension: V = L )
–1
• K is the apparent first-order rate constant for drug elimination (Dimension: T ),

• and τ is the dosing interval (Dimension: T )

Writing the dimensions relating to the properties of the right-hand side of the equa-
tion gives:

M - M
----------------------- = -----
–1 V
V⋅T ⋅T

M
Thus ( C b )∞ has the dimensions of ----- , which are correctly those of concentration.
V

Sometimes dimensional analysis can assist an investigator in proposing equations


which relate several properties one with the other. If the units cancel, and you end
up with the correct unit of measure, you probably did it right. If you obtain units
that do not make sense, it’s guaranteed sure that you did it wrong.

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Mathematics Review

2.3 Calculus
What is Calculus? Calculus concerns either the rate of change of one property with another (differen-
tial calculus), such as the rate of change of drug concentrations in the blood with
time since administration, or the summation of infinitesimally small changes (inte-
gral calculus), such as the summation of changing drug concentrations to yield an
assessment of bioavailability. In this discussion a few general concepts will be pro-
vided, and it is suggested an understanding of graphical methods should precede
this discussion.

2.3.1 DIFFERENTIAL CALCULUS

2.3.2 NON-LINEAR GRAPHS

3
Consider the following relationship: y = x

TABLE 2-5 x, y sample data


x 0 1 2 3 4
y 0 1 8 27 64

As can be seen from the graph (Figure 2-1), a non-linear plot is produced, as
expected.

FIGURE 2-1. y=x3

70
60
50
40
30
20
10
0
1 2 3 4

(Question: How could the above data be modified to give a linear graph?)

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2.3.3 SLOPE OF NON-LINEAR GRAPH

As with a linear graph,

y2 – y1 ∆y
---------------- = ------
x2 – x1 ∆x

Where ∆y is the incremental change in y and ∆x is the incremental change in x

But, as can be seen (Figure 1), the slope is not constant over the range of the graph;
it increases as x increases. The slope is a measure of the change in y for a given
change in x. It may then be stated that:

“the rate of change of y with respect to x varies with the value of x.”

2.3.4 VALUE OF THE SLOPE

3
We need to find the value of the slope of the line y = x when x = 2 (See Figure
1). Hence, we may choose incremental changes in x which are located around
x ≈ 2.

FIGURE 2-2. ∆y / ∆x when x ≈ 2

∆y
------
x1 x2 ∆x y1 y2 ∆y ∆x
0 4 4 0 64 64 16.000
1 3 2 1 27 26 13.000
1.5 2.5 1.0 3.375 15.625 12.250 12.250
1.8 2.2 0.4 5.832 10.648 4.816 12.040
1.9 2.1 0.2 6.859 9.261 2.042 12.010
1.95 2.05 0.1 7.415 8.615 1.200 12.003

As may be seen, the value of the slope ∆-----y- tends towards a value of 12.000 as the
 ∆x 
magnitude of the incremental change in x becomes smaller around the chosen
value of 2.0. Were the chosen incremental changes in x infinitesimally small, the
true value of the slope (i.e., 12.000) would have appeared in the final column of
the above table.

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Calculus deals with infinitesimally small changes. When the value of ∆x is infini-
tesimally small it is written dx and is known as the derivative of x. Hence,

dy
------ = f ( x )
dx

Where dy/dx is the derivative of y with respect to x and f ( x ) indicates some func-
tion of x.

2.3.5 DIFFERENTIATION FROM FIRST PRINCIPLES

Differentiation is the process whereby the derivative of y with respect to x is


found. Thus the value of dy/dx, in this case, is calculated.
(a) Considering again the original expression:

3
y = x

(b) Let the value of y increase to y + dy because x increases to x + dx .

Hence,
3
y + dy = ( x + dx ) (EQ 2-13)

Multiplying out:
3 2 2 3
y + dy = x + 3x ( dx ) + 3x ( dx ) + ( dx ) (EQ 2-14)

(c) The change in y is obtained by subtraction of the original expression from the
last expression. (i.e., Eq. 2 - Eq. 1)
2 2 3
dy = 3x ( dx ) + 3x ( dx ) + ( dx ) (EQ 2-15)

Dividing throughout to obtain the derivative,

dy
------ = 3x 2 + 3x ( dx ) + ( dx )2
dx

When dx is infinitesimally small, its magnitude tends to zero ( dx → 0 ) . The limit-


ing value of this tendency must be dx = 0 . At this limit,

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Mathematics Review

dy
------ = 3x 2 (EQ 2-16)
dx

2
Hence the derivative of y with respect to x at any value of x is given by 3x .

(d) In section 2.3.4 we saw how the true value of the slope (i.e., dy/dx) would be
12.0 when x = 2 . This is confirmed by substituting in Equation 1-16.

dy
------ = 3x 2 = 3 ( 2 2 ) = 12
dx

2.3.6 RULE OF DIFFERENTIATION

Although the rate of change of one value with respect to another may be calculated
as above, there is a general rule for obtaining a derivative.

Let x be the independent variable value, y be the dependent variable value, A be a


constant, and n be an exponential power.

The general rule is:

n
If y = Ax

then

dy
------ = nAx n – 1
dx

The Rules of Indices may need to be used to obtain expressions in the form
n
y = Ax

(e.g., if y = 5 x)

2.3.7 THREE OTHER DERIVATIVES

0
(a) If y = Ax ,

then y = A (i.e., y is constant)

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dy
Hence, ------ = 0
dx

Thus the derivative of a constant is always zero.

(b) Accept that if y = ln ( x )

dy 1
then ------ = --- .
dx x

This derivative is important when considering apparent first-order processes, of


which many bodily processes (e.g., excretion of drugs) are examples.

Ax
(c) Accept that if y = Be where B and A are constants, and e is the natural
dy Ax
base then ------ = ABe
dx

This derivative will be useful in pharmacokinetics for finding the maximum and
minimum concentrations of drug in the blood following oral dosing.

2.3.8 A SEEMING ANOMALY

Consider the following two expressions:

n
(a) If y = Ax , then

dy n–1
------ = nAx
dx

n
(b) If y = Ax + A ,

dy n–1 n–1
then ------ = nAx + 0 = nAx
dx

Both of the original expressions, although different, have the same derivative. This
fact is recognized later when dealing with integral calculus.

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2.3.9 INTEGRAL CALCULUS

Generally integral calculus is the reverse of differential calculus. As such it is used


to sum all the infinitesimally small units (dy) into the whole value (y).

Thus,

∫ dy = y , where ∫ is the symbol for integration.

2.3.10 RULE OF INTEGRATION

The derivative expression may be written:

dy
------ = Ax n , or
dx

n
dy = Ax ⋅ dx

To integrate,

∫ dy ∫ Ax dx = A ∫ x dx
n n
y = =

A general rule states:

n+1
Ax
A ∫ x dx = ---------------- + A
n
n+1

Where A is the constant of integration However, there is one exception - the rule
is not applicable if n = – 1

dy 2
Example: If ------ = 3x (See section 2.3.5),
dx

2+1
3x
then y = --------------- + A , and
2+1

3
y = x +A

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2.3.11 THE CONSTANT OF INTEGRATION

There has to be a constant in the final integrated expression because of the seeming
3 3
anomaly referred to in section 2.3.8. As mentioned, both y = x and y = x + A
dy 2
will give, on differentiation, ------ = 3x .
dx

So whether or not a constant is present and, if so, what is its value, can only be
decided by other knowledge of the expression. Normally this other knowledge
takes the form of knowing the value of y when x = 0 .

In the case of our graphical example we know that when x = 0 , then y = 0 . The
integrated expression for this particular case is:

3
y = x + A , therefore

3
0 = 0 + A , thus A = 0

In some examples, such as first-order reaction rate kinetics, the value of A is not
zero.

2.3.12 THE EXCEPTION TO THE RULE

It occurs when n = – 1

1
y = A ∫ x dx = A ∫ --- dx
–1
x

Upon integration, y = A ⋅ ln ( x ) + A

This is the reverse of the derivative stated in section 2.3.10 (b).

2.3.13 A USEFUL INTEGRAL

Accept that if,

dy
------ = Be Ax
dx

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then,

Ax
Be
y = ----------- + A
A

This integral will be useful for equations which define the bioavailability of a drug
product.

2.3.14 EXAMPLE CALCULATIONS

(a) Consider,

2
c = 3t ( t – 2 ) + 5

Where c is the drug concentration in a dissolution fluid at time t .

Then, multiplying out,

3 2
c = 3t – 6t + 5

The rate of dissolution at time t is

dc
------ = 9t 2 – 12t
dt

So at any time, the rate may be calculated.

dc 2
(b) Consider, ------ = 3t ( t – 4 ) = 9t – 12t
dt

Then rearranging,

2
dc = 9t ⋅ dt – 12 ⋅ dt

The integral of c is:

∫ dc
3 2
c = = 3t + A – 6t + B

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where B is a second constant.

Adding the two constants together,

3 2
c = 3t = 6t + D

where D = A + B

We know, from previous work, that when t = 0 , then c = 5

Substituting 5 = D , the final expression becomes:

2 2
c = 3t + 6t + 5

Which is the initial expression in example (a) above.

(c) Following administration of a drug as an intravenous injection,

– dC p
------------- = KC p
dt

Where C p is the plasma concentration of a drug at time t

K is the apparent first-order rate constant of elimination.

Rearranging,

1
– K ⋅ dt = ------ ⋅ dC p
Cp

1
– Kt = – K ∫ dt = ∫ -----
- ⋅ dC p
Cp

This integral is the exception to the rule (see section 2.3.12).

– Kt = ln ( C p ) + A

We know that when t = 0 , C p = ( C p ) 0 .

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Substituting, 0 = ln ( C p )0 + A

Or,

A = – ln ( C p )0

Hence

– Kt = ln ( C p ) – ln ( C p ) 0

or,

ln ( C p ) = ln ( C p ) 0 – Kt

or,

– Kt
Cp = ( C p )0 ⋅ e

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2.4 Graphs
Why do we graph? We would like to organize the chaotic world around us so that we can predict (see
into the future) and retrodict (see into the past) what will happen or has happened.
Our recorded observations are collectively known as data. We make a theory
about what we think is happening and that theory is expressed in an equation. That
determines our paradigm of how we see the world. This paradigm is expressed as
a graph. The language of science is mathematics and graphs are its pictures.

TABLE 2-6

English Science
Observations Data
Theory Equations
Paradigms (pictures) Graphs

What is a graph? A graph is simply a visual representation showing how one variable changes with
alteration of another variable. The simplest way to represent this relationship
between variables is to draw a picture. This pictorializing also is the simplest way
for the human mind to correlate, remember, interpolate and extrapolate perfect
data. An additional advantage is it enables the experimenter to average out small
deviations in experimental results (non-perfect, real data) from perfect data. For
example:

TABLE 2-7 Perfect vs. Real data

Perfect Real
-3 -5 -4.6
-2 -3 -3.4
-1 -1 -0.6
0 +1 +0.8
+1 +3 +3.4
+2 +5 +4.4

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FIGURE 2-3. Plot of Perfect vs. Real data

-2

-4

-6
-3 -2 -1 0 1 2

Simply looking at the columns x and y (real) it might be difficult to see the rela-
tionship between the two variables. But looking at the graph, the relationship
becomes apparent. Thus, the graph is a great aid to clear thinking. For every graph
relating variables, there is an equation and, conversely for every equation there is a
graph. The plotting of graphs is comparatively simple. The reverse process of find-
ing an equation to fit a graph drawn from experimental data is more difficult,
except in the case of straight lines.

2.4.1 GRAPHICAL CONVENTIONS


How are graphs made? Certain conventions have been adopted to make the process of rendering a data set
to a graphical representation extremely simple.

The ‘y’ variable, known as the dependent variable, is depicted on the vertical axis
(ordinate); and the ‘x’ variable, known as the independent variable, is depicted on
the horizontal axis (abscissa). It is said that ‘y’ varies with respect to ‘x’ and not
‘x’ varies with ‘y’.

A decision as to which of the two related variables is dependent can only be made
be considering the nature of the experiment. To illustrate, the plasma concentration
of a drug given by IV bolus depends on time. Time does not depend on the plasma
concentration. Consequently, plasma concentration would be depicted on the ‘y’
axis and time on the ‘x’ axis.

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Any point in the defined space of the graph has a unique set of coordinates: 1) the
‘x’ value which is the distance along the ‘x’ axis out from the ‘y’ axis and always
comes first; and 2) the ‘y’ value which is the distance, along the ‘y’ axis up or
down from the ‘x’ axis, and always comes second. Several points are shown in
Figure 2. For example, (0,1) is on the line and (1,0) is not.

The intersection of x and y axis is the origin with the coordinates of (0,0). In two
dimensional spaces, the graph is divided into 4 quadrants from (0,0), numbered
with Roman numerals from I through IV. It should be readily apparent that the
coordinates for all points within a particular quadrant are of the same sign type i.e.,

TABLE 2-8 Quadrants on a cartesian graph


Quadrant II (-x, +y) Quadrant I (+x, +y)
Quadrant III (-x, -y) Quadrant IV (+x, -y)

A line (or curve) on a graph is made up of an infinite number of points, each of


which has coordinates that satisfy a given equation. For example, each point on the
line in Figure 2 is such at its coordinates fit the equation y = 2x + 1 . That is for
any value of x (the independent variable), multiplying the x value by 2 and adding
1 results in the y value (the dependent variable).

2.4.2 STRAIGHT LINE GRAPHS


What is a straight line? A graph is a straight line (linear) only if the equation from which it is derived has
the form

y = mx + b

Where:
• y = dependent variable
• x = independent variable
• m = slope of the straight line = ∆
-----y-
∆x
• b = the y intercept (when x = 0)
• or if the equation can be “linearized”, e.g.,

mx′
y′ = b′e is not linear. However. ln y′ = ln b′ + mx′

is of the same general form as: y = b + mx

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and consequently a plot of ln y′ (the dependent variable) versus x′ (the indepen-


dent variable) will yield a straight line with a slope of m and an intercept of ln b′ .

Expressions of any other form are non linear. For example:

An expression relating the plasma concentration of a drug ( C p ) over time ( t ) .

– Kt
C p = C p0 e

this relationship put in linear perspective yields:

ln C p = ln C p0 – Kt , which is in the form

y = b + mx

The graphs that yield a straight line are the ones with the ordinate being ln C p0 ,
and the abscissa being t .

Any other combination of functions of C p and t will be non-linear, e.g.,

• C p versus t

• C p versus ln t

• ln C p versus ln t

The appropriate use of a natural logarithm in this case serves to produce linearity.
However, the use of logarithms does not automatically straighten a curved line in
all examples. Some relationships between two variables can never be resolved into
( n – m) (n – m + 1) x
a single straight line, e.g., y = k 0 + k 1 x + k2 x + … + ( k n )x

where n ≥ 2 ;n = m + 1 or

K a FD Kt –K t
C p = ------------------------- ⋅ ( e – e a )
V ( Ka – K )

(It is possible to resolve this equation into the summation of two linear graphs
which will be shown subsequently.)

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2.4.3 THE SLOPE OF A LINEAR GRAPH (M)


What is the slope of a From the equation a prediction may be made as to whether the slope is positive or
straight line? negative. In the previous example, the slope is negative, i.e: m = – K

TABLE 2-9 Sample data of caffeine elimination

µg
C p  --------
t (min)  mL ln C p

12 3.75 1.322
40 2.80 1.030
65 2.12 0.751
90 1.55 0.438
125 1.23 0.207
173 0.72 -0.329

The differences in both the y-values and the x-values may be measured graphically
to obtain the value of the slope, m. Then knowing the value of m, the value of K
may be found.

FIGURE 2-4. Plasma Concentration ( C p ) of caffeine over time

101
g/mL)
u
Caffeine Concentration (

100

10-1
0 50 100 150 200

Time (min)

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2.4.4 LINEAR REGRESSION: OBTAINING THE SLOPE OF THE LINE


The equation for a straight line is:

y = m⋅x+b
• y is the dependent variable
• x is the independent variable
• m is the slope of the line
• b is the intercept of the line

The equation for the slope of the line using linear regression is:

( Σ ( x ) ⋅ Σ ( y ) ) – ( n ⋅ Σ ( x ⋅ y ) -)
m = --------------------------------------------------------------------
2 2
[ Σ ( x ) ] – ( n ⋅ Σ( x ) )

And the intercept is b = y – ( m ⋅ x )

TABLE 2-10 Linear Regression for data in table 2-9

2
X Y X X⋅Y
12 1.322 144 15.864
40 1.030 1600 41.2
65 0.751 4225 48.815
90 0.438 8100 39.42
125 0.207 15625 25.875
173 -0.329 29929 -56.917
ΣX = 505 ΣY = 3.239 2
ΣX = 59623 ΣXY = 114.257

2
( ΣX ) = 255025

Σx Σy
x = ------ = 4.167 y = ------ = 0.5398
n n

Using the data from table 2-10 in the equation for the slope of the line
( 505 ⋅ 3.239 ) – ( 6 ⋅ 114.257 ) ·
m = --------------------------------------------------------------------- = – 0.01014
255025 – ( 6 ⋅ 59623 )

and the intercept would be b = 0.5398 – ( – 0.01014 ⋅ 4.167 ) = 1.4229 .


Note that this is
ln C . In oder to find the C p0 , the anti-ln of b must be taken. i.e.
b 1.4229
Cpo = e = e = 4.15

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It is important to realize that you may not simply take any two data pairs in the
data set to get the slope. In the above data, if we simply took two successive data
pairs from the six data pairs in the set, this would result in five different slopes
( ∆x ⁄ ∆y ) ranging from -0.0066 to -0.0125 as shown in table 2-11. Clearly, this is
unacceptable. Even to guess, you must plot the data, eyeball the best fit line by
placing your clear straight edge through the points so that it is as close to the data
as possible and look to make sure that there are an equal number of points above
the line as below. Then take the data pairs from the line, not the data set.

TABLE 2-11 Sample slope data from figure 2-4

∆y
------
Time (x) ln Conc. (y) ∆x ∆y ∆x
12 1.322 -28 0.292 -0.0104
40 1.030 -25 0.28 -0.0112
65 0.751 -25 0.312 -0.0125
90 0.438 -35 0.231 -0.0066
125 0.207 -48 0.536 -0.0112
173 -0.329

2.4.5 PARALLEL LINES


Two straight lines are parallel if they have the same slope.

Calculating for the intercept of a linear graph (b):

(a) Not knowing the value of m; The graph may be extrapolated, or calcu-
lations performed, at the situation where t = 0 . In this case b = ln C p0 .

(b) Knowing the value of m;


• There are two ways: for any point on the graph: y 1 = mx 1 + b and b = y 1 – mx 1
Hence, b may be calculated from a knowledge of y 1 and x 1 .

• Secondly, the graph may be extrapolated or calculations performed, at the situation where
t = 0 . In this case, b = ln C p

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2.4.6 GRAPHICAL EXTRAPOLATIONS


How far can I predict? It is dangerous to extrapolate on non-linear graphs, and it is unwise to extrapolate
too far on linear graphs. Most often extrapolation is used to find the value of y at a
selected value of x.

If the size of the graph does not permit physical extrapolation to the desired value,
the required result may be obtained by calculation. The values of m and b must be
found as shown above. Then: y' = mx' + b , where x' is the selected value of x,
and y' is the new calculated value for y.

2.4.7 SIGNIFICANCE OF THE STRAIGHT LINE

The more closely the experimental points fit the best line, and the higher the num-
ber of points, the more significant is the relationship between y and x. As you may
expect, statistical parameters may be calculated to indicate the significance.
What good is a straight By using all the experimental data points, calculations may be made to find the
line? optimum values of the slope m, and the intercept, b. From these values the corre-
lation coefficient (r).and the t-value may be obtained to indicate the significance.
Exact details of the theory are available in any statistical book, and the calculations
may most easily be performed by a computer using The Scientist or PKAnalyst in
this course.

The advantage of computer calculation is that it gives the one and only best fit to
the points, and eliminates subjective fitting of a line to the data.

2.4.8 GRAPHICAL HONESTY


How many points are Any graph drawn from 2 points is scientifically invalid. Preferably, straight-line
needed? graphs should have at least 3 - 5 points, and non-linear graphs a few points more.
Can I discard points that As a graph is a visual representation which enables the experimenter to average
don’t fit? out the small deviations in results from the “perfect” result, no one result can be
unjustifiably ignored when the best fitting line is drawn. Still, an “errant” point
may be justifiably ignored if there were unusual experimental circumstances
which may have caused the deviation. Thus it is not justifiable to omit a point
solely because it “does not fit”.

2.4.9 AXES WITH UNEQUAL SCALES

In mathematical studies, the scales of the x and y are almost always equal but very
often in plotting chemical relations the two factors are so very different in magni-

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tude that this can not be done. Consequently, it must be borne in mind that the rela-
tionship between the variables is given by the scales assigned to the abscissa and
ordinate rather than the number of squares counted out from the origin.

FIGURE 2-5. y = 0.1 x

0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0 2 4 6 8 10

10
8
6
4
2
0
0 2 4 6 8 10

For example (shown in Figure 2-5), these two parabolic curves represent the same
equation the only difference is the scales are different along the y axis.

Frequently it is not convenient to have the origin of the graph coincide with the
lower left hand corner of the coordinate paper. Full utilization of the paper with
suitable intervals is the one criteria for deciding how to plot a curve from the
experimental data. For example, the curve below (Figure 2-6) is poorly planned,
where the following (Figure 2-7) is a better way of representing the gas law
PV = nRT

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FIGURE 2-6. Poorly presented graph

50
40
30
20
10
0
0 4 8 12 16 20

FIGURE 2-7. Well arranged graph

25
20
15
10
5
0
1 2 3 4 5 6 7 8 9 10

P ( )

2.4.10 GRAPHS OF LOGARITHMIC FUNCTIONS

2
Previously variables were raised to constant powers; as y = x . In this section
x
constants are raised to variable powers; as y = 2 . Equations of this kind in which
the exponent is a variable are called (naturally) exponential equations. The most
x
important exponential equation is where e is plotted against x .

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2.4.11 SEMILOGARITHMIC COORDINATES

Exponential or logarithmic equations are very common in physical chemical phe-


nomenon. One of the best ways of determining whether or not a given set of phe-
nomenon can be expressed by a logarithmic or exponential equation is to plot the
logarithm of one property against another property. Frequently a straight line is
obtained and its equation can be readily found. For example:

In the following table the plasma concentration ( C p ) of the immunosuppressant


cyclosporine was measured after a single dose (4mg/kg) as a function of time.

TABLE 2-12 Plasma concentration of cyclosporine

ng
Concentration ------
Time (hours) ml
0.25 1900
.75 1500
1.5 1300
4 900
6 600
8 390

D’mello et al., Res. Comm. Chem. Path. Pharm. 1989: 64 (3):441-446

These can be illustrated in three different ways (Figures 2-8, 2-9, 2-10),
• Concentration vs. time directly
• Log concentration vs. time directly
• Log concentration vs. time with concentration plotted directly on to log scale of ordinate.

FIGURE 2-8. Concentration (ng/ml) vs. time (hr)

2000
1800
1600
1400
1200
1000
800
600
400
200
0 1 2 3 4 5 6 7 8

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FIGURE 2-9. Log Concentration vs. time

3.200
Log Concentration - Time Curve
3.100
3.000
2.900
2.800
2.700
2.600
2.500
2.400
2.300
0 1 2 3 4 5 6 7 8

FIGURE 2-10. Log concentration (on log scale) vs. time

10000

1000

100
0 1 2 3 4 5 6 7 8

Graphing is much easier because the graph paper itself takes the place of a loga-
rithmic table, as shown in Figure 1-10.

Only the mantissa is designated by the graph paper. Scaling of the ordinate for the
characteristic is necessary. The general equation y = Be ax can be expressed as a
straight line by basic laws of indices.

ax
ln y = ln B + ln ( e ) → ln y = ln B + ax or ln y = ax + ln B

One axis is printed with logarithmic spacing, and the other with arithmetic spac-
ing. It is used when a graph must be plotted as in the example (Figure 1-4)
y = log [ C p ] and x = t .

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In this example, the vertical logarithmic axis is labelled “Plasma concentration of


cyclosporine” and the values plotted are the ordinary values of [ C p ] . Thus, there is
no need to use logarithmic tables, because the logarithmic spacing is responsible
for obtaining a straight line.

Two problems may occur when graphing on a logarithmic mantissa:

a) there are not enough cycles to incorporate all the data

b) obtaining the value of the slope is difficult. In this instance the slope is given by:

y2 – y1 ln [ C p ] 2 – ln [ C p ] 1
m = ---------------
- = --------------------------------------------
x2 – x1 t2 – t1

Hence, before calculating the value of m, the two selected values of [ Cp ] 1 and [ Cp ] 2
must be converted, using a calculator, to ln [ Cp ] 1 and ln [ C p ] 2 in order to satisfy the
equation. The same problem may arise in obtaining the intercept value, b.

The two problems may be avoided by plotting the same data on ordinary paper, in
which case the vertical axis is labelled “log plasma concentration”. However, in
this instance the ordinary values of [ C p ] must be converted to ln [ Cp ] prior to plot-
ting. It is the ln [ Cp ] values which are then plotted.

The calculation of the slope is direct in this case, as the values of y 1 and y 2 may be
read from the graph. Hence, one must consider the relative merits of semilogarith-
mic and ordinary paper before deciding which to use when a log plot is called for.

In the case of semilog graphs the slope may be found in a slightly different manner,
i.e., taking any convenient point on the line ( y 1 ) we usually take the as the second
point, ( y 2) one half of ( y 1 ) . Thus,

y1 
ln  ------------------- ln  ----------
- 1
ln y 1 – ln ( ( 1 ⁄ 2 )y 1 )  ( 1 ⁄ 2 )y 1  1⁄2 ln 2 - 0.693
m = ----------------------------------------------
- = ------------------------------
- = --------------------- = ------------- = -------------
t 1 – t2 t 1 – t2 t 1 – t2 t1 – t2 –t1 ⁄ 2

(in which case, t 2 – t 1 is called the half-life t½ ). Since t1 < t2 , then t1 – t2 = –t1 ⁄ 2
0.693 0.693
because m = ------------- = – k
–t1 ⁄ 2
and k = ------------- .
t1 ⁄ 2

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2.4.12 LOG - LOG COORDINATES

a
Functions of the type y = Bx give straight lines when plotted with logarithms
along both axis.

i.e., equation in logarithmic form is:

log y = log B + a log x or log y = a log x + log b which is in the form

y = mx + b . This is directly applicable to parabolic and hyperbolic equations


previously discussed (see Figure 1-5).

2.4.13 PITFALLS OF GRAPHING: POOR TECHNIQUE

The utility of these procedures requires proper graphing techniques. The picture
that we draw can cause formation of conceptualizations and correlations of the
data that are inconsistent with the real world based simply on a bad picture. Conse-
quently the picture must be properly executed.

The most common error is improper axes labelling. On a single axis of rectilinear
coordinate paper (standard graph paper), a similar distance between two points
corresponds to a similar difference between 2 numbers. Thus,

FIGURE 2-11. Graphing using standard number spacing

40
30
20
10
0
0 5 10 15 20 25 30

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FIGURE 2-12. Nonstandard (incorrect) graph

40
30
20
10
1

0
0 2 5 10 20 30

Obviously, the distance (Time) on the graph 12 between 0 and 2 hours should not
be the same as the distance between 10 and 20 hours. It is, and therefore Figure 2-
12 is wrong.

Similarly, the use of similar paper may result in some confusion. With logarithms
the mantissa for any string of numbers, differing only by decimal point placement,
is the same. What differentiates one number from another, in this case, is the char-
acteristic. Thus,

TABLE 2-13 Logarithmic graphing

Number Mantissa Characteristic Log


234 .3692 2 2.3692
23.4 .3692 1 1.3692
2.34 .3692 0 0.3692
0.234 .3692 -1 1.3692

The paper automatically determines the relationship between strings of numbers


(mantissa) by the logarithmic differences between the numbers on the axis within a
cycle. The student must determine the order of magnitude (characteristic) to be rel-
egated to each cycle.

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FIGURE 2-13. Logarithmic mantissa

Logarithmic Plot
103
234

102
23.4

101

Y axis (units)
2.34

100

0.234

10-1
1.0 1.5 2.0 2.5 3.0 3.5 4.0

X axis (units)

Thus, we see, in Figure 2-13, the cycle on the semilog paper to relate to orders of
magnitude (e.g., 1, 10, 100, 1000, etc.) and consequently the characteristic of the
exponent.

The third common problem is labelling the log axis as log “y”. This is improper. It
is obvious from the spacing on the paper that this function is logarithmic, and thus
the axis is simply labelled “y”.

There are almost as many different errors as there are students and it is impossible
to list them all. These few examples should alert you to possible problems.

2.4.14 GRAPHICAL ANALYSIS

We will look at several different types of plots of data:

FIGURE 2-14. Straight line going down on semi-log paper

0 1 2 3 4 5

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Find the slope by taking any two values on the Y axis such that the smaller value is
one half of the larger. The time that it takes to go from the larger to the smaller is
the half-life. Dividing 0.693 by the half-life yields the rate constant.

Extrapolating the line back to t = 0 yields the intercept.

FIGURE 2-15. Curved line which plateaus on semi-log paper.

0 2 4 6 8 10 12

FIGURE 2-16. Curved line which goes up and then straight down on semi-log paper.

0 5 10 15 20 25

Find the terminal slope by taking any two values on the Y axis such that the
smaller value is one half of the larger. The time that it takes to go from the larger to
the smaller is the half-life. Dividing 0.693 by the half-life yields the rate constant.

Plot type one is reasonably easily evaluated. There are 2 important things that can
be obtained: Slope and Intercept. However, the slope and intercept have different
meanings dependent on the data set type plotted. The slope is the summation of all
the ways that the drug is eliminated, -K.

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TABLE 2-14 Plot type 1 examples

Data Type Y axis X axis Slope Intercept


IV Bolus Parent Drug Conc. parent compound Time -K dose
C p0 = -----------
Vd
IV Bolus Parent dXu Time -K Kr ⋅ X 0
---------- urine rate of excretion
dt (mid)
parent compound
IV Bolus Parent Xu ∞ – Xu Cumulative urine Time -K kr
--------------
data K ⋅ X0

Plot type two is not usually evaluated in its present form as only the plateau value
can be obtained easily. But again it has different meanings dependent on the data
plotted.

TABLE 2-15 Plot Type 2 examples

Data Type Y axis X axis Plateau Value


IV Bolus Parent Xu Cumulative urine Time kr
Xu ∞ = --------------
data parent compound K ⋅ X0

IV Infusion Drug concentration Time Q Q


Parent parent compound ( C p )ss = ------------ = ----
K⋅V cl

Usually urine data of this type (parent compound - IV bolus) is replotted and eval-
uated as plot 1 (above). Infusion data can be replotted using the same techniques,
but usually is not.

Plot type 3 must be stripped of the second rate constant from the early time points,
thus:

There are 3 things that can be obtained from the plot: the terminal slope (the
smaller rate constant), the slope of the stripped line (the larger rate constant) and
the intercept. The rate constants obtained from a caternary chain (drug moving
from one box to another in sequence in compartmental modeling) are the summa-
tion of all the ways that the drug is eliminated from the previous compartment and
all the ways the drug is eliminated from the compartment under consideration. See
LaPlace Transforms for further discussion.

Again, dependent on the data set type being plotted they will have different values.

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TABLE 2-16 Plot Type 3 examples

Data
Type Y axis X axis S1 S2 Intercept
IV Bolus Metabolite conc. Time -K small -Klarge km ⋅ X 0
Parent -------------------------------------------------------
( K l arg e – K smal l ) ⋅ V dm

IV Bolus dXmu
--------------- excretion
Time -K small -Klarge k mu ⋅ k m ⋅ X 0
Parent dt (mid) -----------------------------------
-
K l arg e – K smal l
rate of metabolite
into urine
Oral Drug conc. Time -K small -Klarge k a ⋅ fX 0
---------------------------------------------------
-
( K l arg e – K smal l ) ⋅ V d

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2.5 Pharmacokinetic MoKdeling


It has been observed that, after the administration of a drug, the concentration of
the drug in the body appear to be able to be described by exponential equations.
Thus, it appears that, even though the processes by which the drug is absorbed. dis-
tributed, metabolized and excreted (ADME) may be very complex, the kinetics
(math) which mimics these processes is made up of relatively simple first order
processes and is called first order pharmacokinetics. A second observation is that
the resulting concentration is proportional to dose. When this is true, the kinetics is
called linear. When this math is applied to the safe and effective therapeutic man-
agement of an individual patient, it is called clinical pharmacokinetics. Thus, in
clinical pharmacokinetics, we monitor plasma concentrations of drugs and suggest
dosage regimens which will keep the concentration of drug within the desired ther-
apeutic range. Pharmacodynamics refers to the relationship between the drug con-
centration at the receptor and the intensity of pharmacological (or toxicological)
response. It is important to realize that we want to control the pharmacological
response. We do that indirectly by controlling the plasma concentration. In order
for this to work, we assume kinetic homogeneity, which is that there is a predict-
able relationship between drug concentration in the plasma (which we can mea-
sure) and drug concentration at the receptor site (which we can not measure). This
assumption is the basis for all clinical therapeutics.

Models are simply mathematical constructs (pictures) which seem to explain the
relationship of concentration with time (equations) when drugs are given to a per-
son (or an animal). These models are useful to predict the time course of drugs in
the body and to allow us to maintain drug concentration in the therapeutic range
(optimize therapy). The simplest model is the one used to explain the observations.
We model to summarize data, to predict what would happen to the patient given a
dosage regimen, to conceptualize what might be happening in disease states and to
compare products. In every case, the observations come first and the explanation
next. Given that a data set fits a model, the model can be used to answer several
different types of questions about the drug and how the patient handles the drug
(its disposition), for example: if the drug were to be given by an oral dose, how
much is absorbed and how fast? Are there things which might affect the absorp-
tion, such as food or excipients in the dosage form itself. What would happen if the
drug were to be given on a multiple dose regimen? What if we increased the dose?
etc.

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You should be able to:


• be facile in the use of the equations. You should be able to graphically manipulate data sets and
extract pharmacokinetic parameters, applying the appropriate equations or variations of them.
• define all new words used in this section. e g.: Succinctly define, stating rigorously the meaning
of any symbols used and the dimensions of measurement.
• compare and contrast new concepts used in this section. e. g.: rate and rate constant, zero and
first order kinetics, bolus and infusion methods, excretion and elimination, the assumptions
made in pharmacokinetic models with physiological reality. Why can these assumptions be
made?
• pictorially represent any two variables (graph) one vs. the other. e.g. for each of the following
pairs of variables (ordinate against abscissa), draw a graph illustrating the qualitative profile of
their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and
values. Unless you specifically indicate on your plot that semi-log paper is being considered
(write “S-L”), it will be assumed that rectilinear paper is being considered. Graphs are for a
drug given by IV Bolus where applicable.

2.5.1 MAKING A MODEL

The differential equations used result from the


ka model which is our conceptualization of what is
X happening to the drug in the body.

The box (compartment) is the area of interest. We


want to find out how the mass of drug, X , changes
with time in that compartment, the rate, and how the rates change with time, the
differential equations.
How do we make a dif- The picture that we build is made up of building blocks, consisting of the arrow
ferential equation? and what the arrow touches. The arrow demonstrates how quickly the mass of
drug, X , declines. The arrow times the box that the arrow touches = the rate. Rates
can go in, i.e. arrows pointing to a box mean drug is going in (+ rate). Rates can go
out, i.e. arrows pointing away means drug is going out (- rate). Rate = rate constant
(arrow) times mass of drug (box). So the arrow and box really is a pictorial repre-
sentation of a rate where the rate is the rate constant on the top of the arrow times
what the tail of the arrow touches.

Again, the rate constant, k , tells the magnitude of the rate, k⋅X.

Consider the following simple chain:

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k12 k23
X1 X2 X3

The building blocks are k 12 ⋅ X1 and k 23 ⋅ X2 . Every arrow that touches the compart-
ment of interest becomes part of the differential equation. If the arrow goes to the
box, it’s positive; if it goes away from the box, it’s negative.

To find dX1 ⁄ dt (the rate of change of X 1 with time), we simply add up all of the
rates which affect X1 (all of the arrows that touch X1 )

dX 1
--------- = – k 12 ⋅ X 1
dt

and thus:

dX 2
--------- = k 12 ⋅ X 1 – k 23 ⋅ X2
dt

dX 3
--------- = k 23 ⋅ X 2
dt

(Note: the first subscript of the rate constant and the subscript of the box from
which it originates are the same.)

You should be able to develop the series of interdependent differential equations


which would result from any model. The integration of those equations by use of
the Laplace Table is done by transforming each piece of the equation into the
Laplace domain (looking it up on the table and substituting). The algebra per-
formed solves for the time dependent variable: put everything except the variable
(including the operator, s) on the right side and put the variable on the left. Find the
resulting relationship on the left side of the table. The corresponding equation on
the right side of the table in the integrated form.

You should be able to integrate any differential equation developed from any
model (within reason) that we can conceptualize.
(Note: Each subsequent variable is dependent on the ones that precedes it. In fact,
the solutions to the preceding variables are substituted into the differential to
remove all but one of the time dependent functions - the one that we are currently
attempting to solve.)

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2.5.2 ONE COMPARTMENT OPEN MODEL

A simplified picture (mathematical construct) of the way the body handles drug is
one where the body can be conceived to be a rapidly stirred beaker of water (a sin-
gle compartment). We put the drug in and the rate at which the drug goes away is
proportional to how much is present (first order). Thus the assumptions are:
• Body homogeneous (one compartment)
• Distribution instantaneous
• Concentration proportional to dose (linear)
• Rate of elimination proportional to how much is there. (First order)

It is important to note that we know some of these assumptions are not true. It is of
little consequence, as the data acts as if these were true for many drugs. The visual
image which is useful is one of a single box and a single arrow going out of the
box depicting one compartment with linear kinetics. The dose is placed in the box
and is eliminated by first order processes. In many cases, more complicated mod-
els (more boxes) are necessary to mathematically mimic the observed plasma ver-
sus time profile when one or more of these assumptions are not accurate. For
example, the two compartment (or multi-compartment) model results when the
body is assumed to not be homogeneous and distribution is not instantaneous.

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2.6 The LaPlace Transform


Why do we need to One of the important facets of biopharmaceutics is a familiarity with the principles
know the LaPlace trans- of pharmacokinetics. This latter discipline describes the study of the dynamic pro-
form? cesses by which the body “handles” or “disposes of” an administered drug. These
processes (absorption, distribution, metabolism, and excretion (ADME) are
dynamic in that they represent the time-dependent changes occurring to the drug.
Thus, in pharmacokinetics the time course of these changes, which overall
describe the fate of the administered drug, is described mathematically. If the
mathematical principles are understood, it is then possible to use pharmacokinetics
in clinical practice, such as the design of rational dosage regimens (T.S. Foster and
D.U.A. Bourne, Amer. J. Hosp. Pharm., 34, 70-75 (1977). Understanding
(Bloom’s level 4) is not simply memorizing (Bloom’s level 1) nor calculating
using a memorized equation (Bloom’s level 3). The authors believe that the proper
conceptualizing of the process and the subsequent derivation of the appropriate
equations will lead to an understanding of the mathematical principles, and thus, a
better, more optimal dosing regimen.

Since a mathematical description of the time-dependent ADME processes is


required, it becomes necessary to deal with their corresponding rate equations.
Inevitably this will involve calculus (mainly integral calculus). However, the
LaPlace Transform provides a method whereby calculus can be performed with
minimal trauma. If a conscientious effort to learn the method is made and applied,
a potentially serious obstacle (the fear of calculus) to the understanding and appre-
ciation of biopharmaceutics will be removed. Indeed, many students will find they
no longer fear integration and are thus free to comprehend the principles underly-
ing pharmacokinetics, which, after all, is the primary aim. So, the LaPlace Trans-
form is a tool which is of great assistance in pharmacokinetics; its utility and
importance should not be lightly disregarded.
The LaPlace Trans- There is, of course, a theoretical background to the LaPlace Transform. However,
form: What Is It? it can be used without recourse to a complete theoretical discussion, though appro-
priate pharmaceutical use of the method is found in the following references:

M. Mayersohn and M. Gibaldi, Amer. J. Pharm. Ed., 34, 608-614 (1970).

M. Gibaldi and D. Perrier, “Pharmacokinetics”, Marcel Dekker, pp. 267-272


(1975).

Basically, the LaPlace Transform is used to solve (integrate) ordinary, linear differ-
ential equations. In pharmacokinetics such equations are zero and first-order rate
equations in which the independent variable is time. For instance, if a differential
equation describing the rate of change of the mass of drug in the body with time is

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integrated, the final equation will describe the mass of drug actually in the body at
any time.

The procedure used is to replace the Independent variable (time) by a function


containing the LaPlace Operator, whose symbol is “s”. In doing so we have
replaced the time domain by a complex domain. This is analogous to replacing a
number by its logarithm. Once in the complex domain, the transformed function
may be manipulated by regular algebraic methods. Then the final expression in the
complex domain is replaced by its equivalent in the time domain, yielding the inte-
grated equation. This ultimate process is analogous to taking an antilogarithm.

2.6.1 TABLE OF LAPLACE TRANSFORMS


A table of useful LaPlace The replacement of expressions in one domain by their equivalents in another is
transforms is given in accomplished by reference to tables. One column shows time domain expressions,
Section 2.7. Page 2-56.
stated as f ( t ) , and second column shows the corresponding complex domain
expressions, stated as the LaPlace Transform. Note that “ f ( t ) ” simply means
– at
“some function of time”. For example, when f ( t ) is Be , then the LaPlace
Transform is B ⁄ ( s + a ) , where “B” is a constant and “a” is a rate constant

For example, when the LaPlace Transform is A⁄s


2
, then f ( t ) is At .

2.6.2 SYMBOLISM

For simplicity in writing transformed rate expressions (and to distinguish them


from untransformed (time domain) expressions), the following symbolism will be
employed:

“a bar will be placed over the dependent variable which is being transformed”.

Example:

If X is the mass of unchanged drug in the body at any time, then X is the LaPlace
Transform of this mass.

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2.6.3 CONVENTIONS USED IN DRAWING PHARMACOKINETIC SCHEMA.

When drugs enter the body, they will encounter many different fates. It is impor-
tant to set up the possible fates of the drug by creating a well thought out flow
chart or scheme in order to follow all the events that are occurring in the body as
described by the pharmacokinetic description of the drug. For example, a drug
may be excreted unchanged or may undergo hepatic metabolism to yield active or
inactive metabolites. All of these components are part of pharmacokinetics, which
by definition, includes ADME (the Absorption, Distribution, Metabolism and
Excretion of drugs), and must be considered. This flow chart becomes the back-
bone or the framework upon which to build the equations which describe the phar-
macokinetics of the drug. The differential equations result as a direct consequence
of the flow chart. Using Laplace transforms, the integration of these differential
equations are simplified and provide the pharmacokineticist to (easily?) keep track
of all of the variables in the equation. If the drug scheme or flow chart is set up
incorrectly, this would have a definite negative impact or the expected equations
(as well as the answers and your grade). Below are two examples of how to con-
struct a flow chart. Note that not all drugs follow the same flow chart and it is
quite possible that you will need only to use a portion of these examples when con-
struction your own.

In general, schema are relatively consistent in the placement of the compartments


in relationship to one another. You might consider, for example a drug, given by
IV bolus, which is metabolized and both the metabolite and the parent compound
are excreted unchanged as shown below:
Feces Body Urine

Dose

Parent Compound kf ku
Xf X Xu

km
kmf kmu
Metabolite Xmf Xm Xmu

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Using the pharmacokinetic symbolism from chapter one, the compartments are
named and placed: metabolites below (or above the plane of the parent com-
pound): compounds going into the urine, to the right; and compounds going into
the feces, to the left of the compounds in the body. The rate constants connecting
the compartments also follow the symbolism from chapter one. In the above flow
chart, K, the summation of all the ways that X is removed from the body, is ku + kf
+ km while K1, the summation of all the ways that Xm is removed from the body,
is kmu +kmf.

Only those compartments are used which correspond to the drug’s pharmacoki-
netic description, thus when a drug is given by IV bolus and is 100% metabolized
with the metabolite being 100% excreted into the urine the model would look like
this:

Dose

km

kmu
Xm Xmu

Thus in this flow chart, K, the summation of all the ways that X is removed from
the body, is km while K1, the summation of all the ways that Xm is removed from
the body, is kmu.

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Drugs sometimes are metabolized to two (or more) different metabolites. In the
first case, the drug is metabolized by two separate pathways resulting in this flow
chart:

Xmf1 kmf1 Xm1 kmu1 Xmu1

Dose
km1

kf X ku Xu
Xf

km2

kmf2 kmu2 Xmu2


Xmf2 Xm2

In this flow chart, K, the summation of all the ways that X is removed from the
body, is ku + kf + km1 + km2 while K1, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1 and K3, the summation of all the ways
that Xm2 is removed from the body, is kmu2 + kmf2.

While in a second case, the drug is metabolized and the metabolite is further
metabolized resulting in this flow chart:
Dose

kf X ku Xu
Xf

km1

kmf1 kmu1
Xmf1 Xm1 Xmu1

km2

kmf2 kmu2 Xmu2


Xmf2 Xm2

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In this flow chart, K, the summation of all the ways that X is removed from the
body, is ku + kf + km1 while K1, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1+ km2 and K3, the summation of all the
ways that Xm2 is removed from the body is kmf2 + kmu2.

Both of these flow charts result in very different end equations, so it is imperative
that the flow charts accurately reflect the fate of the drug.

2.6.4 STEPS FOR INTEGRATION USING THE LAPLACE TRANSFORM


• Draw the model, connect the boxes with the arrows depicting where the drug goes.
• The building blocks of the differential rate equations are the arrows and what the tail touches.
• Write the differential rate equation for the box in question. The box is on the left side of the
equal sign and the building blocks are on the other. If the arrow goes away from the box, the
building block is negative, if it is going towards the box, the building block is positive.
• Take the LaPlace Transform of each side of the differential rate equation, using the table where
necessary.
• Algebraically manipulate the transformed equation until an equation having only one trans-
formed dependent variable on the left-hand side is obtained.
• Convert the transformed expression back to the time domain, using the table where necessary to
yield the Integrated equation.

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2.6.5 EXAMPLE INTEGRATION USING THE LAPLACE TRANSFORM

Following an intravenous injection of a drug (bolus dose), its excretion may be


represented by the following pharmacokinetic scheme:

(Scheme I)
ku
X Xu

Where X is the mass of unchanged drug in the body at any time.

X u is the cumulative mass of unchanged drug in the urine up to any time, and k u is
the apparent first-order rate constant for excretion of unchanged drug.

Consider how the body excretes a drug

a. The building block is the arrow and what it touches. This first box (compart-
ment) of interest is [ X ] . The arrow ( k u) is going out, therefore, the rate is going out
and is negative, thus

dX
------- = –k u X (EQ 2-17)
dt

The negative sign indicates loss from the body.

Taking the LaPlace Transform of each side of equation 2-17:

sX – X0 = – k u X (EQ 2-18)

Note that because the independent variable (time) did not appear on the right-hand
side of equation 2-17, neither did the LaPlace Operator, s, appear there in equation
2-18. All that was necessary was to transform the dependent variable ( X ) into X .
Hence, the table was only required for transforming the left-hand side of equation
2-18.

Manipulating the transformed equation:

1. Get only one variable which changes with time (X)

2. Get X on the left and everything else on the right.

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sX + k u X = X0

X ( s + k u ) = X0

X0
X = ------------- (EQ 2-19)
s + ku

A
LetX0 = A Letk u = a X = ---------------- (EQ 2-20)
(s + a)

Note that X is the only transformed dependent variable and is on the left-hand side
of equation 2-19.

Converting back to the time domain:

–ku t
X = X0e (EQ 2-21)

A
Note that the right-hand side of equation 2-21 was analogous to ---------------- in the
(s + a)
table, because X0 is a constant (the initial dose administered). The left-hand side
of equation 2-21 could be converted back without the table.

The final expression is the familiar first-order integrated expression.

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2.6.6 SECOND EXAMPLE INTEGRATION USING THE LAPLACE


TRANSFORM

Look at Scheme I again. Consider how the drug goes from the body into the urine.
The next box of interest is Xu . The arrow is coming in, therefore the rate is com-
ing in and is positive. thus,

dXu
--------- = k u X (EQ 2-22)
dt

(b) Taking the LaPlace Transform of each side of equation 2-22:

sX u – ( X u ) 0 = k u X (EQ 2-23)

But, at zero time, the cumulative mass of unchanged drug in the urine was zero:
that is ( Xu ) 0 = 0 .

sX u = k u X (EQ 2-24)

(c) Manipulating the transformed equation:

ku X
Xu = --------
- (EQ 2-25)
s

Note that there are two transformed dependent variables. One of them ( X ) can be
replaced by reference to equation 2-19.

ku X0
Xu = --------------------
- (EQ 2-26)
s(s + ku)

A
Let ( k u X0 ) = A Let ( k u ) = a X = ------------------- (EQ 2-27)
s(s + a)

(d) Converting back to the time domain:

–k t
kuX0 ⋅ ( 1 – e u )
X u = ----------------------------------------
ku

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Where k u X 0 and k u are analogous to “A” and “a” respectively in the table. Sim-
plifying,
– kut
Xu = X0 ( 1 – e ) (EQ 2-28)

2.6.7 THIRD EXAMPLE INTEGRATION USING THE LAPLACE TRANSFORM

During the intravenous infusion of a drug, its excretion may be represented by the
following pharmacokinetic scheme:
(Scheme II)

Infusion Q ku
X Xu

Where Q is the zero-order infusion rate constant (the drug is entering the body at a
constant rate and the rate of change of the mass of drug in the body is governed by
the drug entering the body by infusion and the drug leaving the body by excretion).
The drug entering the body does so at a constant (zero-order) rate.

dX
------- = Q – k u X (EQ 2-29)
dt

(b) Taking the LaPlace Transform of each side of equation 2-29:

Q
sX – X 0 = ---- – k u X
s

Note that because Q is a rate, and is therefore a function of the independent vari-
able (time), its transformation yields the LaPlace Operator. In this case, Q was
analogous to “A” in the table. But, at zero time, the mass of unchanged drug in the
body was zero: that is, X0 = 0

Q
sX = ---- – k u X (EQ 2-30)
s

(c) Manipulating the transformed equation:

Q
X = --------------------- (EQ 2-31)
s ( s + ku )

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A
Let ( Q = A ) Let ( k u = a ) X = ------------------- (EQ 2-32)
s( s + a)

(d) Converting back to the time domain:


–k t
Q(1 – e u )
X = ----------------------------- (EQ 2-33)
ku

2.6.8 CONCLUSIONS

The final integrations (Eqs. 24, 24, and 28) are not the ultimate goal of pharmaco-
kinetics. From them come the concepts of:
1. (a) elimination half-life
1. (b) apparent volume of drug distribution
2. (c) plateau drug concentrations

These, and other concepts arising from still other equations, are clinically useful.

Once the method of LaPlace Transforms is mastered, it becomes easy to derive


equations given only the required pharmacokinetic scheme. Under such circum-
stances, it no longer becomes necessary to remember a multitude of equations,
many of which, though very similar, differ markedly in perhaps one minute detail.
As with any new technique, practice is required for its mastery. In this case, mas-
tery will banish the “calculus blues.”

It is also possible to see certain patterns which begin to emerge from the derivation
of the equations. For example, for a drug given by IV bolus the equation is
monoexponential, with the exponent being K, summation of all the ways that the
drug is removed form the body. A graph of the data (Cp v T on semi-log paper)
results in a straight line the slope of which is K, always. If the drug is entirely
metabolized K = km. If the drug is entirely excreted unchanged into the urine, K =
ku. If the drug is metabolized and excreted unchanged into the urine, K = km +ku.
thus K can have different meanings for different drugs, depending on how the
body removes the drug. Following the drug given by IV bolus a second example
of a pattern would be that of the data of the metabolite of the drug. From the
LaPlace, the equation for the plasma concentration of the metabolite of the drug
has in it K and K1, the summation of all the ways that the metabolite is removed
from the body, always. K1 would have different meanings depending on how the
metabolite is removed from the body.

Basic Pharmacokinetics REV. 00.1.6 2-57


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Mathematics Review

After several years teaching, I was fortunate to have a resident rotate through our
pharmacokinetic site. She had come with a strong Pharmacokinetcs background
and during our initial meeting, she had told me that she had a copy of John Wag-
ner’s new textbook on pharmacokinetcs. She was excited that, finally, there was a
compilation of all the equations used in pharmacokinetics in one place.

“There are over 500 equations in the new book and I know every one,” she said.
“I’m not sure which one goes with which situation, though.” OOPS!

Throughout this text and on each exam, each equation is derived from first princi-
ples using scientific method, modeling and LaPlace Transforms in the hopes that
memorization will be minimized and thought (and consequently proper interpreta-
tion) would be maximized.

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Mathematics Review

2.6.9 TABLE OF LAPLACE TRANSFORMS


A, B are constants

a, b, c are rate constants ( a ≠ b ≠ c )

s is the LaPlace Operator

x is a variable, dependent on time ( t )

m is a power constant

TABLE 2-17 Table of LaPlace Transforms

Time Function, F ( t ) LaPlace Transform, f ( s )

A A
---
s
At A-
---
2
s

At
m A ( m! -)
--------------
m+1
s
– at A-
Ae ----------
s+a
m – at A
At e --------------------------
-
m+1
(s + a)
– at A
A(1 – e ) -------------------
-------------------------- s (s + a )
a
– at A -
At (1 – e )
----- – A
-------------------------- --------------------
2
a a
2 s (s + a)
– at As – B-
– at B( 1 – e ) ------------------
Ae – -------------------------- s (s + a )
a
– at As – B -
A + B
---  ------------------ – Bt
1–e
----- --------------------
 a   a  a
2
s (s + a)

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TABLE 2-17 Table of LaPlace Transforms

Time Function, F ( t ) LaPlace Transform, f ( s )

– bt – at A
A ( e – e )- --------------------------------
-
-------------------------------- (s + a)(s + b)
(a – b)
– bt – at A
A
----------------  1-----------------
– e -  -----------------
1 – e - -----------------------------------
-
(a – b)  b  –
a  s( s + a )( s + b )

 1 – e –bt  1 – e –at A
At- ----------------
A -------------------------------------
-
----- –  ------------------ –  ------------------ 2
s ( s + a) ( s + b)
ab ( a – b )  b2   a2 

1 – at – bt As – B -
---------------- [ ( B + Aa )e – ( B + Ab )e ] --------------------------------
( a – b) (s + a)(s + b)
As – B -
1  ( 1 – e –bt ) ( 1 – e – at )  -----------------------------------
---------------- – bt – at
A ( e – e ) – B  ---------------------- – ----------------------  s( s + a )( s + b )
(a – b)  b a 

  ( 1 – e –bt )  ( 1 – e – at ) As – B
1 B B Bt --------------------------------------
( a – b )  b   ----------------------
---------------- A + --
- ---------------------- – A + --
- – ------ 2
s ( s + a) ( s + b)
b  a  a ab

– ct – bt – at A
e e e -------------------------------------------------
-
A --------------------------------- + --------------------------------- + --------------------------------- (s + a)(s + b)(s + c)
(a – c)(b – c) (a – b )(c – b) (b – a )(c – a)
– ct – bt – at A
(1 – e ) (1 – e ) (1 – e ) ----------------------------------------------------
A ------------------------------------ + ------------------------------------- + ------------------------------------- s( s + a )( s + b )( s + c )
c( a – c )( b – c ) b( a – b)( c – b ) a( b – a )( c – a)
– ct – bt – at A
At- (1 – e ) ( 1 – e ) - --------------------------------------
(1 – e ) - ------------------------------------------------------
-
----- – A -------------------------------------- + -------------------------------------- + 2 2
bc 2 2 s ( s + a) ( s + b ) ( s + c )
c ( a – c) ( b – c ) b ( a – b) ( c – b) a ( b – a )( c – a)
dX
------- sX – X 0
dt
(m + 1 ) A
At -----
------------------- m
(m + 1) s

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2.6.10 LAPLACE TRANSFORM PROBLEMS

By means of the LaPlace Transform, find the equation for:


1. The amount of drug in the body when the drug is given by IV Bolus (assume no metabolism).
2. The amount of drug in the urine when the drug is given by IV Bolus (assume no metabolism).
3. The amount of metabolite in the body when the drug is given by IV Bolus (assume no parent
drug excretion)
4. The amount of metabolite of the drug in the urine when the drug is given by IV Bolus (assume
no parent drug excretion)
5. The amount of metabolite of the drug in the urine when the drug is given by IV Bolus (assume
both parent drug and metabolite excretion)
6. The amount of drug in the body when the drug is given by IV infusion (assume no metabolism).
7. The amount of drug in the urine when the drug is given by IV infusion (assume no metabolism).
8. The amount of metabolite in the body when the drug is given by IV infusion (assume no parent
drug excretion).
9. The amount of metabolite in the urine when the drug is given by IV infusion (assume no parent
drug excretion).
10. The Rate of excretion of the metabolite into the urine for a drug given by IV bolus when
km+ku=kmu.
11. The amount of the principle metabolite (Xm1) when the drug is eliminated by several pathways
(Xu, Xm1,Xm2,Xm3,etc)
X
12. The concentration of drug, ------ , in the body when the drug is given orally by a delivery system
Vd
which is zero order. What is the concentration at equilibrium ( T ∞ ).
13. The amount of metabolite of a drug in the body when the drug is given by IV Bolus and con-
comitant IV infusion.
14. Disopyramide (D) is a cardiac antiarrythmic drug indicated for the suppression and prevention
of ectopic premature ventricular arrythmias and ventricular tachycardia. It appears that disopy-
ramide is metabolized by a single pathway to mono-dealkylated disopyramide (MND). In a
recent study, the pharmacokinetics of disopyramide were attempted to be elucidated by means
of a radioactive tracer. Since both D and MND would be labeled by the tracer, any equations
showing the time course of the label would show both the D and MND. By means of the
laPlace transform, find the equation for the rate of appearance of tracer into the urine if the drug
were given by IV Bolus.

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2.6.11 LAPLACE TRANSFORM


SOLUTIONS
1. The amount of drug in the body when the drug is given
by IV bolus (assume no metabolism).

Dose

X ku Xu

X = Xo At time zero, all of the IV bolus is in the com-


partment.
Here K = ku
dX
------- = – k u X
dt

sX – X0 = –kuX

sX + kuX = X o

X ( s + k u )= Xo

Xo
X = -------------
s + ku

A
Let ( X0 ) = A , k u = a ,X = ----------------
(s + a)
– kut
X = Xo e

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2. the amount of a drug in the urine when the drug is – kut


Xu= Xo ( 1 – e )
given by IV bolus (assume the drug is NOT metabolized

Dose

X ku Xu

NOTE: You must start where the drug is at time = 0.


Again K = ku

dX
------- = – k u X
dt

sX – X0 = –kuX

sX + kuX = X o

X ( s + k u )= Xo

Xo
X = ------------- You only need to go this far because you
s + ku
need to know X to put it in the equation for Xu. Thus:

dX
--------u- = k u X
dt

sX u – Xuo = k u X (Xuo = 0. No drug in urine at time = 0)

sX u = k u X Substituting from above for X.

X o ku
sX u = -----------------
-
(s + ku)

Xo ku
X u = --------------------
-
s(s + ku)

A
Let ( X0 k u ) = A , k u = a , X u = -------------------
s( s + a )
– kut
ku X o ( 1 – e )
X u = ------------------------------------
-
ku

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3. the amount of metabolite of a drug in the body km X 0


when the drug is given by IV bolus (assume no parent sX m = -------------- – k mu Xm Substituting for X from above
drug excretion). s + km

km ⋅ Xo
X m = -----------------------------------------
-
( s + k mu ) ( s + k m )
Dose Let ( k m X 0 ) = A , k m = a = K , k mu = b = K1

A
X m = ---------------------------------
X (s + a)(s + b )
( km ⋅ X o ) –k t –k t
- ⋅ ( e mu – e m ) or
X m = ------------------------
km ( k m – k mu )

( km ⋅ Xo )
Xm kmu Xmu - ⋅ ( e – K 1t – e –K t ) in general terms.
X m = ---------------------
( K – K1 )

Remember: NOTE: We could also:


You must start where the drug is at time = 0. Let ( k m X 0 ) = A , k m = b , k mu = a
Here K = km and K1 = kmu
and then
dx
------ = – k m X
dt ( km ⋅ X o ) –k t –k t
X m = ------------------------- ⋅ ( e m – e mu ) or
( k mu – k m )
sX – Xo = – k m X
( km ⋅ Xo )
sX + k m X = Xo - ⋅ ( e – K t – e –K1t )
X m = ---------------------
( K1 – K )
X ( s + km ) = Xo Both of those equations are identical.

Xo
X = --------------
s + km

A
Let ( X0 ) = A , k m = a , X = ----------------
(s + a)
– kmt
X = Xo e

dX
---------m- = k m X – k mu X m
dt

sX m – Xm0 = k m X – kmu X m

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4. the amount of metabolite of a drug in the urine X om = 0


when the drug is given by IV bolus (assume the parent
compound is not excreted). sX mu = k mu X m
Here, again, K = km and K1 = kmu
( k mu ) ( k m X o )
sX mu = -----------------------------------------
-
( s + k mu ) ( s + k m )
Dose
( k mu ) ( k m ) ( X o )
X mu = --------------------------------------------
-
s ( s + kmu ) ( s + k m )
X
k mu k m Xo  1 – e –kmt 1 – e –kmut
-  --------------------- – -----------------------
X mu = --------------------
k mu – k m  k m k mu 
km

Xm kmu Xmu

dXm
----------- = k m X – k mu X m
dt

sX m – Xom = k m X – kmu X m

sX m + k mu Xm = k m X

o X
substitute previously solved X = --------------
s + km

km Xo
X m ( s + k mu ) = --------------
s + km

km X o
X m = -----------------------------------------
-
( s + k mu ) ( s + k m )
– kmt – kmut
km Xo ( e –e )
X m = --------------------------------------------------
-
( k mu – k m )

dXmu
------------
- = k mu Xm
dt

sX mu – Xom = k muX m
Remember at time zero,

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5. the amount of metabolite of a drug excreted in dX mu


the urine when both the parent and metabolite are ------------- = k mu Xm
excreted.
dt

Here K = km + ku and K1 = kmu sX mu – Xom = k muX m = K1Xm

sX mu = K1X m
Dose
( k mu ) ( kmXo )
sX mu = --------------------------------------
( s + K1 ) ( s + K )
ku Xu
X ( k mu ) ( k m ) ( Xo )
X mu = ----------------------------------------
-
s ( s + K1 ) ( s + K )
km
k mu k m X o 1 – e – Kt 1 – e – K1t
X m u = ----------------------  ------------------- – ---------------------
K1 – K  K K1 
Xm kmu Xmu

dX
------- = – k u X – k m X
dt

sX – Xo = – k u X – k m X

sX + k u X + k m X = X o

X ( s + ku + km ) = Xo

( ku + km ) = K

Xo
X = ------------
s+K
– Kt
X = Xo e

dXm
------------ = k m X – k mu Xm = k m X – K1Xm
dt

sXm – X om = k m X – K1Xm

sX m + K1Xm = k m X

km Xo
X m = --------------------------------------
( s + K1 ) ( s + K )

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Mathematics Review

6. The amount of drug in the body from a drug given by


IV infusion (assume no metabolism).

Q X ku Xu

At time zero, all the drug is still in the IV bag, therefore


there is no drug in the body. X0 = 0
Here K = ku
dX
------- = Q – k u X
dt
Q
sX – X0 = ---- – K u X
s
Q
sX + k u X = ----
s
Q
X = ---------------------
s ( s + ku )

Q –k t
X = ----- ( 1 – e u ) or X = Q
---- ( 1 – e –Kt )
ku K

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Mathematics Review

7. the amount of drug in the urine when the drug is


given by infusion (assume the drug is NOT metabolized).

Q X ku Xu

Here K = ku

dX
------- = Q – k u X
dt
Q
sX – Xo = ---- – k u X
s
Q
sX + k u X = ----
s
Q
X ⋅ ( s + k u ) = ----
s
Q
X = -------------------------
s ⋅ (s + ku )

dX
--------u- = k u X
dt

sX u – Xo = k u X

sX u = k u X

ku Q
sX u = ------------------------
-
s ⋅ (s + ku)

ku Q
X u = ---------------------------
2
-
s ⋅ ( s + ku )

k u Qt  1 – e –kut
X u = ----------- – Qk u  -------------------
-
ku  k2  u

– kut – Kt
(1 – e ) (1 – e )
X u = Qt – Q ------------------------- or Xu = Qt – Q -----------------------
ku K

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8. the amount of metabolite of a drug in the body – bt – at


X m = ----------------  ------------------ –  ------------------
A 1–e 1–e
from a drug given by IV infusion (assume no parent drug
excretion) Here K = km and K1 = kmu (a – b) b a

km Q  1 – e – k m t  1 – e – k mu t
X m = -------------------------  -------------------- –  --------------------- or
( k mu – k m )  k m   k mu 
Q X
k m Q  1 – e –Kt  1 – e –K1t
Xm = ---------------------
- ------------------ – ---------------------
( K1 – K )  K   K1 
km

Xm kmu Xmu

dX
------- = Q – k m X
dt
Q
sX – Xo = ---- – k m X
s
Q
sX + k m X = ----
s
Q
X ( s + k m ) = ----
s
Q
X = ----------------------
s ( s + km )
– kmt
(1 – e )
X = Q --------------------------
km

dX
---------m- = k m X – k mu X m
dt

sX m – Xo = k m X – k mu Xm

sX m = k m X – k mu Xm

km Q
X m = ---------------------------------------------
s ( s + k mu ) ( s + k m )

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Mathematics Review

9. the amount of metabolite of a drug in the urine dX mu


from a drug given by IV infusion (assume that the parent ------------- = k mu Xm
compound is not excreted). Here K = km and K1 = kmu
dt

sX mu – Xomu = k mu X m substitute X m

k mu k m Q
Q X mu = ----------------------------------------------
2
-
X s ( s + k m ) ( s + k mu )

k mu k m Qt k mu k m Q  ( 1 – e –kmut ) ( 1 – e – k mt )
km X mu = ---------------------- –  ---------------------  ----------------------------- – -------------------------- or
k m ⋅ k mu  k m – k m u  k
2
k
2

mu m

Xm kmu Xmu k mu k m Qt k mu k m Q  ( 1 – e –Kt ) ( 1 – e –K1t )


X mu = ---------------------- –  --------------------  ------------------------ – --------------------------
K1 ⋅ K  K1 – K   2 2

K K1

dX
------- = Q – k m X
dt
Q
sX – Xo = ---- – k m X
s
Q
sX + k m X = ----
s
Q
X ( s + k m ) = ----
s
Q
X = ----------------------
s ( s + km )

dX
---------m- = k m X – k mu X m
dt

sX m – Xo = k m X – k mu Xm

sX m + k mu X m = k m X

km Q
X m ( s + k mu ) = ----------------------
s ( s + km )

km Q
X m = ---------------------------------------------
s ( s + k m ) ( s + k mu )

k m Q  1 – e –kmut  1 – e –kmt
X m = --------------------  ----------------------- – ---------------------
k m – k mu  k mu   k m 

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Mathematics Review

10. the rate of excretion of the metabolite into the dX m


urine for a drug given by IV bolus when ---------- = ( k m X – k muX m )
dt
k m + k u = k mu
sX m – Xom = ( k m X – K1Xm )
In this case, K = ku +km and K1 = kmu and thus K = K1.
This is not normal but could happen. The problem arises sX m + K1X m = k m X
when we get to the LaPlace that assumes the rate con-
stants are different (i.e. a ≠ b ) because for this special km X o
case a = b . X m ( s + K1 ) = ------------
s+K
km Xo
X m = -------------------------------------- (remember- K1 = K)
( s + K ) ( s + K1 )
Dose
km Xo
X m = ------------------------------------------
( s + K1 ) ( s + K1 )
ku Xu km Xo
X
X m = ----------------------2- (kmX0 = A)
( s + K1 )
km
– K1t
X m = k m Xo te
Xm kmu Xmu dX mu
------------
- = k mu Xm
dt
dX mu
dX
. ------- = – k u X – k m X - = k mu k m Xo te –K1t
------------
dt dt

sX – Xo = – k u X – k m X

sX + k u X + k m X = X o

X ( s + ku + km ) = Xo

Xo
X = -------------------------------
( s + k u + km )

K = ( ku + km )

k mu = K1

Xo
X = ----------------
-
(s + K)
– Kt
X = Xo e

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Mathematics Review

11. the principal metabolite ( X m1 ) when the drug is k m1 Xo


cleared by several pathways ( X u, X m 1, X m 2 ) X m1 ( s + K1 ) = ----------------
-
(s + K)
In this case K = km1 + km2 + ku, K1 = kmu1 and K2 = k m1 X o
kmu2 X m1 = --------------------------------------
( s + K1 ) ( s + K )
k m1 Xo – K1t –Kt
-(e
X m1 = ---------------- –e )
K – K1
Xm1 kmu1 Xmu1

Dose
km1

X ku Xu

km2

kmu2 Xmu2
Xm2

dX
------- = – k u X – k m1 X – k m2 X
dt

sX – Xo = – k u X – k m1 X – k m2 X

sX + k u X + k m1 X + km2 X = Xo

X ( s + k u + k m1 + k m2 ) = Xo Let K = ku + km1 + km2

Xo
X = ----------------
-
(s + K)
K = ( k u + k m1 + k m2 ) and K1 = k mu1

dXm1
------------
- = k m1 X – K1X m1
dt

sX m1 – Xm1o = k m1 X – K1X m1

X m1o = 0

k m1 Xo
sX m1 + K1X m1 = ----------------
-
(s + K)

Basic Pharmacokinetics REV. 00.1.6 2-72


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Mathematics Review

12. the concentration of drug X ⁄ Vd in the body k a Q  ( 1 – e –Kt ) ( 1 – e –kat ) 


( k a – K ) 
when the drug is given orally by a delivery system which - ------------------------ – ------------------------- 
X = -------------------
is zero order. What is the concentration in the body at K ka 
equilibrium ( t ∞ )
 1 – e –Kt ) ( 1 – e –kat ) 
-  (-----------------------
ka Q
Here K = ku C = -------------------------- - – ------------------------- 
( k a – K )Vd  K ka 
Q Xa ka X ku Xu k Q
1- ----
1  
If t= ∞ , then e –kt = 0 , thus C = --------------------------
a
-  --- – -
( k a – K )Vd  K ka 

Q
simplified yields: C = ----------
-
KVd
dX
--------a- = Q – k a X a
dt
Q
sX a – Xao = ---- – k a Xa
s

X a0 = 0

sX a + k a Xa = ( Q ⁄ s )

X a ( s + ka ) = ( Q ⁄ s )

Q
X a = ---------------------
s(s + ka)
– kat
Q( 1 – e )
X a = -----------------------------
ka

dX
------- = k a X a – KX
dt

sX – Xo = k a Xa – KX

Xo= 0

ka Q
sX + KX = ---------------------
s ( s + ka )

ka Q
X ( s + K ) = --------------------
-
s ( s + ka )

ka Q
X = --------------------------------------
-
s ( s + ka ) ( s + K )

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Mathematics Review

13 the metabolite of a drug in the body Xm given


k m Q  ( 1 – e –K1t ) ( 1 – e –Kt ) 
( K – K1 ) 
by IV infusion and concomitant IV bolus dose. - -------------------------- – ----------------------- 
X m = ---------------------
K1 K 
Infusion:
Here K = km and K1 = kmu IV Bolus:

dX
------- = – KX
dt
Dose
sX – Xo = – KX

Q sX + KX = X o
X
X ( s + K )= Xo
km
Xo
X = -----------
-
s+K
Xm kmu Xmu
dX m
---------- = k m X – K1X m
dt
dX sX m – Xo = k m X – K1X m
------- = Q – KX
dt
Q sX m + K1X m = k m X
sX – Xo = ---- – KX
s
km X o
X m ( s + K1 ) = ------------
Q s+K
sX + KX = ----
s
km Xo
Q X m = --------------------------------------
X ( s + K ) = ---- ( s + K1 ) ( s + K )
s
km Xo – Kt – K 1t
Q -(e – e
X m = --------------------- )
X = -------------------- ( K1 – K )
s( s + K )
Thus,
dX
---------m- = k m X – K1X m km X o
X m =  ---------------------- ( e – e
dt – Kt – K 1t 
) + …
( K1 – K )
sX m – Xo = k m X – K1Xm
 k m Q  ( 1 – e –Kt ) ( 1 – e –K1t ) 
sX m + K1X m = k m X  -----------------  ----------------------- – -------------------------- 
 K1 – K  K K1 
km Q
X m ( s + K1 ) = -------------------
-
s( s + K )
km Q
X m = ----------------------------------------
-
s ( s + K1 ) ( s + K )

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Mathematics Review

14. By means of the LaPlace transform, find the km X o


equation for the rate of appearance of the tracer in the X m ( s + K1 ) = -----------
-
urine if the drug were given by IV bolus.
s+K

Here K = ku + km and K1 = kmu km Xo


X m = --------------------------------------
( s + K ) ( s + K1 )
Dose km Xo
- { e –K1t – e –Kt }
X m = ---------------------
( K – K1 )

ku Xu dX mu k mu k m Xo –K1t – Kt
X -{e
------------- = k mu Xm = --------------------- –e }
dt ( K – K1 )
dX dX mu  k mu k m X o
- = k u ( X o e ) +  ---------------------
- { e – e }
– Kt –K1t – Kt
km --------u- + ------------
dt dt   ( K – K1 ) 

Xm kmu Xmu

dX
------- = – k u X – k m X
dt

sX – Xo = – k u X – k m X

sX + k u X + k m X = X o

X ( s + ku + km ) = Xo

( ku + km ) = K

Xo
X = -----------------
(s + K)
– Kt
X = Xo e

dX
--------u- = k m X = k u ( Xo e –Kt )
dt
dX
---------m- = k m X – K1X m
dt

sX m – Xo = k m X – k1Xm

km Xo
sX m + K1X m = ----------------
-
(s + K)

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CHAPTER 3 Pharmacological Response

Author: Michael Makoid and John Cobby


Reviewer: Phillip Vuchetich

OBJECTIVES
After completing this chapter, the student will be able to:
1. Given patient data of the following types, the student will be able to properly con-
struct (III) a graph and compute (III) the slope using linear regression: response
(R) vs. concentration (C), response (R) vs. time (T), concentration (C) vs. time (T)
2. Given any two of the above data sets, the student will be able to compute (III) the
slope of the third by linear regression.
3. Give response vs. time and response versus concentration data, the student will be
able to compute (III) the terminal (elimination) rate constant and half life of the
drug.

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Pharmacological Response

3.1 Pharmacological Response


Drug must get into blood One theory (A.J. Clarke) on the mechanism of action of drugs is the occupation
and blood is in contact theory. It suggests that the intensity of a pharmacological response (E) is propor-
with receptor. tional to the concentration of a reversible drug-receptor complex

3.1.1 THE HYPERBOLIC RESPONSE EQUATION


A mathematical description of the occupation theory, assuming complete and
instantaneous drug distribution, yields

[ D ]E max
E = ---------------------
- (EQ 4-34)
KR + [D ]

where E is the intensity of the pharmacological response, Emax is the maximum


1.0
PKAnalyst Plot attainable value of E , [ D ] is the molar concentration of free drug at the active com-
0.8
plex and K R is the dissociation constant of the drug-receptor complex.
0.6

If E is plotted against [D] a hyperbolic curve will result; the asymptote will be
E

0.4

0.2
E max .

0.0
0.0 0.8 1.6 2.4 3.2 4.0

D
a. If linear pharmacokinetics hold, the molar concentration of free drug at the
active site is proportional to the plasma concentration of the drug once equilibrium
has been established. Hence, a plot of E against Cp will also be hyperbolic.

b. Because the mass of drug in the body is X = V ⋅ Cp , a plot of E against X will be


hyperbolic.

c. For a series of doses the value of X at the same given time after dosing is propor-
tional to the dose (D). Thus, a plot of E against D will also be hyperbolic at a spe-
cific time.

1.0 d. Any hyperbolic curve, if plotted on reverse semilogarithmic paper (i.e.,


0.8 abscissa is logarithmic), has a sigmoid shape. If we plot E against Cp (of X , or D )
0.6
in this manner, the plot is virtually linear in the range E ⁄ E max = 0.2 → 0.8 ; and if
Response

0.4

0.2 this is the clinical range of responses, linear equations may be written. For exam-
0.0 ple,
10 -810-710 -610-510 -410-310-210-1

Conc. E = m ⋅ ln x + b (EQ 4-35)

where m is the slope

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Pharmacological Response

Plot of Response vs. This example equation shows that, in the clinical range, the intensity of a pharma-
Ln(C) is a straight line in cological response is proportional to the logarithm of the administered dose, pro-
the middle (if you viding response is measured at a consistent time after dosing. The proportionality
squint), but only
between 20% and 80%
constant (slope, m ) is a function of the affinity of the drug for the receptor. In fact,
maximum response equation 4-35 yields a log-dose response plot. Note that doubling the dose does not
double the response.

3.1.2 INTERRELATIONSHIPS BETWEEN CONCENTRATION, TIME AND


RESPONSE

Pharmacological Response (R), Concentration (C), and Time (t) are interrelated.
The response and concentration relationship is studied in pharmacology. The con-
centration and time relationship is studied in pharmacokinetics. The response and
time relationship is applied in therapeutics.
Remember: Use only You should know what the various graphical relationships look like. Response vs.
the data between 20% natural log of concentration is sigmoidal. (S shaped). We are interested in the mid-
and 80% of maximum dle almost straight part. The slope is dR ⁄ d ln c .
response for the straight
part of both response
vs. Ln(c) and response Response vs. time is a straight line. The slope is dR ⁄ dt .
vs. t.
Natural log of concentration vs. time (drug given by IV bolus) is a straight line.
The slope is d ln c ⁄ dt .

You should be able to obtain the slope of each of these relationships from data sets.

You should be able to obtain the third slope’s relationship given the other two (or
data sets with which to get the other two).

dR dR- d----------
ln c- (EQ 4-36)
------- = ---------- ⋅
dt d ln c dt

dR - dR ⁄ dt
---------- = -------------------- (EQ 4-37)
d ln c d ln c ⁄ dt

d----------
ln c- dR ⁄ dt
= ---------------------- (EQ 4-38)
dt dR ⁄ d ln c
NOTE: Only between You should be able to apply the equation y = mx + b to each of the above relation-
20% and 80% of maxi- ships. Given the slope (or having obtained the slope) and two of the three variables
mum response!!!!!! (y, x, b), you should be able to find the third.

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Pharmacological Response

3.2 Change in Response with Time

3.2.1 ONE-COMPARTMENT OPEN MODEL: INTRAVENOUS BOLUS


INJECTION
– Kt – Kt
X = X0 e = De (EQ 4-39)

or

Ln ( X ) = Ln ( D ) – Kt (EQ 4-40)

Substituting twice from eq. 4-35 once at time t and once at zero time

E – b- E 0–b
----------- = --------------- – Kt → E = E0 – Rt (EQ 4-41)
m m

Hence a plot of the intensity of the pharmacological response at any time ( E )


against time declines linearly. The slope is –R = ( –K ⋅ m ) and the intercept is E0 (the
initial intensity).

3.2.2 ONE-COMPARTMENT OPEN MODEL: ORAL ADMINISTRATION


Response follows Because E is proportional to ln x at any time, a plot of E against t will be analo-
plasma profile. gous to a plot of ln x against t . Hence E will rise at first and then decline with time.
When t is large, the terminal slope will be –R .

3.2.3 DURATION OF EFFECTIVE PHARMACOLOGICAL RESPONSE ( t dur )


Duration of action is Once equilibrium has been established, there is a minimum plasma concentration
related to how long below which no pharmacological response is seen; this concentration is ( C p ) eff or
plasma concentration is
above Minimum Effec- MEC . For an intravenous bolus injection, the time to reach ( C p ) eff is t dur .
tive Concentration.
– Ktd ur
( C p )eff = ( C p ) 0 e multiplying by the volume of distribution we obtain

ln ( X eff ) = ln ( D ) – Kt dur (EQ 4-42)

Rearranging,

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Pharmacological Response

ln  --------
D
X eff
t dur = -------------------- (EQ 4-43)
K

The duration of effective pharmacological response is proportional to the (natural)


logarithm of the dose. A second rearangement of equation 4-42 results in :

ln ( Dose ) ln ( Xeff )
t dur = ----------------------- – ------------------
- (EQ 4-44)
K K

Thus a plot of duration of action vs ln dose would result in a straight line with a
ln ( X ef f )
slope of 1/K and an x intercept of – ------------------- .
K

3.2.4 PHARMACOKINETIC PARAMETERS FROM RESPONSE DATA


How can I get the elimi- The measurement of pharmacological effect provides a non-invasive means of
nation rate constant obtaining the value of t 1 ⁄ 2 (but not V ).
from pharmacological
data? Use this “cook-
book.” a. Obtain a log dose-response plot (Eq. 4-37). The response must always be mea-
sured at the same time after administering the dose.
Remember: Use only b. Find the slope (m) of this plot.
the data between 20%
and 80% of maximum c. Obtain a response against time plot for a single dose (Eq. 4-36).
Response for both of
these plots.
d. Find the terminal slope ( –R ) of this plot.

R
e. Calculate K = ---- .
m

t 1 ⁄ 2 =  -------------
0.693
f. Calculate  K 
.

3.2.5 “DELAYED” RESPONSE


Two compartment If a drug does not distribute instantaneously to all the body tissues (including the
model - biophase is in active site), the pharmacological response will not always parallel the drug con-
second compartment. centrations in the plasma. In such a situation the response may parallel the mass of
drug presumed to be in a second compartment ( X 2 ) , and hence seem “delayed”.
Eventually, however, once equilibrium is attained, the response will parallel
plasma concentrations. In such a case, E is proportional to ln X 2 .

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Pharmacological Response

Thus a plot of E against X1 (or E against Cp ) will show a hysteresis loop with time,
most noticeably during an intravenous infusion.

3.2.6 RESPONSE OF ACTIVE METABOLITE:


Parent compound (inac- In the case of an inactive prodrug yielding an active metabolite, the response
tive) yields active curves will mirror the active metabolite plasma profile (assuming the biophase is
daughter compound. the plasma) and not the prodrug plasma profile.

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Pharmacological Response

3.3 Therapeutic Drug Monitoring


Part of Pharmaceutical The pharmacokinetics of a drug determine the blood concentration achieved from
Care! a prescribed dosing regimen. During multiple drug dosing, the blood concentration
will reflect the drug concentration at the receptor site; and it is the receptor site
concentration that determines the intensity of the drug’s effect. Therefore, in order
to predict a patient’s response to a drug regimen, both the pharmacokinetics and
pharmacological response characteristics of the drug must be understood. Phar-
macological response is closely related to drug concentration at the site of action.
We can measure plasma concentration and assume that the site of action is in rapid
equilibrium with the plasma since we usually do not measure drug concentration in
the tissue or at the receptor site. This assumption is called “kinetic homogeneity”
and is the basis for clinical pharmacokinetics.
Need to keep plasma There exists a fundamental relationship between drug pharmacokinetics and phar-
concentration in the macologic response. The relationship between response and ln-concentration is
therapeutic range to sigmoidal. A threshold concentration of drug must be attained before any response
optimize therapy.
is elicited at all. Therapy is achieved when the desired effect is attained because
the required concentration has been reached. That concentration would set the
lower limit of utility of the drug, and is called the Minimum Effective Concentra-
tion (MEC). Most drugs are not “clean”, that is exhibit only the desired therapeu-
tic response. They may also exhibit undesired side effects, sometimes called toxic
effects at a higher, (hopefully a lot higher), concentration. At some concentration,
these toxic side effects become become intolerable/and or dangerous to the
patient.. That concentration, or one below it, would set the upper limit of utility
for the drug and is called the Maximum Therapeutic Concentration or Minimum
Toxic Concentration (MTC). Patient studies have generated upper (MTC) and
lower (MEC) plasma concentration ranges that are deemed safe and effective in
treating specific disease states. These concentrations are known as the “therapeutic
range” for the drug (Table 4-18).

When digoxin is administered at a fixed dosage to numerous subjects, the blood


concentrations achieved vary greatly. Clinically, digoxin concentrations below 0.8
ng ⁄ ml will elicit a subtherapeutic effect. Alternatively, when the digoxin concen-
tration exceeds 2.0 ng ⁄ ml side effects occur (nausea and vomiting, abdominal pain,
visual disturbances). Drugs like digoxin possess a narrow therapeutic index
because the concentrations that may produce toxic effects are close to those

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Pharmacological Response

required for therapeutic effects. The importance of considering both pharmacoki-


netics and pharmacodynamics is clear.

TABLE 4-18 Average therapeutic drug concentration

DRUG RANGE
digoxin 0.8-2.0 ng ⁄ ml
gentamicin 2-10 µg ⁄ ml l
lidocaine 1-4 µg ⁄ ml
lithium 0.4-1.4 mEq ⁄ L
phenytoin 10-20 µg ⁄ ml
phenobarbitol 10-30 µg ⁄ ml
procainamide 4-8 µg ⁄ ml
quinidine 3-6 µg ⁄ ml
theophylline 10-20 µg ⁄ ml

Note that drug concentrations may be expressed by a variety of units.

Pharmacokinetic factors that cause variability in plasma drug concentration are:


• drug-drug interactions
• patient disease state
• physiological states such as age, weight, sex
• drug absorption variation
• differences in the ability of a patient to metabolize and eliminate the drug

If we were to give an identical dose of drug to a large group of patients and then
measure the highest plasma drug concentration we would see that due to individual
variability, the resulting plasma drug concentrations differ. This variability can be
attributed to factors influencing drug absorption, distribution, metabolism, and
excretion. Therefore, drug dosage regimens must take into account any disease
altering state or physiological difference in the individual.

Therapeutic drug monitoring optimizes a patient’s drug therapy by determining


plasma drug concentrations to ensure the rapid and safe drug level in the therapeu-
tic range.
Two components make • Assays for determination of the drug concentration in plasma
up the process of • Interpretation and application of the resulting concentration data to develop a safe and effective
therapeutic drug drug regimen.
monitoring:

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Pharmacological Response

The major potential advantages of therapeutic drug monitoring are the maximiza-
tion of therapeutic drug benefits and the minimization of toxic drug effects. The
formulation of drug therapy regimens by therapeutic drug monitoring involves a
process for reaching dosage decisions.

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Pharmacological Response

3.3.1 THERAPEUTIC MONITORING: WHY DO WE CARE?


The usefulness of a drug’s concentration vs. time profile is based on the observa-
tion that for many drugs there is a relationship between plasma concentration and
therapeutic response. There is a drug concentration below which the drug is inef-
fective, the Minimum Effective Concentration (MEC), and above which the drug
has untoward effects, the Minimum Toxic Concentration (MTC). That defines the
range in which we must attempt to keep the drug concentration (Therapeutic
Range).

The data in Table 4-18 are population averages. Most people respond to drug con-
centrations in these ranges. There is always the possibility that the range will be
different in an individual patient.

For every pharmacokinetic parameter that we measure, there is a population aver-


age and a range. This is normal and is called biological variation. People are differ-
ent. In addition to biological variation there is always error in the laboratory assays
that we use to measure the parameters and error in the time we take the sample.
Even with these errors, in many cases, the therapy is better when we attempt to
monitor the patient’s plasma concentration to optimize therapy than if we don’t.
This is called therapeutic monitoring. If done properly, the plasma concentrations
are rapidly attained and maintained within the therapeutic range throughout the
course of therapy. This is not to say all drugs should be monitored. Some drugs
have a such a wide therapeutic range or little to no toxic effects that the concentra-
tions matter very little. Therapeutic monitoring is useful when:
• a correlation exists between response and concentration,
• the drug has a narrow therapeutic range,
• the pharmacological response is not easily assessed, and
• there is a wide inter-subject range in plasma concentrations for a given dose.

In this era of DRGs, where reimbursement is no longer tied to cost, therapeutic


monitoring of key drugs can be economically beneficial to an institution. A recent
study (DeStache 1990) showed a significant difference with regard to length of
stay in the hospital between the patients on gentamicin who were monitored (and
their dosage regulated as a consequence) vs. those who were not. With DRGs the
hospital was reimbursed a flat fee irrespective of the number of days the patient
stayed in the hospital. If the number of days cost less than what the DRG paid, the
hospital makes money. If the days cost more than the hospital loses money. This
study showed that if all patients in the hospital who were on gentamicin were mon-
itored, the hospital would save $4,000,000. That’s right FOUR MILLION per year.
I would say that would pay my salary, with a little left over, and that is only one
drug!

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Pharmacological Response

The process of • First the MD must order the blood assays.


therapeutic monitoring • Second, someone (nurse, med tech, you) must take the blood.
takes effort.
• Someone (lab tech, you) must assay the drug concentration in the blood.
• You must interpret the data.
• You must communicate your interpretation and your recommendations for dosage regimen
change to the MD. This will allow for informed dosage decisions.
• You must follow through to ensure proper changes have been made.
• You must continue the process throughout therapy. Therapeutic drug monitoring, in many cases,
will be part of your practice. It can be very rewarding.

Thus, if we have determined the therapeutic range, we could use pharmacokinetics


to determine the optimum dosage regimen to maintain the patient’s plasma con-
centration within that range.
Selected References

1. Nagashima, R., O’Reilly, RA., and Levy, G, Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin. Clin.
Pharm. Therap, 10 22-35 (1969).

Remember: We want the straight part!


2. Wagner, J.G, Relations between drug concentration and response. J. Mond. Pharm., 4, 279-310 (1971).

3. Gibaldi M. and Levy, G. Dose-dependent decline of pharmacologic effects of drugs with linear pharmacokinetics characteristics.
J.Pharm.Sci, 61, 567-569 (1972).

4. Brunner, L., Imhof, P., and Jack, D. Relation between plasma concentrations and cardiovascular effects of oral oxprenolol in
man. Europ. J. Clin. Pharmacol., 8, 3-9 (1975).

5. Galeazzi, R.L., Benet, L.Z., and Sheiner, L.B. Relationship between the pharmacokinetics and pharmacodynamics of procaina-
mide. Clin. Pharm. Therap., 20, 67-681 (1976).

6. Joubert, P., et al. Correlation between electrocardiographic changes, serum digoxin, and total body digoxin content. Clin.
Pharm. Therap., 20, 676-681 (1976).

7. Amery, A., et al. Relationship between blood level of atenolol and pharmacologic effect. Clin. Pharm. Therap., 21, 691-699
(1977).

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Pharmacological Response

3.4 Problems
What to do.---> We want to get pharmacokinetic data (elimination rate con-
stant) from pharmacological response data (Response vs concontration and
Response vs time graphs) .

Response vs Time Graph


1. Plot Response vs Time on Cartesian (regular) Graph Paper.
1.0 13. Use Response data between 20 and 80 percent of maximum (Pick the straight part) to do the lin-
ear regression on. (Rule of thumb: Connect first and last data point with a straight line. If all
0.8
the points fall on one side of the line, its not straight!
Response

0.6
dR
14. Find the slope of the straight line, ------- , (eyeball the rise over the run or use linear regression as
0.4 dT
0.2
required). Important: you must determine the best fit line through all of the points that you will
use. Eyeball method: Get the line as close to the points as possible placing as many points
0.0

10 10 10 10 10 10
above the line as below the line. Take two points on the line (not data points) to calculate the
Time
change in Y over the change in X.

Response vs Ln(Concentration) Graph


1. Turn semi-log paper on its side so that the numbers are on the top.

10010
10010

10 10
1

1.0
10

0.8
0

0.6
Response

0.4

0.2
Response

0.0
1010
10-810-710-610-510 -410-310 -210-1

Conc.
1

Concentration
1
10
0 1

What we are attempting to do is get the logarithm part of the paper on the x axis and have the
numbers get bigger as you go from left to right.
15. Plot concentration on the x axis and response on the y.
16. Find the slope of the line plotted this way by the rise over the run method.
Run is change in ln(C).
If you take any two concentrations such that C2 = 2*C1 then the run is (ln(C2) - ln(C1)).
Using rules of logs, when two logs are subtracted, the numbers are devided, thus: = ln(C2/C1).
If C2 = 2*C1 then ln(C2/C1) = ln(2) = 0.693.

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Pharmacological Response

Rise = change in Response.


Take the difference of the two responses coresponding to the concentrations picked. (R2-R1).
rise 2 1 R –R
17. The slope of the line is m = -------- = -----------------
-
run 0.693

Ln(Concentration) vs Time Graph (Pharmacokinetic Data)

If you have concentration vs Time data:


1. Plot Concentration vs time on semi-log paper (Y axis is concentration this time)

100
10
Concentration

1010

110
0 1
Time

18. Find the slope as before, using semi log paper (Remeber the log is on the Y axis this time, so
you find two concentrations such that c2 = 2*c1 and put it in the rise this time. Thus the slop of
rise 0.693 0.693
the line is m = -------- = -------------- = ------------- = – k
run t2 – t1 –t1
---
2

If you have pharmacological response data:


1. Divide the slope of the Response vs Time graph by the slope of the Response vs ln(C) graph:
dR
-------
slope of r vs t dT dln(C)
------------------------------------------ = --------------- = --------------- = m = – k
slope of r vs ln(c) dR -
-------------- dT
dln(C)

Both methods should be equivalent.

Additional problems are available in chapter 14, practice exams.

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Pharmacological Response

3.5 Oxpranolol
Brunner et al, Europ. J. Clin. Pharmacol., 8, 3-9 (1975).

In humans, the pharmacological response to oxpranolol (a beta blocker) is a decrease in beats per minute (bpm) com-
pared to placebo during physical exercise. The following approximate mean data is from 7 healthy volunteers: beats per
minute (bpm) altered with time (t) after oral administration of three doses (D).

TABLE 4-19

Response vs Response vs
Concentration time

BPM Dose (mg) BPM Time (hr)


10 40 17.6 1
13.5 60 13.9 2
16 80 10.2 3
19 120 6.6 4
21 160

TABLE 4-20 Oxpranolol plasma concentration following 160 mg IV dose

C p  ------
ng
Time (min) ml

30 699
60 622
120 413
150 292
240 152
360 60
480 24

1. Calculate the half life ( t 1 ⁄ 2 ) of oxpranolol from the pharmacological response table.

2. Plot plasma concentration data on Cartesian graph paper directly as well as transforming Cp into ln C p .

3. Plot plasma concentration data on semilog paper. Use linear regression to find the rate constant of elimination of
oxpranolol.
4. Calculate the half life obtained from the concentration data and compare it with the half life calculation based on the
pharmacological response.

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Pharmacological Response

Minoxidil (Problem 4 - 1)

Shen et al. Clin. Pcol. Ther 17:593-8 (1975)

Minoxidil is a potent antihypertensive which lowers the mean arterial blood pressure (MAP) in certain patients.

PROBLEM TABLE 4 - 2. Minoxidil

Initial decrease in MAP ( mmHg ) Dose ( mg )


17 2.5
40 5.0
53 7.5
63 10.0
76 15

PROBLEM TABLE 4 - 3. Minoxidil

25 mg I.V. Bolus yielded:

Decrease in MAP ( mmHg ) Time ( hr )


75 20
66 30
56 40
48 50

From the preceding information, determine the following:

dR
1. Graph and find ------------ (slope of (R)esponse vs. ln(C)oncentration graph).
d ln C
dR
2. Graph and find ------- (slope of (R)esponse vs. (T)ime graph).
dt
dR
-------
dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = – K . If you are having problems
dR
------------
d ln C
understanding this, refer to Sections 2.4.2 -2.4.4. K is the elimination rate constant.

4. Calculate t 1 ⁄ 2 =  0.693
-------------  .
K 

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Pharmacological Response

Propranolol (Problem 4 - 4)

Citation?

Beta blockers can be considered first line drugs of choice in the treatment of hypertension in certain patients. The fol-
lowing data was obtained regarding Propranolol used to treat hypertension in a group of patients.

PROBLEM TABLE 4 - 5. Propranolol

Fall in Systolic BP (mmHg) Cp

20 50
16 40
11 30
5 20

PROBLEM TABLE 4 - 6. Propranolol

I.V. Bolus dose of Propranolol

Fall in Systolic BP (mmHg) Time (hr)


24 1
20 2
19 3
9 6

From the preceding information, determine the following:

dR
1. Graph and find ------------ (slope of (R)esponse vs. ln(C)oncentration graph).
d ln C
dR
2. Graph and find ------- (slope of (R)esponse vs. (T)ime graph).
dt
dR
-------
dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = – K . If you are having problems
dR
------------
d ln C
understanding this, refer to Sections 2.4.2 -2.4.4.

4. Calculate t 1 ⁄ 2 =  0.693
-------------  .
K 

Basic Pharmacokinetics REV. 00.1.14 3-16


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Pharmacological Response

3.5.1 ANSWERS: OXPRANOLOL


1. Calculate the half life ( t 1 ⁄ 2 ) of oxpranolol from the pharmacological response table

Oxpranolol
22

20
Response (BPM)

18

16

14

12

10
1 2 3
10 10 10

Dose (mg)

TABLE 5.

X Y 2
ln(Dose) Dose Response X X⋅Y
3.689 40 10 13.61 36.89
4.094 60 13.5 16.76 55.27
4.382 80 16 19.20 70.11
4.787 120 19 22.92 90.96
5.075 160 21 25.75 106.58

ΣX = 22.03 ΣY = 79.5 2
ΣX = 98.25 ΣXY = 359.82

2
( ΣX ) = 485.23

ΣX Σy
)

X = --------- = 4.41 y = ------ = 15.9


n n

( Σ(x) ⋅ Σ(y )) – (n ⋅ Σ(x ⋅ y))


m = ---------------------------------------------------------------------
2 2
Slope of the line from linear regression. Chapter 2.4.4
[Σ(x) ] – ( n ⋅ Σ (x ))

( 22.03 ⋅ 79.5 ) – ( 5 ⋅ 359.82 )


m = -------------------------------------------------------------------- = 7.93
485.32 – ( 5 ⋅ 98.25 )

Basic Pharmacokinetics REV. 00.1.14 3-17


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Pharmacological Response

dR -
---------- = 7.93 the slope is equal to the linear regression of the change in response vs. ln concentration.
d ln c

OXPRANOLOL
18

16
Response (BPM)

14

12

10

6
1.0 1.5 2.0 2.5 3.0 3.5 4.0
Time (hr)

1 R –R 2 16 – 10 dR
The slope of this plot is m = ------------------ = --------------------------- = – 3.71 therefore, ------- = – 3.71 .
T1 – T 2 1.45 – 3.07 dt

dR
-------
dt d ln c –3.71 –1 ln 2 0.693 -
----------- = ----------- = – k = ------------- = – 0.4678hr t 1 ⁄ 2 = -------- = -------------------------- = 1.48hr half life (89 min).
dR dt 7.93 k –1
----------- 0.4678hr
d ln c

2. Plot plasma concentration data on Cartesian graph paper directly as well as transforming Cp into ln C p .

Basic Pharmacokinetics REV. 00.1.14 3-18


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Pharmacological Response

Plasma concentration vs. Time


800 Oxpranolol
3
10

640

Concentration (ng/mL)
480

2
10
320
Concentration (ng/ml)

160

1
10
0 0 100 200 300 400 500
0 100 200 300 400 500
Time (min)
Time (min)

3. Plot plasma concentration data on semilog paper. Use linear regression to find the rate constant of elimination of
oxpranolol.
Using linear regression, as described above, the elimination rate constant is approximately

0.007797 min-1 * (60 min/hr) = 0.4678 hr-1


4. Calculate the half life obtained from the concentration data and compare it with the half life calculation based on the
pharmacological response.
0.693
t 1 ⁄ 2 = ------------------- = 90min = 1.5 hrs compared to 1.48 hours (89 min) from the pharmacological response
0.00763
method.

Basic Pharmacokinetics REV. 00.1.14 3-19


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Pharmacological Response

3.5.2 ANSWERS: MINOXIDIL

NOTE: Answers will vary depending on whether linear regression is calculated


via calculator or using the formula such as observed in Problem 1. Either method
can be used. However, if you use the formula, you should be within 10% of the
calculated answer. A word of caution: if you choose to do linear regression via
calculator make sure you have valid data. This cannot be assured until you have
graphed all the data points given. Many a student has incorrectly calculated
parameters because he/she falsely assumes that all the points are valid. Blindly
choosing data points for linear regression will only lead to error. Every problem
in this manual has been derived from actual journal articles and will therefore be
“real” data. This real-world data is inexact.
dR (slope of (R)esponse vs. ln(C)oncentration graph).
1. Graph and find ------------
d ln C
mHg)

R vs Ln(C)
80

60

40

20

0
10 10 10

Dose (mg)

dR
------------ = 32.96
d ln C

dR
2. Graph and find ------- (slope of (R)esponse vs. (T)ime graph).
dt

Basic Pharmacokinetics REV. 00.1.14 3-20


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Pharmacological Response

R vs T
75

70

65

60

55

50

45
20 25 30 35 40 45 50

Time (hr)

dR
------- = – 0.91
dt
dR
-------
dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = – K .
dR
------------
d ln C
–1
K = 0.028hr
–-------------
0.91
= – ( 0.028 )
32.96

4. Calculate t 1 ⁄ 2 =  0.693
-------------  .
K 

t 1 ⁄ 2 =  -----------------------
0.693 -
– 1
= 24.75hr
0.028hr

Basic Pharmacokinetics REV. 00.1.14 3-21


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Pharmacological Response

3.5.3 ANSWERS: PROPRANOLOL


dR (slope of (R)esponse vs. ln(C)oncentration graph).
1. Graph and find ------------
d ln C

20

15

10

0
10 10

dR
------------ = 16.36
d ln C
dR
2. Graph and find ------- (slope of (R)esponse vs. (T)ime graph).
dt

25

20

15

10

5
0 1 2 3 4 5 6

dR
------- = – 2.93
dt

Basic Pharmacokinetics REV. 00.1.14 3-22


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
Pharmacological Response

dR
-------
dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = – K .
dR
------------
d ln C
–1
K = 0.179hr
–-------------
2.93
= – 0.179
16.36

4. Calculate t 1 ⁄ 2 =  0.693
-------------  .
K 

t 1 ⁄ 2 =  -----------------------
0.693 -
– 1
= 3.87hr
0.179hr

Basic Pharmacokinetics REV. 00.1.14 3-23


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
CHAPTER 4 I.V. Bolus Dosing

Author: Michael Makoid and John Cobby


Reviewer: Phillip Vuchetich

OBJECTIVES
For an IV one compartment model plasma and urine:
1. Given patient drug and/or metabolite concentration, amount, and/or rate vs. time
profiles, the student will calculate (III) the relevant pharmacokinetic parameters
available from IV plasma, urine or other excreta data: e.g.
V d, K, k m, k r, AUC, AUMC, CL, MRT, t 1 ⁄ 2
2. The student will provide professional communication regarding the pharmacoki-
netic parameters obtained to patients and other health professionals.
3. The student will be able to utilize computer programs for simulations and data
analysis.

Basic Pharmacokinetics REV. 00.1.27 4-1


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I.V. Bolus Dosing

4.1 I.V. Bolus dosing of Parent compound

4.1.1 PLASMA
Valid equations: ln C p = – K ⋅ t + ln C p 0 (EQ 4-1)
(Obtained from the
LaPlace transforms
ln X = – K ⋅ t + ln X0 (EQ 4-2)
derived from the
appropriate models
– Kt
derived from the C p = C p0 e (EQ 4-3)
pharmacokinetic
descriptions of the drug)
D-
C p 0 = ----- (EQ 4-4)
Vd

t ½ = 0.693
------------- (EQ 4-5)
K
( ∞)
( Cp n + Cp n + 1 ) Cp last
AUC = ∫ Cp dt = Σ  ------------------------------------- ⋅ ∆t + -------------- (EQ 4-6)
2 K
0

( ∞) t
( t n ⋅ Cp n ) + ( t n + 1 ⋅ Cp n + 1 ) Cp l ast ( t l ast ⋅ Cp last )
AUMC = ∫ t ⋅ C p dt = ∑  -------------------------------------------------------------------
2
- ⋅ ∆t + --------------- + ----------------------------------

K
2 K
(EQ 4-7)
0 0

MRT = AUMC
------------------ (EQ 4-8)
AUC

Cl = K ⋅ Vd (EQ 4-9)

Utilization:
Can you determine the • You should be able to plot a data set Concentration vs. time on semilog yielding a straight line
slope and intercept from with slope = – K and an intercept of C p0 .
a graph? Plot the data
in table 4 -1.on semi-log
graph paper. Extrapo-
late the line back to time TABLE 4-1 Nifedipine 25 mg IV bolus
= 0 to get Cp0. Find the
Cp
half life. Calculate the Time (hr) (mcg/L)
elimination rate con-
2 139
stant.
4 65.6
6 31.1
8 14.6
FIGURE 4-1.

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I.V. Bolus Dosing

Does your Graph look FIGURE 4-1 Nifedipine IV Bolus (25 mg IV Bolus)
like this?
100 10 3

Concentration (mic/L)
Cp0 = 295 mic/L
-K1 = -0.375 hr -1

Concentration (ng/mL)
10 2

50 1.85 hr
10 1
0 2 4 6 8

Time (hr)
Time (hours)

• You should be able to determine K. A plot of the data in TABLE 4-1 results in FIGURE 4-1
dy
Remember from high school algebra, the slope of any straight line is the rise over the run, ------ ,
dx
In the case of semi-log graphs dy is the difference in the logarithms of the concentrations. Thus,
using the rules of logarithms, when two logs are subtracted, the numbers themselves are
divided. i.e. ln ( C1 ) – ln ( C2 ) = ln  ------- . Thus if we are judicious in the concentrations that we
C1
C2
take, we can set the rise to a constant number. So, if we take any two concentrations such that
one concentration is half of the other (In FIGURE 4-1 above, we took 100 and 50), the time it
takes for the concentration to halve is the half life (in the graph above, 1.85 hr). Then
0.693 0.693 –1
K = ------------- = ---------------- = 0.375 hr
t½ 1.85hr

• You should be able to determine V d :. To do this, extrapolate the line to t = 0 . The value of Cp
mic
when t = 0 is C p0 (in the graph above, C p0 = 295 --------- which is equal to D ⁄ V d for an IV bolus
L
dose only.
Dose 25mg ⋅ 1000mic
Thus, Cp 0 = ------------- , V d = Dose
------------- = ------------------ --------------------- = 85L
Vd Cp 0 295mic mg
------------------
L
The volume of distribution is a mathematical construct. It is merely the proportionality constant
between two knowns - the C p0 which results from a given D 0 . It is, however, useful because it
is patient specific and therefore can be used to predict how the patient will treat a subsequent
dose of the same drug. You should be able to obtain the volume of distribution from graphical
analysis of the data. Pay attention to the units! Make sure that they are consistent on both sides
of the equation. NOTE: the volume of distribution is not necessarily any physiological space.
For example the approximate volume of distribution of digoxin is about 600 L If that were a
physiological space and I were all water, that would mean that I would weigh about 1320
pounds. I’m a little overweight (I prefer to think that I’m underheight), but REALLY!
• Given any three of the variables of the IV bolus equation, either by direct information (the vol-
ume of distribution is such and such) or by graphical data analysis, you should be able to find
the fourth.

Basic Pharmacokinetics REV. 00.1.27 4-3


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I.V. Bolus Dosing

• You should be able to calculate Area Under the Curve (AUC) from IV Bolus data (Time vs. Cp).
From the above data in TABLE 4-1 the AUC is calculated using (EQ 4-6):
(∞)
Cpn + Cp n + 1 Cp
AUC = ∫ Cp dt = Σ  --------------------------------- + --------l which in this case is:
 ∆t  K
0

 Cp o + Cp 1 Cp 1 + Cp 2 Cp2 + Cp 3 Cp 3 + Cp last Cp l ast 


Σ  -------------------------- ⋅ ∆t 1 + -------------------------- ⋅ ∆t 2 + -------------------------- ⋅ ∆t 3 + ------------------------------- ⋅ ∆t last + --------------
-
 2 2 2 2 K1 

 295 + 139 139 + 65.6 65.6 + 31.1 31.1 + 14.6 14.6 mcg
Σ  ------------------------ ⋅ 2 + ------------------------- ⋅ 2 + --------------------------- ⋅ 2 + --------------------------- ⋅ 2 + ------------- ---------- hr or
 2 2 2 2 0.375  L

mcg mcg
Σ { 434 + 204.6 + 96.7 + 45.7 + 38.9 } ---------- hr = 819.9 ---------- hr . In tabular format, the AUC calculation
L L
is shown in TABLE 4-2.

TABLE 4-2 AUC

t t
AUC AUC
TIME Cp t–1 0

0 295
2 139 434.0 434.0
4 65.6 204.6 638.6
6 31.1 96.7 735.3
8 14.6 45.7 781.0
∞ 0 38.9 819.9

The AUC of a plot of plasma concentration vs. time, in linear pharmacokinetics, is a number
which is proportional to the dose of the drug which gets into systemic circulation. The propor-
tionality constant, as before, is the volume of distribution. It is useful as a tool to compare the
amount of drug obtained by the body from different routes of administration or from the same
route of administration by dosage forms made by different manufacturers (calculate bioavail-
ability in subsequent discussions).
The AUC of a plot of Rate of Excretion of a drug vs. time, in linear pharmacokinetics, is the
mass of drug excreted into the urine, directly.
• You should be able to calculate the AUMC from IV Bolus data (Time vs. Cp). The equation for
AUMC is equation 4-7:
( ∞) t
( t n ⋅ Cp n ) + ( t n + 1 ⋅ Cp n + 1 ) Cp l ast ( t l ast ⋅ Cp last )
AUMC = ∫ t ⋅ C p dt = ∑  -------------------------------------------------------------------
2
- ⋅ ∆t + --------------- + ----------------------------------

K
2 K
which in the
0 0
data given in TABLE 4-1 is:

T0 ⋅ C po + T1 ⋅ C p1 T1 ⋅ C p1 + T2 ⋅ C p2 T 2 ⋅ C p 2 + T3 ⋅ C p3
Σ ----------------------------------------------- ⋅ ∆t 1 + ----------------------------------------------- ⋅ ∆t 2 + ----------------------------------------------- ⋅ ∆t 3 +
2 2 2

Basic Pharmacokinetics REV. 00.1.27 4-4


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I.V. Bolus Dosing

T 3 ⋅ C p 3 + T last ⋅ C p last T last ⋅ C p l ast Cplast


---------------------------------------------------------- ⋅ ∆t l ast + ------------------------------
- + --------------- and thus,
2 K K
2

 0 ⋅ 295 + 2 ⋅ 139 2 ⋅ 139 + 4 ⋅ 65.6 4 ⋅ 65.6 + 6 ⋅ 31.1 mcg 2


Σ  --------------------------------------- ⋅ 2 + ---------------------------------------- ⋅ 2 + ------------------------------------------ ⋅ 2 ---------- hr +
 2 2 2  L

 6 ⋅ 31.1 + 8 ⋅ 14.6 ⋅ 14.6 14.6  mcg 2


- ⋅ 2 + 8-----------------
 ----------------------------------------- - + ----------------  ---------- hr or
 2 0.375 0.375  L
2

mcg 2
Σ { 278 + 540.4 + 449 + 303.4 + 311.47 + 103.82 } = 1986.1 ---------- hr
L
Thus in tabular format the AUMC for data given in TABLE 4-1 is TABLE 4-3 below.

TABLE 4-3 AUMC

t
AUMC t AUMC
TIME Cp Cp*T 0

0 295 0
2 139 278 278.0 278.0
4 65.6 262.4 540.4 818.4
6 31.1 186.6 449.0 1267.4
8 14.6 116.8 303.4 1570.8
∞ 0 0 415.3 1986.1

The AUMC is the Area Under the first Moment Curve. A plot of T*Cp vs. T is the first
moment curve. The time function buried in this plot, the Mean Residence Time (MRT), can be
extracted using equation 4-8 below.
It is the geometric mean time that the molecules of drug stay in the body. It has utility in the fact
that, as drug moves from the dosage form into solution in the gut, from solution in the gut into
the body, and from the body out, each process is cumulatively additive. That means if we can
physically separate each of these processes in turn, we can calculate the MRT of each process.
The MRT of each process is the the inverse of the rate constant for that process.
• You should be able to calculate MRT from IV Bolus data (Time vs. Cp) using equation 4-8
AUMC 1986.1
MRT = ------------------ = ---------------- = 2.42
AUC 819.9
Since there is only the process of elimination (no release of the drug from the dosage form, no
absorption), the MRT is the inverse of the elimination rate constant, K. Thus MRT = 1/K.

Basic Pharmacokinetics REV. 00.1.27 4-5


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I.V. Bolus Dosing

Flow Chart 4-1 IV Bolus

K
X

MRT(IV) = 1/K

Suppose the drug were given in a solution. Then the drug would have to be absorbed and then
eliminated. Since the MRTs are additive, the MRT of the oral solution would be made up of the
MRTs of the two processes, thus:

Flow Chart 4-2 Oral Solution

Ka K
Xa X

MRT(os) = MAT(os)+MRT(IV)
MRT(os) = 1/Ka + 1/K

Consequently, if a drug has to be released from a dosage form for the drug to get into solution
which is subsequently absorbed, a tablet for example, the MRT of the tablet will consist of the
MRT(IV) and the MAT(os) and the Mean Dissolution Time (MDT), thus:

Flow Chart 4-3 Tablet

Kd Ka K
Xd Xa X

MRT(tab) = MDT + MAT(os) + MRT(IV)


MRT(tab) = 1/Kd + 1/Ka + 1/K
MRT(tab) = MAT(tab) + MRT(IV)
MRT(tab) = 1/Ka (apparent) + 1/K

Basic Pharmacokinetics REV. 00.1.27 4-6


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I.V. Bolus Dosing

Normally, we don’t have information from the oral solution, just IV and tablet. So in that case
the information obtained about absorption from the tablet is bundled together into an apparent
absorption rate constant consisting of both dissolution and absorption.
It should be apparent that this is a reasonably easily utilized and powerful tool used to obtain
pharmacokinetic parameters.

Basic Pharmacokinetics REV. 00.1.27 4-7


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I.V. Bolus Dosing

4.1.2 IV BOLUS, PARENT COMPOUND, PLASMA PROBLEMS


Equations used in this 1. K = –slope from equation 4-3
section:
ln 2- equation 4-5
2. t 1 ⁄ 2 = -------
K

1
3. MRT = ---- ( estimate ) MRT = AUMC
------------------ equation 4-8
K AUC

4. Cp 0 = the y-intercept of the line from equation 4-3

Cp ∞
5. Estimate for AUC = AUC = ---------0 which is
K ∫0 Cp dt
(∞)
( Cp n + Cp n + 1 ) Cp last
AUC = ∫ Cp dt = Σ  ------------------------------------- ( ∆t ) + --------------
2  K
0

Trapezoidal rule applied to equation 4-6

6. Estimate for AUMC = AUMC = AUC ⋅ MRT from equation 4-8

( ∞) t
( t n ⋅ Cp n ) + ( t n + 1 ⋅ Cp n + 1 ) Cp last ( t last ⋅ Cp l ast )
AUMC ∫ Cp dt = ∑  -------------------------------------------------------------------
2
- ⋅ ∆t n + --------------- + ----------------------------------

K
2 K
0 0

from equation 4-7

7. V d = Dose
------------- from equation 4-4
Cp 0

Cp 0 Dose
8. Cl = K1 ⋅ V d = ------------ ⋅ ------------- = Dose
-------------
AUC Cp 0 AUC

Basic Pharmacokinetics REV. 00.1.27 4-8


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I.V. Bolus Dosing

Acyclovir (Problem 4 - 1)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
De Miranda and Burnette, “Metabolic Fate and Pharmacokinetics of the Acyclovir Prodrug Valaciclovir in Cynomolgus Mon-
keys”, Drug Metabolism and Disposition (1994): 55-59.

Acyclovir is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppressive therapy. In
this study, three male cynomolgus monkeys were each given a 10 mg ⁄ kg intravenous dose. The monkeys weighed an
average of 3.35 kg each. Blood samples were collected and the following data was obtained:
PROBLEM TABLE 4 - 1. Acyclovir

Serum concentration

Time (hours) ( µg ⁄ mL )
0.167 26.0
0.300 23.0
0.500 19.0
0.75 16.0
1.0 12.0
1.5 7.0
2.0 5.0

From the data presented in the Preceding table, determine the following:
1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-9


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I.V. Bolus Dosing

(Problem 4 - 1) Acyclovir:

2
10
CONCENTRATION (MIC/ML)

1
10

100
0.0 0.5 1.0 1.5 2.0

TIME (HR)

–1
1. k = 0.93hr
2. t½ = 0.75hr .

3. MRT = 1.08hr .
4. ( C p )0 = 30.4ug ⁄ mL .

5. AUC = 32.75ug ⁄ mL ⋅ hr .
2
6. AUMC = 35.2ug ⁄ mL ⋅ hr .
7. Vd = 1.1L

8. Cl = 1.02L ⁄ hr .

Basic Pharmacokinetics REV. 00.1.27 4-10


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I.V. Bolus Dosing

Aluminum (Problem 4 - 2)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Xu, Pai, and Melethil, "Kinetics of Aluminum in Rats. II: Dose-Dependent Urinary and Biliary Excretion", Journal of Pharmaceu-
tical Sciences, Oct 1991, p 946 - 951.

A study by Xu, Pai, and Melethil establishes the pharmacokinetics of Aluminum in Rats. In this study, four rats with an
average weight of 375g, were given an IV bolus dose of aluminum (1 mg/kg). Blood samples were taken at various
intervals and the following data was obtained:
PROBLEM TABLE 4 - 2. Aluminum

ng
Serum concentration, --------
Time (hours) mL
0.4 19000
0.6 18000
1.4 15000
1.6 14500
2.3 12500
3.0 10500
4.0 8500
5.0 6500
6.0 5000
8.0 3250
10.0 2000
12.0 1250

From the data presented in the preceding table, determine the following:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-11


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I.V. Bolus Dosing

(Problem 4 - 2) Aluminum:

5
10
CONCENTRATION (NG/ML)

4
10

3
10
0 2 4 6 8 10 12
TIME (HR)

–1
1. k = 0.234hr
2. t½ = 3hr .

3. MRT = 4.3hr .
4. ( C p )0 = 21000ng ⁄ mL .

5. AUC = 89285ng ⁄ mL ⋅ hr .
2
6. AUMC = 383926ng ⁄ mL ⋅ hr .
7. Vd = 17.86mL

8. Cl = 4.18mL ⁄ hr .

Basic Pharmacokinetics REV. 00.1.27 4-12


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I.V. Bolus Dosing

Amgen (Problem 4 - 3)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Salmonson, Danielson, and Wikstrom, "The pharmacokinetics of recombinant human erythropoetin after intravenous and subcuta-
neous administration to healthy subjects", Br. F. clin. Pharmac. (1990), p 709- 713.

Amgen (r-Epo) is a form of recombinant erythropoetin. Erythropoetin is a hormone that is produced in the kidneys and
used in the production of red blood cells. The kidneys of patients who have end-stage renal failure cannot produce
erythropoetin; therefore, r-Epo is being investigated for use in these patients in order to treat the anemia that results
from the lack of erythropoetin. In a study by Salmonson et al, six healthy volunteers were used to demonstrate that
both IV and subcutaneous administration of erythropoetin have similar effects in the treatment of anemia due to
chronic renal failure. The six volunteers were each given a 50 U/kg intravenous dose of Amgen. The average weight
of the six volunteers was 79 kg. Blood samples were drawn at various times and the data obtained is summarized
below:
PROBLEM TABLE 4 - 3. Amgen

mU
Serum concentration, ---------
Time (hours) mL
2 700
4 600
6 400
8 300
12 150
24 40

From the data presented in the preceding table, determine the following:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-13


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 3) Amgen:

103
CONCENTRATION (MU/ML)

102
Con (mU/mL)

101
0 5 10 15 20 25
TIME (HR)

–1
1. k = 0.134hr
2. t½ = 5.2hr .

3. MRT = 7.46hr .
4. ( C p )0 = 900mU ⁄ mL .

5. AUC = 6945mU ⁄ mL ⋅ hr .
2
6. AUMC = 49600 mU ⁄ mL ⋅ hr .
7. Vd = 4.44L

8. Cl = 0.6L ⁄ hr .

Basic Pharmacokinetics REV. 00.1.27 4-14


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

Atrial Naturetic Peptide (ANP) (Problem 4 - 4)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Brier and Harding, "Pharmacokinetics and Pharmacodynamics of Atrial Naturetic Peptide after Bolus and Infusion Administra-
tion in the Isolated Perfused Rat Kidney", The Journal of Pharmacology and Experimental Therapeutics (1989), p 372 - 377.

A study by Brier and Harding a dose of 45 ng was given by IV bolus to rats. Samples of blood were taken at various
intervals throughout the length of the study and the following data was obtained:
PROBLEM TABLE 4 - 4. Atrial Naturetic Peptide (ANP)

pg
Serum concentration, --------
Time (minutes) mL
3 380
10 280
20 170
30 130
40 100
50 70
60 50

From the data presented in the preceding table, determine the following:
1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-15


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 4) Atrial Naturetic Peptide (ANP):

103
Con CONCENTRATION (PG/ML)

102
(pg/mL)

101
0 10 20 30 40 50 60

Time (min)
–1
1. k = 0.0345min
2. t½ = 20.09min .

3. MRT = 28.95min .
4. ( C p )0 = 386.6pg ⁄ mL .

5. AUC = 11206.4pg ⁄ mL ⋅ min .


2
6. AUMC = 324425.4pg ⁄ mL ⋅ min .
7. Vd = 116.4mL

8. Cl = 4.02mL ⁄ min .

Basic Pharmacokinetics REV. 00.1.27 4-16


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

Aztreonam (Problem 4 - 5)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Cuzzolim et al., "Pharmacokinetics and Renal Tolerance of Aztreonam in Premature Infants", Antimicrobial Agents and Chemo-
therapy (Sept. 1991), p. 1726 - 1928.

Aztreonam is a monolactam structure which is active against aerobic, gram-negative bacilli. The pharmacokinetic
parameters of Aztreonam were established in a study presented in by Cuzzolim et al in which Aztreonam (100 mg/ kg)
was administered intravenously to 30 premature infants over 3 minutes every 12 hours. The group of neonates had an
average weight of 1639.6g. The following set of data was obtained:
PROBLEM TABLE 4 - 5. Aztreonam

µg
Serum concentration, --------
Time (minutes) mL
1 40.50
2 34.99
3 29.99
4 23.88
5 22.20
6 19.44
7 16.55
8 14.99

From the data presented in the preceding table, determine the following:
1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-17


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 5) Aztreonam:

10 2
CONCENTRATION (UG/ML)
Con (ug/mL)

10 1
0 2 4 6 8
TIME (MIN)

–1
1. k = 0.144min
2. t½ = 4.81min .

3. MRT = 6.94min .
4. ( C p )0 = 45.75ug ⁄ mL .

5. AUC = 317.7ug ⁄ mL ⋅ min .


2
6. AUMC = 2204.8ug ⁄ mL ⋅ min .
7. Vd = 3.58L

8. Cl = 0.516L ⁄ min .

Basic Pharmacokinetics REV. 00.1.27 4-18


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

Recombinant Bovine Placental Lactogen (Problem 4 - 6)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Byatt, et. al., "Serum half-life and in-vivo actions of recombinant bovine placental lactogen in the dairy cow", Journal of Endocri-
nology (1992), p. 185 - 193.

Bovine placental lactogen (bPL) is a hormone similar to growth hormone and prolactin. It binds to both prolactin and
growth hormone receptors in the rabbit and stimulates lactogenesis in the rabbit. In a study by Byatt, et. al., four cows
(2 pregnant and 2 nonpregnant) were given IV bolus injections of 4 mg and the following data was obtained:
PROBLEM TABLE 4 - 6. Recombinant Bovine Placental Lactogen

µg
Serum concentration ------
Time (minutes) L
3.8 117
6.8 72
12.0 43
16.0 27
20.0 18

From the data presented in the preceding table, determine the following:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-19


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 6) Recombinant Bovine Placental Lactogen:


103

(MIC/L)
ConCONCENTRATION
102
(ug/L)

101
0 5 10 15 20

Time (min)

–1
1. k = 0.113min
2. t½ = 6.13min .

3. MRT = 8.85min .
4. ( C p )0 = 167.8ug ⁄ L .

5. AUC = 1484.9ug ⁄ L ⋅ min .


2
6. AUMC = 13141.1ug ⁄ L ⋅ min .
7. Vd = 23.84L

8. Cl = 2.69L ⁄ min .

Basic Pharmacokinetics REV. 00.1.27 4-20


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

Caffeine (Problem 4 - 7)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Dorrbecker et. al., "Caffeine and Paraxanthine Pharmacokinetics in the Rabbit: Concentration and Product Inhibition Effects.",
Journal of Pharmacokinetics and Biopharmaceutics (1987), p.117 - 131.

This study examines the pharmacokinetics of caffeine in the rabbit. In this study type I New Zealand White rabbits
were given an 8 mg intravenous dose of caffeine. Blood samples were taken and the following data was obtained:
PROBLEM TABLE 4 - 7. Caffeine

µg
Serum concentration --------
Time (minutes) mL
12 3.75
40 2.80
65 2.12
90 1.55
125 1.23
173 0.72
243 0.37

From the data presented in the preceding table, determine the following:
1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-21


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 7) Caffeine:

CONCENTRATION (MIC/ML)
Caffeine
101

100

10-1
Con (ug/L)

0 50 100 150 200 250

Time (min)

–1
1. k = 0.00997min
2. t½ = 69.51min .

3. MRT = 100.3min .
4. ( C p )0 = 4.105ug ⁄ mL .

5. AUC = 411.7ug ⁄ mL ⋅ min .


2
6. AUMC = 41293.5ug ⁄ mL ⋅ min .
7. Vd = 1.95L

8. Cl = 19.44mL ⁄ min .

Basic Pharmacokinetics REV. 00.1.27 4-22


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

Ceftazidime (Problem 4 - 8)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Demotes-Mainard, et. al., "Pharmacokinetics of Intravenous and Intraperitoneal Ceftazidime in Chronic Ambulatory Peritoneal
Dyialysis", Journal of Clinical Pharmacology (1993), p. 475 - 479.

Ceftazidime is a third generation cephalosporin which is administered parenterally. In this study, eight patients with
chronic renal failure were each given 1 g of ceftazidime intravenously. Both blood samples were taken the data
obtained from the study is summarized in the following table:

PROBLEM TABLE 4 - 8. Ceftazidime

mg
Serum concentration -------
Time (hours) L
1 50
2 45
4 38
24 21
36 14
48 11
60 8
72 4

From the data presented in the preceding table, determine the following:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-23


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 8) Ceftazidime:

102

CONCENTRATION (MG/L)

101
Con (mg/L)

100
0 20 40 60 80

Time (hours)
–1
1. k = 0.0324hr
2. t½ = 21.39hr .

3. MRT = 30.86hr .
4. ( C p )0 = 47.57mg ⁄ L .

5. AUC = 1468.2mg ⁄ L ⋅ hr .
2
6. AUMC = 45308.6mg ⁄ L ⋅ hr .
7. Vd = 21.02L

8. Cl = 0.681L ⁄ hr .

Basic Pharmacokinetics REV. 00.1.27 4-24


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

Ciprofloxacin (Problem 4 - 9)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Lettieri, et. al., "Pharmacokinetic Profiles of Ciprofloxacin after Single Intravenous and Oral Doses", Antimicrobial Agents and
Chemotherapy (May 1992), p. 993 -996.

Ciprofloxacin is a fluoroquinolone antibiotic which is used in the treatment of infections of the urinary tract, lower res-
piratory tract, skin, bone, and joint. In this study, twelve healthy, male volunteers were each given 300 mg intravenous
doses of Ciprofloxacin. Blood and urine samples were collected at various times throughout the day and the following
data was collected:
PROBLEM TABLE 4 - 9. Ciprofloxacin

mg
Serum concentration -------
Time (hours) L
2 1.20
3 0.85
4 0.70
6 0.50
8 0.35
10 0.25

From the data presented in the preceding table, determine the following:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-25


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 9) Ciprofloxacin:

101

CONCENTRATION (MG/L)
100
Con (mg/L)

10-1
0 2 4 6 8 10

Time (hours)

–1
1. k = 0.1875hr
2. t½ = 3.7hr .

3. MRT = 5.33hr .
4. ( C p )0 = 1.57mg ⁄ L .

5. AUC = 8.395mg ⁄ L ⋅ hr .
2
6. AUMC = 44.74mg ⁄ L ⋅ hr .
7. Vd = 190.6L

8. Cl = 35.74L ⁄ hr .

Basic Pharmacokinetics REV. 00.1.27 4-26


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

The effect of Probenecid on Diprophylline (DPP) (Problem 4 - 10)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Nadai et al, "Pharmacokinetics and the Effect of Probenecid on the Renal Excretion Mechanism of Diprophylline", Journal of
Pharmaceutical Sciences (Oct 1992), p. 1024 - 1027.

Diprophylline is used as a bronchodilator. A study by Nadai et al was designed to determine whether or not coadmin-
istration of Diprophylline with Probenecid affected the pharmacokinetic parameters of Diprophylline. In this study,
male rats (average weight: 300 g) were given 60 mg/kg of Diprophylline intravenously and a 3 mg/kg loading dose of
Probenecid followed by a continuous infusion of 0.217 mg/min/kg of Probenecid. The following set of data was
obtained for Diprophylline (DPP):

PROBLEM TABLE 4 - 10. The effect of Probenecid on Diprophylline (DPP)

µg
Serum concentration --------
Time (minutes) mL
16 40.00
31 27.00
60 13.00
91 6.50
122 3.50

From the data presented in the preceding table, determine the following:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-27


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 10) The effect of probenecid on diprophylline (DPP):

102
CONCENTRATION (MIC/ML)

101
Con (ug/mL)

100
0 20 40 60 80 100

Time (min)
–1
1. k = 0.023min
2. t½ = 30.13min .

3. MRT = 43.48min .
4. ( C p )0 = 55.13ug ⁄ mL .

5. AUC = 2396.96ug ⁄ mL ⋅ min .


2
6. AUMC = 104219.8ug ⁄ mL ⋅ min .
7. Vd = 326.5mL

8. Cl = 7.5mL ⁄ min .

Basic Pharmacokinetics REV. 00.1.27 4-28


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

Epoetin (Problem 4 - 11)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
MacDougall et. al., "Clinical Pharmacokinetics of Epoetin (Recombinant Human Erythropoetin", Clinical Pharmacokinetics
(1991), p 99 - 110.

Epoetin is recombinant human erythropoetin. Erythropoetin is a hormone that is produced in the kidneys and used in
the production of red blood cells. The kidneys of patients who have end-stage renal failure cannot produce erythropo-
etin; therefore, Epoetin is used in these patients to treat the anemia that results from the lack of erythropoetin. Epoetin
has also been used in the treatment of anemias resulting from AIDS. malignant disease, prematurity, rheumatoid arthri-
tis, sickle-cell anemia, and myelosplastic syndrome. In a study by Macdougall et al, eight patients who were on perito-
neal dialysis (CAPD) were given an IV bolus dose of 120 U/kg which decayed monoexponentially from a peak of 3959
U/L to 558 U/L at 24 hours. The following data was obtained:
PROBLEM TABLE 4 - 11. Epoetin

U
Serum concentration ----
Time (hours) L
0.0 4000
0.5 3800
1.0 3600
2.0 3300
3.0 3000
4.0 2550
5.0 2350
6.0 2150
7.0 1900

From the data presented in the preceding table and assuming that the patient weighs 65 kg, determine the following:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-29


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 11) Epoetin:

104
CONCENTRATION (U/L)
Con (U/L)

103
0 1 2 3 4 5 6 7

Time (hours)
–1
1. k = 0.107 hr
2. t½ = 6.5 hr .

3. MRT = 9.38 hr .
4. ( C p )0 = 4023 Units/L .

Units ⋅ hr
5. AUC = 37775 ------------------------ .
L
2
Units ⋅ hr
6. AUMC = 354697 --------------------------- .
L
7. Vd = 1.9 L

L
8. Cl = 0.2065 ----- .
hr

Basic Pharmacokinetics REV. 00.1.27 4-30


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

Famotidine (Problem 4 - 12)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Kraus, et. al., "Famotidine--Pharmacokinetic Properties and Suppression of Acid Secretion in Pediatric Patients Following Car-
diac Surgery", Clinical Pharmacokinetics (1990), p 77 - 80.

Famotidine is a histamine H2-receptor antagonist. The study by Kraus, et. al., focuses on the kinetics of famotidine in
children. In the study, ten children with normal kidney function and a body weight ranging from 14 - 25 kg, were each
given a single intravenous 0.3 mg/kg dose of famotidine. Blood and urine samples were taken providing the following
data:
PROBLEM TABLE 4 - 12. Famotidine

µg
Serum concentration ------
Time (hours) L
0.33 300
0.50 250
1.00 225
4.00 125
8.00 70
12.00 40
16.00 15

From the data presented in the preceding table, determine the following assuming that the patient weighs 17.2 kg:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-31


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 12) Famotidine:

10 3

(MIC/L)
ConCONCENTRATION
10 2
(ug/mL)

10 1
0 5 10 15 20

Time (hours)
–1
1. k = 0.17 hr
2. t½ = 3.9 hr .

3. MRT = 5.7 hr .
µg
4. ( C p )0 = 285 ------ .
L
µg ⋅ hr
5. AUC = 1600 ----------------- .
L
2
µg ⋅ hr
6. AUMC = 9000 ------------------ .
L
7. Vd = 18 L

8. Cl = 3.2L .

Basic Pharmacokinetics REV. 00.1.27 4-32


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

Ganciclovir (Problem 4 - 13)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Trang, et. al., "Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections", Clin-
ical Pharmacology and Therapeutics (1993), p. 15 - 21.

Ganciclovir (mw: 255.23) is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus
infections of the gastrointestinal tract. In this study, twenty-seven newborns with cytomegalovirus disease were given
4 mg/kg of ganciclovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in
the following table:

PROBLEM TABLE 4 - 13. Ganciclovir

Time (hours) Serum concentration


1.50 4.50
2.00 4.00
3.00 3.06
4.00 2.40
6.00 1.45
8.00 0.87

From the data presented in the preceding table and assuming the patient weighs 3.6 kg, determine the following :

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-33


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 13) Ganciclovir:

10

CONCENTRATION (MICMOLE/L)

10

10
0 2 4 6 8

TIME (HR)

–1
1. k = 0.288hr
2. t½ = 2.4hr .

3. MRT = 3.5hr .
µmole
4. ( C p )0 = 23 ---------------- .
mL
µmole ⋅ hr
5. AUC = 80 -------------------------- .
mL
2
µmole ⋅ hr
6. AUMC = 280 ----------------------------- .
mL
mg 1000µg
4 ------- ⋅ 3.6kg ⋅ -------------------
Dose kg mg
7. Vd = ------------- = ------------------------------------------------------------- = 2.45L
Cp 0 µmole µg
23 ---------------- ⋅ 255.23 ----------------
L µmole
L
8. Cl = 0.7 ----- .
hr

Basic Pharmacokinetics REV. 00.1.27 4-34


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

Imipenem (Problem 4 - 14)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Heikkila, Renkonen, and Erkkola, "Pharmacokinetics and Transplacental Passage of Imipenem During Pregnancy", Antimicrobial
Agents and Chemotherapy (Dec. 1992), p 2652 - 2655.

Imipenem is a beta-lactam antibiotic which is used in combination with cilastin and is active against a broad spectrum
of bacteria. The pharmacokinetics of Imipenem in pregnant women is established in this study. Twenty women (six of
which were non-pregnant controls) were given a single intravenous dose of 500 mg of imipenem-cilastin (1:1). Blood
samples were taken at various intervals and the data obtained is summarized in the following table:

PROBLEM TABLE 4 - 14. Imipenem

mg
Serum concentration -------
Time (minutes) L
10 27.00
15 23.50
30 15.50
45 9.50
60 6.50

From the data presented in the preceding table, determine the following:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-35


Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
I.V. Bolus Dosing

(Problem 4 - 14) Imipenem:


2
10

CONCENTRATION (MG/L)

1
10

0
10
0 10 20 30 40 50 60

TIME (MIN)

–1
1. k = 0.029 min
2. t½ = 24 min .

3. MRT = 34.5 min .


mg
4. ( C p )0 = 36.2 ------- .
L
mg ⋅ min
5. AUC = 1250 --------------------- .
L
2
mg ⋅ min
6. AUMC = 43125 ------------------------ .
L
Dose 500mg
7. Vd = ------------- = ------------------ = 13.8L
Cp 0 mg
36.2 -------
L
L
8. Cl = 0.4 --------- .
min

Basic Pharmacokinetics REV. 00.1.27 4-36


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I.V. Bolus Dosing

Methylprednisolone (Problem 4 - 15)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Patel, et. al., "Pharmacokinetics of High Dose Methylprednisolone and Use in Hematological Malignancies", Hematological
Oncology (1993), p. 89 - 96.

Methylprednisolone is a corticosteriod that has been used in combination chemotherapy for the treatment of hemato-
logical malignancy, myeloma, and acute lymphoblastic leukemia. In a study by Patel et. al., eight patients were given
1.5 gram intravenous doses of methylprednisolone from which the following data was obtained:

PROBLEM TABLE 4 - 15. Methylprednisolone

µg
Serum concentration --------
Time (hours) mL
0.5 19.29
1.0 17.56
1.8 15.10
4.0 9.98
5.8 7.10
8.0 4.70
12.0 2.21
18.0 0.71
24.0 0.23

From the data presented in the preceding table, determine the following:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-37


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I.V. Bolus Dosing

(Problem 4 - 15) Methylprednisolone:

102

CONCENTRATION (MIC/ML)
101

100
Con (ug/mL)

10-1
0 5 10 15 20 25

Time (hours)
–1
1. k = 0.188 hr
2. t½ = 3.69hr .

3. MRT = 5.3hr .
µg
4. ( C p )0 = 21.2 -------- .
mL
µg ⋅ hr
5. AUC = 112.5 ----------------- .
mL
2
µg ⋅ hr
6. AUMC = 598.4 ------------------ .
mL
7. Vd = 71L

L
8. Cl = 13.3 ----- .
hr

Basic Pharmacokinetics REV. 00.1.27 4-38


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I.V. Bolus Dosing

Omeprazole (Problem 4 - 16)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Anderson, et. al., "Pharmacokinetics of [14C] Omeprazole in Patients with Liver Cirrhosis", Clinical Pharmacokinetics (1993), p.
71 - 78.

Omeprazole (mw: 345.42) is a gastric proton-pump inhibitor which decreases gastric acid secretion. It is effective in
the treatment of ulcers and esophageal reflux. In normal patients 80% of the omeprazole dose is excreted as metabo-
lites in the urine and the remainder is excreted in the feces. In the study by Anderson, et. al., eight patients with liver
cirrhosis were given 20 mg, IV bolus doses of omeprazole. The patients had a mean body weight of 70 kg. Both blood
were taken at various intervals throughout the study and the following data was obtained:

PROBLEM TABLE 4 - 16. Omeprazole

ρmole
Serum concentration ----------------
Time (hours) mL
0.75 3.49
1.00 3.25
2.00 2.46
3.00 1.86
4.00 1.40
5.00 1.06
6.00 0.80
7.00 0.61
8.00 0.46
10.00 0.26
12.00 0.15

From the data presented in the preceding table, determine the following :

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-39


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I.V. Bolus Dosing

(Problem 4 - 16) Omeprazole:

10 1

(umol/mL) (PICOMOLE/ML)
10 0
ConCONCENTRATION

10-1
0 2 4 6 8 10 12

Time (hours)
–1
1. k = 0.280hr
2. t½ = 2.5hr .

3. MRT = 3.57hr .
ρmole
4. ( C p )0 = 4.3 ---------------- .
mL
ρmole ⋅ hr
5. AUC = 15.4 -------------------------- .
mL
2
ρmole ⋅ hr
6. AUMC = 55 ----------------------------- .
mL
Dose 20mg
7. Vd = ------------- = ------------------------------------------------------------------------------------------------------------ = 13465L
Cp 0 ρmole mmole
4.3 ---------------- ⋅ ------------------------ - ⋅ 345.42mg
------------------------ ⋅ 1000mL
--------------------
mL 10 ρmole mmole 9 L

L
8. Cl = 3.9 ----- .
hr

Basic Pharmacokinetics REV. 00.1.27 4-40


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I.V. Bolus Dosing

Pentachlorophenol (Problem 4 - 17)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Reigner, Rigod, and Tozer, "Absorption, Bioavailability, and Serum Protein Binding of Pentachlorophenol in the B6C3F1 Mouse",
Pharmaceutical Research (1992), p 1053 - 1057.

Pentachlorophenol (PCP) is a general biocide. That is, it is an insecticide, fungicide, bactericide, herbicide, algaecide,
and molluskicide, that is used as a wood preservative. Extensive exposure to PCP can be fatal. In a study by Reigner
et al, six mice (average weight: 27 g) were given 15 mg/kg of PCP by intravenous bolus. Blood samples were taken at
various intervals from which the following data was obtained:
PROBLEM TABLE 4 - 17. Pentachlorophenol

µg
Serum concentration --------
Time (hours) mL
0.083 38.00
4.000 22.00
8.000 14.00
12.000 7.90
24.000 1.30
28.000 0.75
32.000 0.60
36.000 0.40

From the data presented in the preceding table, determine the following :
1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-41


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I.V. Bolus Dosing

(Problem 4 - 17) Pentachlorphenol:

CONCENTRATION (MIC/ML)
102

101

100
Con (ug/mL)

10-1
0 10 20 30 40

Time (hours)

–1
1. k = 0.134 hr
2. t½ = 5.2hr .

3. MRT = 7.5hr .
µg
4. ( C p )0 = 35.6 -------- .
mL
µg ⋅ hr
5. AUC = 281 ----------------- .
mL
2
µg ⋅ hr
6. AUMC = 2100 ------------------- .
mL
7. Vd = 11.4mL

ml
8. Cl = 1.5 ------ .
hr

Basic Pharmacokinetics REV. 00.1.27 4-42


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I.V. Bolus Dosing

9-(2-phophonylmethoxyethyl) adenine (Problem 4 - 18)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Naesens, Balzarini, and Clercq, "Pharmacokinetics in Mice of the Anti-Retrovirus Agent 9-(2-phophonylmethoxyethyl) adenine",
Drug Metabolism and Disposition (1992), p. 747- 752.

9-(2-phophonylmethoxyethyl) adenine (PEMA) is an anti-retrovirus (anti-HIV) agent. The pharmacokinetics of


PEMA in mice were established in a study by . In this study there were three different PEMA doses given: 25 mg/kg,
100 mg/kg, and 500 mg/kg. Each of these doses was injected intravenously into male mice. The data obtained from
study using the 25 mg/kg dose is summarized in the following table:

PROBLEM TABLE 4 - 18. 9-(2-phophonylmethoxyethyl) adenine

µg
Serum concentration --------
Time (minutes) mL
2.0 90.3
2.9 83.9
5.6 67.3
8.9 51.5
10.5 45.2
13.5 35.4
15.0 31.3
20.0 20.9
24.0 15.1
59.6 0.9

From the data presented in the preceding table, determine the following. (Assume that the mouse weighs 200g.)

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-43


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I.V. Bolus Dosing

(Problem 4 - 18) Pema:

10 2

ConCONCENTRATION (MIC/ML) 10 1

10 0
(ug/mL)

10 -1
0 10 20 30 40 50 60

Time (min)

–1
1. k = 0.08min
2. t½ = 8.67min .

3. MRT = 12.5min .
µg
4. ( C p )0 = 105 -------- .
mL
µg ⋅ hr
5. AUC = 1300 ----------------- .
mL
2
µg ⋅ hr
6. AUMC = 16250 ------------------- .
mL
7. Vd = 47.6ml

mL
8. Cl = 3.8 --------- .
min

Basic Pharmacokinetics REV. 00.1.27 4-44


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I.V. Bolus Dosing

Thioperamide (Problem 4 - 19)


Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Sakurai, et. al., "The Disposition of Thioperamide, a Histamine H3-Antagonist, in Rats", J. Pharm. Pharmacol. (1994), p. 209 -
212.

Thioperamide is a histamine (H3) receptor-antagonist. In a study by Sakurai et al, rats were given 10 mg/kg intrave-
nous injections of Thioperamide. The following data was obtained from the study:
PROBLEM TABLE 4 - 19. Thioperamide

µg
Serum concentration --------
Time (minutes) mL
3.7 3.1
7.5 2.8
13 2.4
45 1.1
60 0.74
120 0.16

From the data presented in the preceding table, determine the following:

1. Find the elimination rate constant, k .

2. Find the half life, t ½ .

3. Find MRT .

4. Find ( C p )0 .

5. Find the Area Under the Curve, AUC .

6. Find the area under the first moment curve, AUMC .

7. Find the volume of distribution, V d

8. Find the clearance, Cl .

Basic Pharmacokinetics REV. 00.1.27 4-45


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I.V. Bolus Dosing

(Problem 4 - 19) thioperamide:

101

ConCONCENTRATION (MIC/ML)

100
(ug/mL)

10-1
0 20 40 60 80 100 120

Time (min)
–1
1. k = 0.0254min
2. t½ = 27.3min .

3. MRT = 39.4min .
µg
4. ( C p )0 = 3.39 -------- .
mL
µg ⋅ min
5. AUC = 133.5 --------------------- .
mL
2
µg ⋅ min
6. AUMC = 5256 ----------------------- .
mL
mg
10 -------
Dose kg L
7. Vd = ------------- = -------------------------------------------------------------------- = 2.95 ------
Cp 0 µg mg 1000mL kg
3.39 -------- ⋅ ------------------- ⋅ --------------------
mL 1000µg L
–1 L 1000ml mL
8. Cl = 0.0254min ⋅ 2.95 ------ ⋅ ------------------ = 75 -------------------- .
kg L min ⋅ kg

Basic Pharmacokinetics REV. 00.1.27 4-46


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I.V. Bolus Dosing

Cocaine (Problem 4 - 20)

Khan,vM. et. al. “Determination of pharmacokinetics of cocaine in sheep by liquid chromatography” J. Pharm. Sci. 76:1 (39-43)
Jan 1987

Basic Pharmacokinetics REV. 00.1.27 4-47


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I.V. Bolus Dosing

4.1.3 URINE

From the Laplace Transform of a drug given by IV bolus we find that :

k ( –K ⋅ t )
Xu = ----u- ⋅ X0 ⋅ ( 1 – e ) (EQ 4-10)
K

where Xu is the cumulative amount of drug in the urine at time t. Rearranging, we


get:

k
( Xu )∞ – Xu =  ----u- ⋅ X 0 ⋅ e
– Kt
 K
(EQ 4-11)

ku
where the amount of drug that shows up in the urine at infinite time, ( X u ) ∞ = ----- ⋅ X 0 .
K
Thus a plot of ( Xu )∞ – X u vs. time on semi-log paper would result in a straight line
with a slope of -K and an intercept of ( X u ) ∞ .. and we can get ku from the intercept
( X u )∞
and the slope. Rearranging the intercept equation, we get k u = K ⋅ -------------- This method
X0
of obtaining pharmacokinetic parameters is known as the Amount Remaining to be
Excreted (ARE) method.
TABLE 4-4 Enalapril urinary excretion data from 5 mg IV Bolus
Cumulative

Enalapril in urine X – X u mg
Time (hr) (mg) u
1 0.41 0.59
2 0.65 0.35
3 0.80 0.20
4 0.88 0.12
6 0.96 0.04
∞ 1.0 ------

Basic Pharmacokinetics REV. 00.1.27 4-48


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I.V. Bolus Dosing

Utilizations: A.R.E. FIGURE 4-2. Cumulative Enalapril in urine


Method
10
0

0.2

Xu(inf) - Xu
0.1
-1
10

1.3 hr

half life
-2
10
0 1 2 3 4 5 6
Hours

• You should be able to transform a data set containing amount of drug in the urine vs. time into
cumulative amount of drug in the urine vs. time and plot the ARE. (Amount Remaining to be
Excreted -> { ( Xu )∞ – Xu ( cum ) } vs. time on semi-log yielding a straight line with a slope of

–1 ku ⋅ X0
– K = – 0.533 hr and an intercept of ( Xu ) ∞ = --------------- = 1.0 mg
K
• You should be able to determine the elimination rate constant, K1, from cumulative urinary
excretion data. (Calculate the slope of the graph on SL paper.)
• You should be able to determine the excretion rate constant, ku, from cumulation urinary excre-
tion data. (Divide the intercept of the graph by X0 and multiply by K1.
( X u )∞ –1 1.0 mg –1
k u = K ⋅ -------------- = 0.53 hr ⋅ ----------------- = 0.106 hr )
X0 5.0 mg

• You should be able to determine k m . K = k u + k m


• You should be able to calculate percent metabolized or excreted from a data set. Thus,
km k
Percent metabolized = ------ ⋅ 100 and percent excreted unchanged = ----u- ⋅ 100 assuming
K K
K = k u + km

A second method is to plot the rate at which the drug shows up in the urine over
time. Again, using the LaPlace transforms, we find that:

dX u –K t –K t
--------- = k u ⋅ X0 ⋅ e = R0 ⋅ e (EQ 4-12)
dt
Utilization: Rate of Thus, a plot of the rate of excretion vs. time results in a straight line on semi-log
excretion method paper with a slope of -K1 and an intercept, R0 , of kuX0 . Rearranging the intercept

Basic Pharmacokinetics REV. 00.1.27 4-49


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I.V. Bolus Dosing

R
equation yields k u = -----0- . In real data, we don’t have the instantaneous excretion
X0

dX u ∆X
rate , but the average excretion rate, ---------u- , over a much larger interval. What
dt ∆t
that means to our calculations is that over the interval of data collection, the total
amount of drug collected divided by the total time interval is the average rate. In
the beginning of the interval the rate was faster than at the end of the interval. So
the average rate must have occurred in the middle of the interval. Thus equation 4-
12 which is the instantaneous rate can be rewritten to

∆Xu –K t
mid
–K t
mid
---------- = k u ⋅ X 0 ⋅ e = R0 ⋅ e (EQ 4-13)
∆t
TABLE 4-5 Enalapril Urinary Rate Data

Enalapril in ∆X
urine ∆X u ,(mg) ---------u-
Interval (hr) t(mid) ∆t ∆t
0-1 0.5 1 0.41 0.41
1-2 1.5 1 0.24 0.24
2-3 2.5 1 missed sample ?
3-4 3.5 1 0.08 0.08
4-6 5 2 0.08 0.04
• You should be able to transform a data set containing amount of drug in the urine vs. time inter-
∆X
val into Average Rate, ---------u- , vs. t ,(t mid the time of the midpoint of the interval), on semilog
∆t
yielding a straight line with a slope of – K and an intercept of k u ⋅ X 0 . as shown below.

-1
0
10
R0 = 0.53 mg/hr
Urinary Excretion Rate (mg/hr)

-1
-2
10

1.3 hr

half life
-2
10
0 1 2 3 4 5
T (Mid)

• You should be able to determine k u extrapolate the line to t = 0 . The value of Rate (at
t = 0 ), R0, = k r ⋅ X0 = 0.53 ( mg ⁄ hr ) which when divided by X 0 .is kr.

Basic Pharmacokinetics REV. 00.1.27 4-50


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I.V. Bolus Dosing

R 0.53mg/hr –1
Thus, -----0- = ------------------------- = 0.106hr
X0 5mg

• You should be able to determine k m . K = k u + k m


• You should be able to calculate percent metabolized or excreted from a data set.

The rate equation is superior clinically because the ARE method requires collec-
tion of all of the urine which is usually only possible when you have a catheterized
patient while the Rate Method does not. (People don’t urinate on command, and
your data could be in the toilet, literally.)


An additional advantage of the rate equations is that the AUC has the units of
0
mass, which gives the total amount of drug excreted into the urine directly. Thus:

∞ R 0 0.53 mg/hr
AUC = ------ = --------------------------
–1
= 1 mg
0 K 0.53 hr

AN INTERESTING OBSERVATION: If you look at the LaPlace Transform of the


rate equation for any terminal compartment, you would see that the resulting equa-
tion is that of the previous compartment times the rate constant through which the
drug entered the terminal compartment. Thus, the rate of drug showing up in the
urine (terminal compartment) is:

dX –K t –K t
--------u- = k u ⋅ X 0 ⋅ e = R0 ⋅ e
dt

where ku is the rate constant through which the drug entered the urine and
dX –K t
------- = X 0 ⋅ e is the equation of the previous compartment.
dt

Basic Pharmacokinetics REV. 00.1.27 4-51


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I.V. Bolus Dosing

4.2 Metabolite

4.2.1 PLASMA

Remember, the LaPlace Transform of the metabolite data yielded


( km ⋅ Xo ) –Kt – K 1t ( km ⋅ Xo ) – K 1t – Kt
X m = ---------------------- ⋅ ( e – e ) or Xm = ---------------------- ⋅ ( e – e ) depending on
( K1 – K ) ( K – K1 )
which rate constant that we arbitrarily assigned to be K, the summation of all the
ways that the drug is removed from the body and K1, the summation of all the
ways that the metabolite is removed from the body. When we begin to manipulate
the data, we know that we have a curve with two different exponents in it. (If they
were the same, the equation would be different.) We don’t know which is bigger,
K1 or K, but we can rewrite the equation to simply reflect Klarge and Ksmall, know-
ing that one is K1 and the other is K but not which is which. If we, then, devided
both sides of the equation by Vdm, the volume of distribution of the metabolite,
we would get :

– ( K l arg e ⋅ t )
 km   X 0   – ( Ksmall ⋅ t ) 
C pm =  --------------------------------------  ----------  e –e  (EQ 4-14)
 K l arg e – K small  V dm  
Utilization: • You should be able to plot a data set of plasma concentration of metabolite vs. time on semi-log
Curve Stripping paper yielding a bi-exponential curve.
–k t –k t
– Kt l arg e small
e → 0 as t → ∞ . And e → 0 faster than e → 0 . So, at some long
–K t –K t –K t
l arg e small l arg e
time, t, e «e . In fact e is small enough to be ignored. Thus at long
time, t, the equation becomes :

km X0   –( Ksmall ⋅ t )
C pm =  ----------------------------------
-  --------
- e
K l arg e – K small  V dm   (EQ 4-15)

So that the plot of the terminal portion of the graph would yield a straight line with a slope of
km
 ---------------------------------- X0 
-Ksmall and an intercept of I = -  --------
-
 K l arg e – K small  Vdm
• You should be able to obtain the slope of the terminal portion of the curve, the negative of
which would be the smaller of the two rate constants, K small , (either the summation of all the
ways that the drug is eliminated, K , or the summation of all the ways that the metabolite is
eliminated, K1 ).
• Subtracting the two previous equations yields

Basic Pharmacokinetics REV. 00.1.27 4-52


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I.V. Bolus Dosing

km X 0   –( Kbig ⋅ t )
C pm – C pm =  ----------------------------------
-  --------
- e
K l arg e – K small  Vdm   (EQ 4-16)

which is a straight line on semi-log paper with a slope of -kbig and an intercept of
km X0
I =  ------------------------------------  --------- . Note: we can get the larger of the two rate constants from this
 K l arg e – K small  V dm
method.
TABLE 4-6

Drug Metabolite

(1) (2) (3) (4) (5)

Cp
Time (hr) (mcg/L) Cpm1 (mcg/L) Cpm Cpm – Cpm
0 0 181.2 181.2
0.5 24.7 175 150.3
1 44.4 168.9 124.5
2 139 71.8 157.5 85.7
4 65.6 96.5 136.9 40.4
6 31.1 100 119 19
8 14.6 94.7
12 76.5
24 34
In the above data Cp vs. Time is the plasma profile of the drug from Table 4-1 on page 2 and
Cpm1 vs. Time is the plasma profile of the metabolite. A plot of Cp vs. Time yielded a straight
0.693 –1
line with a slope,(-K) of -0.375 hr-1, K = ---------------------- = 0.375 hr and and intercept of 295 mic/
–1
1.85 hr
L,

Basic Pharmacokinetics REV. 00.1.27 4-53


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I.V. Bolus Dosing

Figure 4-1 on page 3 (column 2 vs. 1 in Table 4-6 on page 53)

10 3

Cpo = 295 mic/L

Concentration (mic/L)
100

10 2

Concentration (ng/mL)
50
1.85 hr
10 1
0 2 4 6 8

Time (hours)

Time (hr)

while a plot of Cpm1 vs. Time( Figure 4-3 on page 54) yields a biexponential plot with a termi-
nal slope of 0.07 hr-1 , k small = 0.693
------------- and extrapolating the terminal line back to time = 0
10 hr
yields 181 mic/L.

FIGURE 4-3. Nifedipine Metabolite (column 3 vs. 1 in Table 4-6 on page 53)
)

Nifedipine IV bolus - Metabolite


103

mic
Cpm0 = 181 ---------
L
Concentration (mic/L)

80
102

40
10 hr
101
0 4 8 12 16 20 24

Time (hours)

Basic Pharmacokinetics REV. 00.1.27 4-54


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I.V. Bolus Dosing

• You should be able to feather (curve strip) the other rate constant out of the data by plotting the
difference between the extrapolated (to t = 0 ) terminal line (column 4 vs. 1 in Table 4-6 on
page 53) and the observed data (at early times) (column 3 vs. 1 in Table 4-6 on page 53) yield-
ing a straight line with the slope of the line equal to the negative of the other (larger) rate con-
stant (column 5 vs. 1 in Table 4-6 on page 53).

First you would fill in the Cpm column (column 4 in Table 4-6 on page 53) by computing Cpm
– k small t
for various values of time i.e Cpm = Cpm 0 ⋅ e where – k small is the terminal slope of the

graph. Then Cpm – Cpm (column 5 in Table 4-6 on page 53) would be column 4 - column 3.

Then a plot of Cpm – Cpm vs. time (column 5 vs. 1 in Table 4-6 on page 53) is shown below.

FIGURE 4-4. Curve strip of Nifedipine Metabolite data

10
3

Intercept
2
Column 5

100
102

50 1.85 hr
Half life
1
10
0 1 2 3 4 5 6

Time (hr)

In this case, the slope of the stripped line line is -0.375 hr-1 and the intercept is 0.181.2 mic/L.
The slope of -0.375 hr-1 should not be surprising as the plot of the data in Figure 4-3 on page 54
resulted in a terminal slope of -.07 hr-1 . Since the data set yielded a bi-exponential plot, sepa-
rating out the exponents could only yield K (0.375 hr-1) or K1 as determined by our Laplace
Transform information. Thus, the terminal slope could be either -K1 or -K. Since it was obvi-
ously not -K, it had to be -K1. Thus the other rate constant obtained by stripping has to be K.
You can determine which slope is which rate constant if you have any data regarding intact drug
(i e. either plasma or urine time profiles of intact drug) as the slope of any of those profiles is
always –K .
• You should be able to determine V dm if you have any urine data regarding intact drug (i.e.
urine time profiles of intact drug) as the intercept of those profiles allow for the solution of k m .
Thus the intercept, I, of the extrapolated line of equation 4-14 could be rearranged to contain
–1 1000 mic
km ⋅ X0 0.375hr ⋅ 25mg ⋅ ----------------------
mg
only one unknown variable, V dm = ----------------------------------------------- = -------------------------------------------------------------------------- = 170 L .
( K l arg e – K small ) ⋅ I –1 mic
( 0.375 – 0.07 ) hr ⋅ 181.2 ---------
L

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I.V. Bolus Dosing

Utilization: • You should be able to determine the rate constants using MRT calculations.
MRT Calculations In a caternary chain, each compartment contributes its MRT to the overall MRT of the drug,
thus:

Flow Chart 4-4 IV Bolus

K
X

MRT(IV) = 1/K

Suppose the drug were given by IV bolus. Then the drug would have to be metabolized and the
metabolite eliminated. Since the MRTs are additive, the overall MRT of the metabolite would
be made up of the MRTs of the two processes, thus:

Flow Chart 4-5 Metabolite

km kmu
X Xm

MRT(met) = MRT(elim)+MRT(IV)
MRT(met) = 1/K1 + 1/K

Thus, using the data from Table 4-3 on page 5 the MRT(IV)Trap is
------------------ = 1986.1
MRT = AUMC ---------------- = 2.42 hr or about MRT = AUMC
------------------ = 2100
------------ = 2.67 hr using calculus.
AUC 819.9 AUC 787
And using the data from columns 1 and 3 from Table 4-6 on page 53 the MRT(met) using calcu-
------------------ = 36000
lus is MRT = AUMC --------------- = 17 hr.
AUC 2116

MRT(elim) = MRT(met) - MRT(IV) = 17 hr - 2.67 hr = 14.33 hr = 1/K2. Thus K2 = 0.07 hr-1.

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I.V. Bolus Dosing

4.2.2 URINE
Valid equations:

dXmu k mu ⋅ k m X0  – K small t – K l arg e t 


------------- = ---------------------------------------- ⋅  e –e  (EQ 4-17)
dt ( K l arg e – K small )  
Utilization: as in the previous urinary rate equation, clinically we work with the average rate
over a definite interval which results in rewriting equation 4-17 as:

∆Xmu k mu ⋅ k m X 0  – Ksmall tmid – K l arg e t mid 


- ⋅ e
------------- = --------------------------------------- –e  (EQ 4-18)
∆t ( K l arg e – K small )  
• You should be able to plot a data set of rate of metabolite excreted vs. time (mid) on semi-log
paper yielding a bi-exponential curve.
• You should be able to obtain the slope of the terminal portion of the curve, the negative of
which would be the smaller of the two rate constants (either K1 or K ).
• You should be able to feather (curve strip) the other rate constant out of the data by plotting the
difference between the extrapolated (to t = 0 ) terminal line and the observed data (at early
times) yielding a straight line with the slope of the line equal to the negative of the other (larger)
rate constant (either K1 or K ).
• You should be able to utilize MRT calculations to obtain K1 and K .
• You should be able to determine which slope is which rate constant if you have any data regard-
ing intact drug (i.e. either plasma or urine time profiles of intact drug) as the slope of any of
those profiles is always –K .

By this time, it should be apparent that data which fits the same shape curve
(mono-exponential, bi-exponential, etc.) are treated the same way. When the
curves are evaluated, the slopes and intercepts are obtained in the same manner.
The only difference is what those slopes and intercepts represent. These represen-
tations come from the equations which come from the LaPlace Transforms which
come from our picture of the pharmacokinetic description of the drug. Please
refer back to the section on graphical analysis in the Chapter 1, Math review for a
interpretation of slopes and intercepts of the various graphs.

Temporarily, please refer to exam section 1, chapter 14 for problems for this sec-
tion (until problems can be generated) as well as additional problems for the previ-
ous sections.

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CHAPTER 5 I.V. Infusion

Author: Michael Makoid and John Cobby


Reviewer: Phillip Vuchetich

OBJECTIVES
1. Given patient drug concentration and/or amount vs. time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters available ( V d , K, k m , k r ,
AUC , Clearance, MRT) from IV infusion data.
2. I.V. Infusion dosing for parent compounds
3. Plasma concentration vs. time profile analysis
4. Rate vs. time profile analysis
5. Professional communication of IV Infusion information
6. Computer aided instruction and simulation
7. Metabolite (active vs. inactive)

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I.V. Infusion

5.1 Parent compound

5.1.1 PLASMA
Valid equations:

Q – Kt
C p = -------------- ( 1 – e ) or (EQ 5-1)
K ⋅ Vd

Dose – Kt
-( 1 – e )
C p = -------------------------------------- (EQ 5-2)
K ⋅ Vd ⋅ T infusion
at any time during the infusion

Q
( C p )ss = -------------- (EQ 5-3)
K ⋅ Vd
at steady state (t is long)

– Kt
C p = C p( term ) ⋅ e (EQ 5-4)

after termination of infusion

Where C p is the plasma concentration

Dose is the infusion rate shown in equation 5-1 and equation 5-2.
Q = -------------------
T infusion

Q – Kt infusion
C p( term ) = -------------- ( 1 – e ) is the plasma concentration when the
K ⋅ Vd
infusion is stopped.

Rewriting equation 5-4 to an equation which may be used by a computer results in:

Q - ( e – K ⋅ T∗ – e – K ⋅ T )
Cp = ----------- (EQ 5-5)
K⋅V

where T∗ = ( T – T i v ) for ( T > T iv )

and T∗ = 0 for ( T < T iv ) .

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I.V. Infusion

Using The Scientist@‘s Unit function makes the change in T∗ straight forward. In
The Scientist@, Unit(+) = 1 and Unit(-) = 0, so defining T∗ = ( T – T iv ) ⋅ UNIT ( T – Ti v )
meets these needs.

This equation is utilized in The Scientist@’s companion product PKAnalyst@ also


by MicroMath. Since the route of administration is an infusion and we would
know how much we gave (Dose), how fast we gave it (Q), and over how long the
infusion lasted (Tiv), the only other variables in the equation are K and Vd. PKAn-

alyst asks for Tiv and yields DoverV ( Dose


------------- ) and K as parameters resulting from
Vd

non-linear regression analysis. Dividing Dose by Dose


------------- yields Vd.
Vd

Utilization: You should be able to determine the infusion rate necessary to obtain a desired
plasma concentration. Rearranging equation 5-3 results in:

K ⋅ V d ⋅ ( C p )ss = Q (EQ 5-6)

You should be able to determine how long it would take to get to a desired plasma
concentration. Using equation 5-1 and equation 5-3, it looks like it will take for-
ever to get exactly to steady state because in order for
Q = --------------
Q ( 1 – e – Kt ) , e – Kt → 0 which occurs when t = ∞ . So,
( C p )ss = --------------
K ⋅ Vd K ⋅ Vd
how close is close enough? If ( C p ) = 0.95 ⋅ ( C p )ss , that’s good enough in most
people’s estimation. So in order to find out how long it will take we use equation
5-1, setting ( C p ) = 0.95 ⋅ ( C p )ss and solve for time. Thus:

Q ( 1 – e – Kt ) which results in
( C p ) = 0.95 ⋅ ( C p )ss = --------------
K ⋅ Vd

– Kt
0.95 = ( 1 – e )

– Kt
0.95 – 1 = – e

ln ( 0.05 ) = – Kt

– 2.996 = – Kt

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I.V. Infusion

–----------------
2.996 = t
–K

2.996
-------------t 1--- = 4.32t 1--- = t , (EQ 5-7)
0.693 2 2

or about 4.32 half lives to get to 95% of steady state. Generalizing, then, the num-
ber of half-lives it takes to get to steady-state is equal to the logarithm of the
inverse of how close is close (in this case, 5% or 0.05 = 20) devided by the loga-
rithm of two.
Changing infusion rates: Occasionally, it is necessary to change infusion rates to stabilize the patient. If a
patient were started on an infusion rate, Q1, and then at some subsequent time,
T>T*, the infusion rate was changed to Q2, the equation for the concentration after
the change would be:

Q1 – ( K ⋅ T∗ ) – ( k ⋅ ( T – T∗ ) ) Q2 - ⋅ ( 1 – e – ( k ⋅ ( T – T∗ ) ) )
Cp = ------------ ⋅ ( 1 – e )⋅e + ----------- (EQ 5-8)
K⋅V K⋅V

Assuming equilibrium was reached at infusion rate Q1, we could simplify equation
5-8 by setting T = 0 at the time of the rate change (thus we would be interested in
the time after the change) resulting in:

Q1 –k ⋅ T Q2 –k ⋅ T
-⋅e
Cp = ----------- + ------------ ⋅ ( 1 – e ) (EQ 5-9)
K⋅V K⋅V

Under these conditions, it would be useful to determine the time to reach the new
equilibrium. As before, within 5% is close enough. Thus if we are coming down
Q2- and if we were
(lowering the Cp, i.e. Q2 < Q1), we would want Cp = 1.05 -----------
K⋅V
Q2 . Taking
going up (raising the Cp, i.e. Q2 > Q1), we would want Cp = 0.95 -----------
-
K⋅V
the first condition we find:

Q2 Q1 –k ⋅ T Q2 - ⋅ ( 1 – e – k ⋅ T )
Cp = 1.05 ------------ = ------------ ⋅ e + ----------- (EQ 5-10)
K⋅V K⋅V K⋅V

Rearranging and solving for T results in:

⋅ Q2
ln  0.05
----------------------
Q1 – Q2 
T = ---------------------------------- (EQ 5-11)
–K

Similarly, under the second condition, we would find:

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I.V. Infusion

0.05 ⋅ Q2
ln  –-------------------------
Q1 – Q2 
T = ------------------------------------- (EQ 5-12)
–K
Combining equation 5-11 and equation 5-12 and rearranging results in:

ln  -----------------------
Q1 – Q2- ⋅ 20 ln  ----------------------- Q1 – Q2- ⋅ 20
Q2   Q2 
T = ---------------------------------------------- = ---------------------------------------------- ⋅ t 1 ⁄ 2 (EQ 5-13)
K 0.693
Thus it is the absolute value of the difference of the two rates and the elimination
rate constant which determine the length of time needed to establish a new equilib-
rium. Under the conditions of Q1 = 0 , that is no previous infusion, and the dif-
ference is maximal equation 5-13 simplifies to equation 5-7. Under the conditions
of Q1 = Q2 , the equation is undifined and has no utility (as well as makes no
sense, because the equation was designed to be used when there was a change in
rate.) However, lim T = 0 , thus no change results in zero time to get to the new
Q2 → Q1
equilibium. Similar to equation 5-7 as before, the generalization for the number of
half-lives it takes to obtain the new steady-state is the logarithm of (the fractional
difference of the rates (or the steady-state concentrations) times the inverse of how
close is close) devided by the logarithm of two.
As pharmacokinetic equations are additive, you should be able to determine a
loading dose (by I.V. bolus, for example) and a maintenance dose (infusion rate)
for a patient to extablish an equilibrium. If, for example, you want to give a load-
ing dose followed by an IV infusion, the generalization for the number of half-
lives it takes to obtain the new steady-state is the logarithm of (the fractional dif-
ference of the concentrations, Cp0 and Cpss, times the inverse of how close is
close) devided by the logarithm of two.

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I.V. Infusion

Discussion: IV infusion is a controlled way to get drug into your patient. Using patient popula-
tion average pharmacokinetic parameters (K, Vd) available in the drug mono-
graphs, you are able to make a professional judgement about:
1. the plasma concentration that you would like to achieve (from therapeutic range) and the time in
which you would like to get there.
2. the infusion rate necessary to get to the target concentration, and
3. the time necessary to to get there.

Example: Using As an example, theophylline is a bronchodilator used in asthma with a therapeutic


population average range of 10 to 20 mg/L, a volume of distribution of 0.45 (0.3 - 0.7) L/kg and a half
pharmacokinetic life of about 8 (6 - 13) hours for a non-smoking adult. Your patient weighs 200
parameters to make
pounds and meets these these criteria. The physician decides to maintain him at 15
professional judgements.
mg/L. What do you do?

Using population average parameters for K and Vd, equation 5-6 results in:

 0.693 - ⋅  0.45 ----- kg - ⋅ 200 lb ⋅  15 mg


L- ⋅ -------------  = 53.2mg
 ------------   ------- ------- .
8 hr   kg 2.2 lb L hr

For an eight hour IV infusion, you would need

53.2 mg
------- ⋅ 8 hr = 425 mg of theophylline.
hr

IV Theophylline comes as aminophylline which is theophylline compound con-


taining 85% theophylline and 15% ethylenediamine. So in order to get 425 mg of
theophylline we have to give
100 mg aminophylline
425 mg theophylline ⋅ ------------------------------------------------------ = 500 mg aminophylline . So we
85 mg theophylline
prepare our IV infusion using Aminophylline U.S.P. for injection (500 mg amino-
phylline in 20 mL) by placing the contents of the ampule in 1000 mL of D5W and
calculate the drip rate using an adult IV administration set which regulates the drip
to 10 gtts/mL. Thus the drip rate is:

1020 ml- ⋅ ----------------


hr - ⋅ 10 gtts- ∼ 21 --------
gtts- ∼ --------------
7 gtts-
------------------- ---------------
8 hr 60 min ml min 20 sec

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I.V. Infusion

How long to get to steady After setting up the infusion, the doctor asks, “How long to steady state?
state?
Using equation 5-7, our patient who has an eight hour half life, will take about
4.32 ⋅ 8 hr = 34.6 hr to get to 95% of steady state. The patient doesn’t want
relief in a day and a half. He needs to breathe NOW. What would you suggest?
Infusion takes too long. It might be possible to give him an IV Bolus dose stat which would get him to
How do we get relief Dose-
now? IV Bolus stat. ( C p )ss right away. This is done by converting ( C p )ss = ------------ to
Vd
V d ⋅ ( C p ) ss = Dose .

 0.45 ----- kg - ⋅ 200 lb ⋅  15 mg


L- ⋅ ------------- ------- = 613.6 mg Theophylline
 kg 2.2 lb   L

Converting to aminophylline yields:


613.6 mg Theophylline ⋅ 100 mg aminophylline ∼ 725 mg aminophylline . Thus,
------------------------------------------------------
85 mg theophylline
if we gave a 725 mg IV bolus dose of aminophylline followed by a concomitant
IV infusion of 500 mg aminophylline over 8 hours, our patient should get to
steady state right away and stay there.
Some protocols require Sometimes the physician might want to just increase the infusion rate (say double
starting with faster it for a short time, 2Q) to get to the target concentration faster and then just back
infusion, then changing the infusion down. If that is the protocol, the question becomes, “ How long do
to a slower one to get to
steady state faster.
you run the infusion in at the faster rate?” Thus:

Q 2Q – Kt – Kt
( C p )ss = -------------- = -------------- ( 1 – e ) which yields 1 = 2 ( 1 – e ) and so
K ⋅ Vd K ⋅ Vd
1 – Kt 1 – Kt
--- = 1 – e . Thus --- – 1 = – e . Taking the ln of both sides ln ( 0.5 ) = –Kt
2 2

ln ( 0.5 ) = 0.693
------------------ ------------- t 1--- = t 1--- = t or that it will take one half-life to get to the target
–K 0.693 2 2
plasma concentration (which is the Cpss obtained by the infusion rate of 1Q) if you
run the infusion at a faster rate, 2Q. So for your patient, you might suggest an
infusion of 1000 mg over 8 hours (2Q for one half life) to get to steady state
quickly and then back off to 500 mg over 8 hours for the second 8 hours.

Basic Pharmacokinetics REV. 99.4.25 5-7


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I.V. Infusion

Clearance: New Clearance ( Cl = K ⋅ Vd ) is a pharmacokinetic parameter which relates the fraction


pharmacokinetic
of the volume of distribution which is cleared of the drug per unit time. The vol-
parameter
ume of distribution is a mathematical construct which relates two knowns, the
Dose of the drug and the resultant Concentration. In linear kinetics, the Dose is
proportional to the Concentration. C ∝ D . The units of concentration are
Mass - while the units of dose are Mass. So the units of the proportionality con-
-------------------
Volume
stant must be volume in order for the equation to balance. Thus, the volume of dis-
tribution is a hypothetical volume and not necessarily a real volume or
physiological space. Consequently, clearance is the hypothetical volume of fluid
from which the drug is irreversibly removed per unit time. So equation 5-3 can be
rewritten:

Q-
( C p )ss = ----- (EQ 5-14)
Cl
How do we calculate and equation 5-14 can be rewritten to:
Clearance from IV infu-
sion data? Q -
Cl = -------------- (EQ 5-15)
( C p )ss

Thus, assuming steady state, the clearance can be calculated by dividing the infu-
sion rate by the resultant steady state plasma concentration.
How do we separate K Graphing equation 5-4 which relates the decline in plasma concentration after ces-
and Vd out of Clear- sation of the infusion, the resultant slope of the line yields - K, the elimination rate
ance? constant. Dividing the elimination rate constant, - K, obtained by equation 5-4 into
the clearance obtained by equation 5-15 results in the other necessary pharmacoki-
netic parameter, Vd.
How can we utilize the From our original model
rate of change of
plasma concentration to d
determine the pharma- X = Q – (K ⋅ X ) (EQ 5-16)
dt
cokinetic parameters, K
and Vd?
X- . Thus , V ⋅ C p = X . Rewriting equation 5-16 yields:
and Cp = ----- d
Vd

Basic Pharmacokinetics REV. 99.4.25 5-8


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I.V. Infusion

dCp Q- – K ⋅ C and rearranging and incorporating equation 5-1 yields


= ----- p
dt Vd
dCp Q- – K ⋅  --------------
Q  ( 1 – e – Kt ) which can be simplified to
= -----
dt Vd  K ⋅ Vd
dCp Q- – ----- Q- e – Kt or
Q- + -----
= -----
dt V d V d Vd

dC p Q- e – Kt
= ----- (EQ 5-17)
dt Vd

vs. t ( actually, ∇
dCp Cp
Thus a plot of ----------- vs. tmid exactly like we did in urinary
dt ∇t
rate graphs) of the ascending portion of the plasma profile would result in a
straight line with a slope of -K and an intercept of ----- Q- .
Vd

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I.V. Infusion

5.2 Problems
Equations needed for solving the problems:
1. k from the slope of the terminal portion of the graph of Cp vs. T

0.693
2. t 1 ⁄ 2 = ------------
-
k

3.
Q
Volume of distribution from Cp = -------------- ( 1 – e
– Kt
)
K ⋅ Vd

4. Clearance Cl = K ⋅ V d

5. You wish to maintain a plasma concentration of Cpss.


a. Calculate the infusion rate necessary to maintain

Cpss. Q = Cp ss ⋅ K ⋅ V d

b. Suggest a loading dose which would give you Cpss immediately.

Dose loading = Cp ss ⋅ V d
c. How long will it take to reach steady state?

T 95 = 4.32 ⋅ T 1 ⁄ 2
d. Find the plasma concentration if the infusion is discontinued at time = Tdc hours.

Q ( 1 – e – ( K ⋅ Tdc ) ) .
Cp dc = --------------
K ⋅ Vd
e. Find the plasma concentration Tpost hours after infusion is discontinued at time = Tdc hours.
– ( K ⋅ T post )
Cp post = Cp dc ⋅ e

Basic Pharmacokinetics REV. 99.4.25 5-10


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I.V. Infusion

Acyclovir (Problem 5 - 1)

Problem Submitted By: Maya Leicht AHFS 08:18.00 Antivirals


Problem Reviewed By: Vicki Long GPI: 1200001000 Antivirals
Laskin, O., "Clinical pharmacokinetics of acyclovir", Clinical Pharmacokinetics (1983), p. 187 - 201.

Acyclovir (225.21 g/Mole) is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppres-
sive therapy. In this study, patients were given varying doses of acyclovir over one hour by infusion. Acyclovir distrib-
utes uniformly into the plasma and tissues such that the plasma concentration is representative of tissue concentration.
Acyclovir is 30% metabolized and 70% renally excreted. The following data was obtained from an intravenous infu-
sion dose of 2.5 mg/kg over one hour where the patient weighed 70 kg.
PROBLEM TABLE 5 - 1. Acyclovir

 umol -
Plasma concentration
 ------------
L
Time (hours)
0 0
0.25 7
0.5 12
0.75 17
1 20
2 10
3 5
5 1

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Volume of distribution
4. Clearance

5. You wish to maintain a plasma concentration of 25 umol ⁄ L .

a. Calculate the infusion rate necessary to maintain a plasma concentration of 25 umol ⁄ L


b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.

Basic Pharmacokinetics REV. 99.4.25 5-11


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I.V. Infusion

“Acyclovir” on page 11

102
Concentration

101

100
0 1 2 3 4 5
Time

1. k = 0.751 hr-1 (from slope of graph).

2. t 1 ⁄ 2 = 0.923 hr (from slope of graph).


3. Volume of distribution = 26.2 L
4. Clearance = 19.67 l/hr

5. You wish to maintain a plasma concentration of 25 umol ⁄ L .

a. Calculate the infusion rate necessary to maintain a plasma concentration of 25 umol ⁄ L = 111 mg/hr
b. Suggest a loading dose for the patient which would give you Cpss immediately. 148 mg
c. How long will it take to reach steady state? 4 hr

d. Find the plasma concentration if the infusion is discontinued at time = 5 hours. = 25 umol ⁄ L

e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours. = 5.6 umol ⁄ L

Basic Pharmacokinetics REV. 99.4.25 5-12


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I.V. Infusion

Aminophylline (Problem 5 - 2)

Problem Submitted By: Maya Leicht AHFS 12:12.00 Sympathomimetics


Problem Reviewed By: Vicki Long GPI: 4430001000 Xanthine Sympathomimetic
Gilman, T., et al., "Estimation of theophylline clearance during intravenous aminophylline infusions", Journal of Pharmaceutical
Sciences (May 1985), p. 508 - 514.

Aminophylline is used in the treatment of bronchospasm. In this study, aminophylline was given by intravenous infu-
sion to patients with a mean weight of 75.7 kg. The doses given were chosen to maintain a between 10 -20 mg/L based
on desirable body weight. The doses were given at a rate of 0.5 mg/kg/hour (Theophylline) for 84 hr. The following
set of data was collected.
PROBLEM TABLE 5 - 2. Aminophylline

 mg 
Plasma concentration
 -------
L
Time (hours)
0 0.
6 5
12 8
24 11
30 11.6
36 12.0
48 12.4
54 12.5
66 12.6
72 12.8
84 12.8
88 9
92 6.4
96 4.6
100 3.2

From this data determine the following:

1. k 2. t1 ⁄ 2
3. Volume of distribution 4. Clearance
5. 6. You wish to maintain a plasma concentration of 15 mg/L in your patient.
a. Calculate the infusion rate necessary to maintain a plasma concentration of 15 mg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.

Basic Pharmacokinetics REV. 99.4.25 5-13


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I.V. Infusion

“Aminophylline” on page 13
102
CONCENTRATION

101

0
10
0 20 40 60 80 100
Time

1. k = 0.085 hr-1
2. t 1 ⁄ 2 = 8.15 hr
3. Vd = 35.3 L
4. Cl = 3 L/hr

5a. Q = 45 mg/hr
5b. D L = 530 mg

ss
5c. t = 35 hr
95%
5d. C p = 5.2 mg/L

5e. C p = 4.4 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-14


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Carmustine (Problem 5 - 3)

Problem Submitted By: Maya Leicht AHFS 10:00.00 Antineoplastics


Problem Reviewed By: Vicki Long GPI: 2110201000 Antineoplastics, Nitrosoureas
Henner, W., et al., "Pharmacokinetics and immediate effects of high-dose carmustine in man", Cancer Treatment Reports vol.70
(1986), p. 877 - 880.

Carmustine (BCNU) is an antineoplastic agent with a molecular weight of 214.04 g.


2
In this study a 70 kg, 1.8 M2 patient was given 600 mg ⁄ m by intravenous infusion over 2 hours. The following data
was obtained.
PROBLEM TABLE 5 - 3. Carmustine

mg
Plasma concentration -------
Time (minutes) L
15 .3
30 .5
60 .7
90 .75
120 .8
135 .5
142.5 .4
150 .3

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4 Cl
2
5. A patient with a BSA of1.8 M is to be given BCNU by IV infusion. You wish to maintain a plasma

concentration of 2 uM . Determine the following:

a. Calculate the infusion rate necessary to maintain a plasma concentration of 2 uM .


b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 10 minutes.
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 10 minutes.

Basic Pharmacokinetics REV. 99.4.25 5-15


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I.V. Infusion

“Carmustine” on page 15

0
10
CONCENTRATION

-1
10
0 50 100 150

TIME

1. k = 0.031 min-1

2. t 1 ⁄ 2 = 22 min

3. Vd = 198 L/M2

4 Cl = 6.15 L/M2/hr
2
5. A patient with a BSA of1.8 M is to be given BCNU by IV infusion. You wish to maintain a plasma

concentration of 2 uM . Determine the following:

a. Calculate the infusion rate necessary to maintain a plasma concentration of 2 uM .

Q = Cp ss ⋅ V d ⋅ K = 2µmole 214µg- ⋅ ------------------


mg - ⋅ ------------
198L ⋅ 1.8M 2 ⋅ 0.031min– 1 = 4.73mg
------------------- ⋅ --------------- ------------------ ∼ 285mg
-----------------
L µmole 1000µg M2 min hr

b. Suggest a loading dose for the patient which would give you Cpss immediately.
Dose = Cp ss ⋅ Vd = 2µmole 214µg- ⋅ ------------------
mg - ⋅ ------------
198L ⋅ 1.8M 2 = 150mg
------------------- ⋅ ---------------
L µmole 1000µg M 2

c. How long will it take to reach steady state? 4.32 * T 1/2 = 97 min.
d. Find the plasma concentration if the infusion is discontinued at time = 10 min. = 0.1197 mg/L
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 10 min. = 0.017 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-16


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Cefotaxime (Problem 5 - 4)

Problem Submitted By: Maya Leicht AHFS 08:12.06 Cephalosporins


Problem Reviewed By: Vicki Long GPI: 0230007510 Cephalosporins - 3rd Generation
Kearns, G., Young, R., and Jacobs, R., "Cefotaxime dosage in infants and children--pharmacokinetic and clinical rationale for an
extended dosage interval", Clinical Pharmacokinetics (1992), p. 284 - 297.

Cefotaxime is a third generation cephalosporin which is widely used as an antimicrobial in neonates, infants, and chil-
dren. In this study, infants and children were given a 50 mg/kg dose of cefotaxime intravenously over 0.25 hour. The
following data was collected:
PROBLEM TABLE 5 - 4. Cefotaxime

 mg 
Plasma concentration
 -------
L
Time (hours)
0.00 0
0.05 35
0.10 70
0.20 140
0.35 155
0.60 130
0.85 110
1.20 80
1.30 75
2.00 45
2.40 35
3.40 15
4.50 8
6.50 1.7

From this data, assuming that the patient weighs 30 kg, determine the following:
1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. You wish to maintain a plasma concentration of 80 mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 80mg/L
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 0.25 hours.

Basic Pharmacokinetics REV. 99.4.25 5-17


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

e. Find the plasma concentration 2 hours after infusion is discontinued at time = 0.25 hours.
“Cefotaxime” on page 17
103
CONCENTRATION

102

101

100
0 1 2 3 4 5 6 7
TIME

1. k = 0.733 hr-1
2. t 1 ⁄ 2 = 0.945 hr
3. Vd = 0.276 L/kg
4. Cl = 0.202 L/kg/hr

4a. Q = 16.2 mg/kg/hr


4b. D L = 22.1 mg/kg

ss
4c. t = 4.1 hr
95%
4d. C p = 13.35 mg/L

4e. C p = 3.09 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-18


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Ganciclovir (Problem 5 - 5)

Problem Submitted By: Maya Leicht AHFS 08:18.00 Antivirals


Problem Reviewed By: Vicki Long GPI: 1200002010 Antivirals
Trang, J., et al., "Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections",
Clinical Pharmacology and Therapeutics (1993), p. 15 - 21.

Ganciclovir is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus infections of the
gastrointestinal tract. In this study, twenty-seven newborns with cytomegalovirus disease were given 4 mg/kg of ganci-
clovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in the following
table:
PROBLEM TABLE 5 - 5. Ganciclovir

Plasma concentration  --------


ug
 mL
Time (hours)
0.5 3.10
1.5 4.50
2.0 3.80
3.0 2.90
4.0 2.30
6.0 1.50
8.0 0.88

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl
4. A patient is to be given ganciclovir by IV infusion to an infant weighing 6.1 kg. You wish
to maintain a plasma concentration of 5.5 mcg/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 5.5mcg/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 1 hour.

Basic Pharmacokinetics REV. 99.4.25 5-19


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

“Ganciclovir” on page 19
10 1
CONCENTRATION

10 0

10-1
0 2 4 6 8
Time

1. k = 0.255 hr-1
2. t 1 ⁄ 2 = 2.72 hr
3. Vd = 0.687 L/kg
4. Cl = 0.175 L/kg/hr

1000ml ⋅  0.687L
Q = Cp ss ⋅ V d ⋅ K = 5.5µg - ⋅ 6.1kg ⋅ 0.255
mg - ⋅ ------------------
-------------- ⋅ ------------------ ------------- = 5.9mg
 ----------------
5a. ---------------
ml 1000µg L kg hr hr

1000ml ⋅  0.687L
D L = Cp ss ⋅ Vd = 5.5µg ----------------- ⋅ 6.1kg = 23mg
mg - ⋅ ------------------
5b. -------------- ⋅ ------------------
ml 1000µg L  kg 

ss
5c. T = 4.32 ⋅ t1 ⁄ 2 = 11.75hr
95%
5.9mg
---------------
Q hr – K ⋅ 1hr
) = 1.24mg
– Kt
5d. C p term = -------------- ( 1 – e ) = -----------------------------------------------------
- (1 – e ------------------
K ⋅ Vd 0.255
------------- ⋅ 0.687L L
----------------- ⋅ 6.1kg
hr kg
– K ⋅ 2hr
5e. C p = C p term ⋅ e = 1.24mg
------------------ ⋅ 0.6 = 0.74mg
------------------
L L

Basic Pharmacokinetics REV. 99.4.25 5-20


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Gentamicin (Problem 5 - 6)

Problem Submitted By: Maya Leicht AHFS 00:00.00


Problem Reviewed By: Vicki Long GPI: 0700002010 Aminoglycosodes
Kaojarern, S., et al., "Dosing regimen of gentamicin during intermittent peritoneal dialysis", Journal of Clinical Pharmacology
(1989), p. 140 - 143.

Gentamicin is an aminoglycoside antibiotic which is frequently used in the treatment of gram-negative bacilli infec-
tions. Since it has a low therapeutic index, it is important to determine proper dosage regimens. In this study, patients
on peritoneal dialysis received a 30 minute intravenous infusion of 80 mg gentamicin in 100 mL of 5% dextrose in
water. The following data was collected:
PROBLEM TABLE 5 - 6. Gentamicin

 -------
ug 
Plasma concentration
 mL-
Time (hours)
0.50 5.68
1.50 5.15
3.70 4.80
7.35 3.99
11.30 3.35
24.00 2.02

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given gentamicin by IV infusion. You wish to maintain a plasma concentration
of 5.2 ug ⁄ mL . Determine the following:

a. Calculate the infusion rate necessary to maintain a plasma concentration of 5.2 ug ⁄ mL


b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 0.5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 0.5 hours.

Basic Pharmacokinetics REV. 99.4.25 5-21


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

“Gentamicin” on page 21
101
CONCENTRATION

100
0 5 10 15 20 25

Time

1. k = 0.0431 hr-1
2. t 1 ⁄ 2 = 16.1 hr

3. V d = 14.5 L
4. Cl =0.625 L/hr

5a. Q = 3.25 mg/hr


5b. D L = 75 mg

ss
5c. t = 69.6 hr
95%
5d. C p = 0.11 mg/L

5e. C p = 0.10 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-22


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Human Monoclonal Anti-lipid A antibody (HA-1A) (Problem 5 - 7)

Problem Submitted By: Maya Leicht AHFS 24:06.00 Antilepemics


Problem Reviewed By: Vicki Long GPI: 3900000000 Antihyperlipidemic
Fisher, C., et al., "Initial evaluation of human monoclonal anti-lipid A antibody (HA-1A) in patients with sepsis syndrome", Criti-
cal Care Medicine (1990), Vol.18, No. 12, p. 1311 - 1315.

HA-1A is an immunoglobulin antibody. In this study, patients received a 250 mg intravenous infusion of HA-1A over
15 minutes. Serum levels were measured before and after infusion and the following data was collected:
PROBLEM TABLE 5 - 7. Human Monoclonal Anti-lipid A antibody (HA-1A)

Plasma concentration  -------


ug-
 mL
Time (hours)
0.00 0
0.75 80
1.00 75
2.00 74
5.00 65
15.00 50
25.00 40
48.00 21
72.00 10

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given HA-1A by IV infusion. You wish to maintain a plasma concentration of 100 µg/mL.
Determine the following:

a. Calculate the infusion rate necessary to maintain a plasma concentration of 100 ug ⁄ mL .


b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 3 hours after infusion is discontinued at time = 1 hour.

Basic Pharmacokinetics REV. 99.4.25 5-23


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

“Human Monoclonal Anti-lipid A antibody (HA-1A)” on page 23


102
CONCENTRATION

101
0 20 40 60 80
Time
1. k = 0.0282 hr-1
2. t 1 ⁄ 2 = 24.4 hr

3. V d = 3.2 L

4. Cl = 0.09 L/hr
5a. Q = 9 mg/hr
5b. D L = 320 mg

ss
5c. t = 105 hr
95%
5d. C p = 2.78 mg/L

5e. C p = 2.56 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-24


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Ifosfamide (Problem 5 - 8)

Problem Submitted By: Maya Leicht AHFS 00:00.00


Problem Reviewed By: Vicki Long GPI: 0000000000
Lewis, L., "The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients", British Journal
of Clinical Pharmacology Vol. 31 (1991), p. 77 - 82.

Ifosfamide is an agent which has shown some pharmacological response in the treatment of cancer. In this study, a 5
2 2
g⁄m dose of ifosfamide was infused over 30 minutes. The median BSA for the subjects was 1.8 m . The
following data was obtained:
PROBLEM TABLE 5 - 8. Ifosfamide

 -------
ug 
Plasma concentration
 mL-
Time (hours)
0 0.0
0.5 285.0
1 260.0
2 220.0
4 160.0
6 112.0
8 80.0
10 60.0
24 5

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl

5. A patient is to be given ifosfamide by IV infusion. The patient has a BSA 1.8 M2. You wish to maintain a
plasma concentration of 336 µg/mL. Determine the following:

a. Calculate the infusion rate necessary to maintain a plasma concentration of 336 ug ⁄ mL


b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 20 min.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 20min.

Basic Pharmacokinetics REV. 99.4.25 5-25


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

“Ifosfamide” on page 25
103

102
CONCENTRATION

101

100
0 5 10 15 20 25
Time

1. k = 0.1716 hr-1
2. t 1 ⁄ 2 = 4.04 hr

3. V d = 16.6 L/M2

4. Cl = 2.85 L/hr/M2
5a. Q = 1.725 g/hr
5b. D L = 10 g

ss
5c. t = 17.5
95%
5d. C p = 18.7 mg/L

5e. C p = 13.25 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-26


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Isosorbide 5-mononitrate (Problem 5 - 9)

Problem Submitted By: Maya Leicht AHFS 00:00.00


Problem Reviewed By: Vicki Long GPI: 0000000000
Major, R., et al., "Isosorbide 5-mononitrate kinetics" (1983), p. 653- 660.

Isosorbide 5-mononitrate (5-ISMN) is a metabolite of isosorbide dinitrate. In this study, the kinetics of isosorbide 5-
mononitrate were looked at in 12 healthy patients after an intravenous infusion of 20 mg at 8 mg/hour for 2.5 hours.
This drug follows one-compartment, open model kinetics. The following data was collected:
PROBLEM TABLE 5 - 9. Isosorbide 5-mononitrate

Time (hours) Plasma concentration (ng/mL)


0.25 40
0.50 91
0.75 141
1.00 181
1.50 239
2.00 305
2.50 351
3.00 335
3.50 303
4.50 257
5.50 216
7.50 162
9.50 117
11.50 77
14.50 47
18.50 24
26.50 7

From this data determine the following:


1. k 2. t1 ⁄ 2
3. Vd 4. Cl
5. A patient is to be given 5-ISMN by IV infusion. You wish to maintain a plasma concentration
of 300 ng/mL. If the volume of distribution of 5-ISMN is 44.5, determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 300 ng/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 1 hour.

Basic Pharmacokinetics REV. 99.4.25 5-27


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

“Isosorbide 5-mononitrate” on page 27


103
CONCENTRATION

102

101

100
0 5 10 15 20 25 30

Time

1. k = 0.168 hr-1
2. t 1 ⁄ 2 = 4.125 hr

3. V d = 44.6 L

4. Cl = 7.5 L/hr
5a. Q = 2.25 mg/hr
5b. D L = 13.4 mg

ss
5c. t = 17.8 hr
95%
5d. C p = 46.4 ng/mL

5e. C p = 33.2 ng/mL

Basic Pharmacokinetics REV. 99.4.25 5-28


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Moclobemide (Problem 5 - 10)

Problem Submitted By: Maya Leicht AHFS 00:00.00


Problem Reviewed By: Vicki Long GPI: 0000000000
Schoerlin, M., et al., "Disposition kinetics of moclobemide a new MAO-A inhibitor, in subjects with impaired renal function", Jour-
nal of Clinical Pharmacology Vol 30 (1990), p. 272 - 284.

Moclobemide is reversibly inhibits the A-isozyme of the monoamine oxidase enzyme system. In this study, twelve
patients received a 96.7 mg dose as an intravenous infusion over 20 minutes. Blood samples were obtained during the
infusion and after the infusion was ended and the following data was obtained:
PROBLEM TABLE 5 - 10. Moclobemide

Time (hours) Plasma concentration (mg/L)


0.0 0.000
0.2 0.6
0.4 1
0.7 0.85
0.9 0.750
1.2 0.70
1.6 0.60
1.9 0.50
2.4 0.40
3.4 0.25
4.5 0.15
5.5 0.10
6.4 0.070

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given moclobemide by IV infusion. You wish to maintain a plasma concentration
of 1mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 1mg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 15 min.

Basic Pharmacokinetics REV. 99.4.25 5-29


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

e. Find the plasma concentration 3 hours after infusion is discontinued at time = 15 mins.
“Moclobemide” on page 29
10 0
CONCENTRATION

10-1

10-2
0 1 2 3 4 5 6 7
Time

1. k = 0.44 hr-1
2. t 1 ⁄ 2 = 1.6 hr.

3. V d = 90.4 L

4. Cl = 39.8 L/hr
5a. Q = 40 mg/hr
5b. D L = 90 mg

ss
5c. t = 6.8 hr
95%
5d. C p = 0.1 mg/L

5e. C p = 0.028 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-30


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Obidoxime (Problem 5 - 11)

Problem Submitted By: Maya Leicht AHFS 00:00.00


Problem Reviewed By: Vicki Long GPI: 0000000000
Bentur, Y., et al., "Pharmacokinetics of obidoxime in organophosphate poisoning associated with renal failure", Clinical Toxicol-
ogy (1993), Vol. 31, p. 315 - 322.

Obidoxime is an agent which is used as an antidote in organophosphate poisoning. In this study, the pharmacokinetics
of obidoxime were studied in a 20 year old patient who attempted to commit suicide by ingesting Tamaron (60% meth-
amidophos, an organophosphate, in ethylene glycol monethyl ether). She was given 4 mg/kg Obidoxime by intrave-
nous infusion over 10 minutes and the following data was collected:
PROBLEM TABLE 5 - 11. Obidoxime

Time (minutes) Plasma concentration µg ⁄ mL


5 9
10 18
15 17
30 16
45 15
60 14
90 12
120 11
150 9.3
180 8
240 6.1
300 4.6

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given obidoxime by IV infusion. The patient has a body weight of 60 kg.
You wish to maintain a plasma concentration of 10 µg/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 10 ug ⁄ mL .
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 30 minutes.

Basic Pharmacokinetics REV. 99.4.25 5-31


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

e. Find the plasma concentration 1 hour after infusion is discontinued at time = 30 minutes.
“Obidoxime” on page 31
102
CONCENTRATION

101

100
0 50 100 150 200 250 300
Time

1. k = 0.00463 min-1
2. t 1 ⁄ 2 = 150 min

3. V d = 0.22L/kg

4. Cl = 1 mL/min
5a. Q = 0.61 mg/min
5b. D L = 132 mg

ss
5c. t = 10.8 hr
95%
5d. C p = 1.3 mg/L

5e. C p = 0.98 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-32


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Perindoprilat (Problem 5 - 12)

Problem Submitted By: Maya Leicht AHFS 00:00.00


Problem Reviewed By: Vicki Long GPI: 0000000000
Macfadyen, R., Lees, K., and Reid, J., "Studies with low dose intravenous diacid ACE inhibitor (perindoprilat) infusions in normo-
tensive male volunteers", Journal of Pharmaceutical Sciences (1991), p. 115 - 121.

Perindoprilat and other ACE inhibitors are used in the management of hypertension and chronic congestive heart fail-
ure. In this study, a 1 mg dose was infused over a one hour period. The following data was collected:
PROBLEM TABLE 5 - 12. Perindoprilat

Time (minutes) Plasma concentration ng ⁄ mL


5 4.0
10 9.0
20 16.0
30 24.0
40 30.0
50 36.0
60 42.0
65 40.0
70 38.0
80 35.0
90 32.0
100 29.0
110 27.0
120 24.0

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given perindoprilat by IV infusion. You wish to maintain a plasma concentration
of 30 ng/ml. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 30 ng/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.

Basic Pharmacokinetics REV. 99.4.25 5-33


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.
“Perindoprilat” on page 33

102
CONCENTRATION

101

100
0 20 40 60 80 100 120
Time

1. k = 0.0087 min-1
2. t 1 ⁄ 2 = 79.6 min

3. V d = 18.9 L

4. Cl =164 mL/min
5a. Q = 5 µg/min
5b. D L = 0.57 mg

ss
5c. t = 5.73 hr
95%
5d. C p = 27.8 ng/mL

5e. C p = 9.8 ng/mL

Basic Pharmacokinetics REV. 99.4.25 5-34


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Sulfonamides (Problem 5 - 13)

Problem Submitted By: Maya Leicht AHFS 00:00.00


Problem Reviewed By: Vicki Long GPI: 0000000000
Boddy, A., Edwards, P., and Rowland, M., "Binding of sulfonamides to carbonic anhydrase: influence on distribution within blood
and on pharmacokinetics", Pharmaceutical Research (1989), p. 203- 209

This study looks at the affinity of sulfonamides for carbonic anhydrase. Doses of 8 micromoles/kg were administered
via the jugular vein cannula in approximately 0.5 mL of PEG 400 over 5 minutes at a constant rate. Samples were col-
lected during the infusion period and for 30 minutes afterward. The following set of data was collected:
PROBLEM TABLE 5 - 13. Sulfonamides

Time (minutes) Plasma concentration ( µM )


2.0 17.0
4.0 31.0
5.0 37.0
7.5 32.0
9.0 28.0
12.0 22.5
15.0 18.0
18.0 14.0
23.0 11.0
30.0 6.5
35.0 4.5

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A 70-kg patient is to be given a sulfonamide by IV infusion. You wish to maintain a plasma
concentration of 30 µM. Determine the following:
a. Calculate the infusion rate which would be necessary to maintain the plasma concentra-
tion of 30 µM.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 4 hours.

Basic Pharmacokinetics REV. 99.4.25 5-35


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

e. Find the plasma concentration 30 minutes after stopping infusion at time = 4 hours.
“Sulfonamides” on page 35

102
CONCENTRATION

101

100
0 5 10 15 20 25 30 35

Time

1. k = 0.0705 min-1
2. t 1 ⁄ 2 = 9.8 min

3. V d = 0.18 L/kg

4. Cl = 12.7 mL/min/kg
5a. Q = 26.9 µmole/min
5b. D L = 380 µmole

ss
5c. t = 42 min
95%
5d. C p = 30 µmole/L

5e. C p = 3.6 µmole/L

Basic Pharmacokinetics REV. 99.4.25 5-36


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Terodiline (Problem 5 - 14)

Problem Submitted By: Maya Leicht AHFS 00:00.00


Problem Reviewed By: Vicki Long GPI: 0000000000
Hallen, B. ,et al., "Bioavailability and disposition of terodiline in man", Journal of Pharmaceutical Sciences (1994), p. 1241 -
1246.

Terodiline is an agent which works as an anticholinergic and a calcium antagonist. It is used to treat incontinence. It
is metabolized into p-Hydroxyterodiline, which is further metabolized to 3,4-dihydroxyterodiline. The parent drug and
all of its metabolites are excreted into the urine as well as the feces. A patient is given 12.5 mg of Terodiline by IV
infusion at a rate of 1 mL/ minute for 5 minutes. The following data is collected:
PROBLEM TABLE 5 - 14. Terodiline

Time (hours) Plasma concentration µg ⁄ L


25.000 31
50.000 23
75.000 15
100.000 12
125.000 8
150.000 6
175.000 4
200.000 3
225.000 2

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given terodiline by IV infusion. You wish to maintain a plasma concentration
of 40 mcg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of40 mcg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after stopping infusion if the infusion ended at
time = 5 hours.

Basic Pharmacokinetics REV. 99.4.25 5-37


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

“Terodiline” on page 37

102
CONCENTRATION

101

100
0 50 100 150 200 250

Time

1. k = 0.0136 hr-1
2. t 1 ⁄ 2 = 50.9 hr

3. V d = 283 L

4. Cl =3.85 L/hr
5a. Q = 0.154 mg / hr
5b. D L = 11.32 mg

ss
5c. t = 220 hr
95%
5d. C p = 2.63 µg/L

5e. C p = 2.56 µg/L

Basic Pharmacokinetics REV. 99.4.25 5-38


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Tinidazole (Problem 5 - 15)

Problem Submitted By: Maya Leicht AHFS 00:00.00


Problem Reviewed By: Vicki Long GPI: 0000000000
Robson, R., Bailey, R., and Sharman, J., "Tinidazole pharmacokinetics in severe renal failure", Clinical Pharmacokinetics (1984),
p. 88 - 94.

Tinidazole is an antimicrobial similar to metronidazole which is used in the treatment of trichomoniasis, giardiasis,
amoebiasis, and anaerobic infections. This study focuses on the pharmacokinetics of tinidazole in patients suffering
from severe renal failure. Twelve patients received 800 mg of tinidazole dissolved in 400 mL of dextrose monohydrate
solution as an intravenous infusion at a rate of 60 mg/min. Blood samples were taken and the following data was
obtained:
PROBLEM TABLE 5 - 15. Tinidazole

Time (hours) Plasma concentration (mg/L)


1 14.9
3 13.1
6 11.2
12 8.9
24 5.1
48 2.1

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given tinidazole by IV infusion. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of 25 mg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 2 hours after stopping infusion if the infusion was stopped
at time = 1 hour.

Basic Pharmacokinetics REV. 99.4.25 5-39


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

“Tinidazole” on page 39

102
CONCENTRATION

101

100
0 10 20 30 40 50
Time

1. k = 0.04136 hr-1
2. t 1 ⁄ 2 = 16.75 hr

3. V d = 54.7 L

4. Cl = 2.26 L/hr
5a. Q = 56.6 mg/hr
5b. D L = 1.37 g

ss
5c. t = 72.4 hr
95%
5d. C p = 1 mg/L

5e. C p = 0.93 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-40


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Tobramycin (Problem 5 - 16)

Problem Submitted By: Maya Leicht AHFS 00:00.00


Problem Reviewed By: Vicki Long GPI: 0000000000
Cooney, G., et al., "Absolute bioavailability and absorption characteristics of aerosolized tobramycin in adults with cystic fibro-
sis", Journal of Clinical Pharmacology Vol. 34, (1994), p. 255- 259.

Most persons with cystic fibrosis (CF) become colonized with Pseudomonas aeruginosa in their bronchial secretions
within their second decade of life. These patients require frequent treatment with potent anti-pseudomonal antibiotics
such as Tobramycin. In this study, an intravenous infusion of 2.5 mg/kg tobramycin was given over 35 minutes. The
following data was collected:
PROBLEM TABLE 5 - 16. Tobramycin

 mg 
 -------
L
Plasma concentration
Time (minutes)
35 8.00
60 6.00
90 4.50
150 2.50
270 0.75

From this data determine the following:


1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given tobramycin by IV infusion. The patient has a body weight of 70 kg. You wish
to maintain a plasma concentration of 10 mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of 10 mg/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 30 minutes.
e. Find the plasma concentration 1 hour after stopping infusion if the infusion wasstopped at
time = 30 minutes.

Basic Pharmacokinetics REV. 99.4.25 5-41


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

“Tobramycin” on page 41
101
CONCENTRATION

100

10-1
0 50 100 150 200 250 300

Time
1. k = 0.01 min-1
2. t 1 ⁄ 2 = 69.3 min

3. V d = 0.269 L/kg

4. Cl = 2.7 mL/min
5a. Q = 0.027mg/kg/min = 1.62 mg/kg/hr
5b. D L = 2.7 mg/kg

ss
5c. t = 300 min = 5 hr
95%
5d. C p = 2.6 mg/L

5e. C p = 1.43 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-42


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
CHAPTER 6 Biopharmaceutical Factors

Author: Michael Makoid


Reviewer: Phillip Vuchetich

OBJECTIVES
After successfully completing this chapter, the student shall understand:
1. Physiology and machanisms of absorbtion
2. Effects of diffusion, cardiac output / blood perfusion, physical properties of the
drug and body on distribution
3. Biotransformation, first pass effect, and clearance
4. Renal, biliary, mammary, salivary, other forms of excretion.
5. identify the effects of physiological changes with age, sex, and disease on the
absorption, distribution, metabolism, and excretion of a drug.

Basic Pharmacokinetics REV. 99.4.25 6-1


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
CHAPTER 7 Oral Dosing

Author: Michael Makoid and John Cobby


Reviewer: Phillip Vuchetich

OBJECTIVES
After successfully completing this chapter, the student shall be able to
1. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters ( V d , K, k m , k r , k a , AUC ,
Clearance, MRT, MAT) available from oral data.
2. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the K from the terminal portion of the curve.
3. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the k a from either the curve stripping Moment techniques.

4. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the Absolute Bioavailability from comparing IV and oral (or
some other process which involves absorption) data.
5. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the Comparative Bioavailability from comparing the generic to the
inovator product.
6. Given patient drug concentration and/or amount vs. Time profiles, the student will
qualitatively evaluate (IV) bioequivalence as determined by rate of absorption
(peak time) and extent of absorption (Area Under the Curve - AUC, and ( Cp ) max ).

7. Given patient drug concentration and/or amount vs. Time profiles, the student will
evaluate (IV) bioequivalence data.
8. Given patient drug concentration and/or amount vs. Time profiles, the student will
lucidly discuss (IV) bioequivalence and recommend (V) to another competant
professional if s/he believes products to be equivalent.

Basic Pharmacokinetics REV. 99.4.25 7-1


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Oral Dosing

9. The student shall be able to properly use vocabulary relative to bioequivalence.

Basic Pharmacokinetics REV. 99.4.25 7-2


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

7.1 Oral dosing

7.1.1 VALID EQUATIONS: ( ORAL DOSING, PLASMA)

ka –k t
C p = fD
– Kt
------ ⋅ --------------
- ⋅ (e – e a ) (EQ 5-18)
Vd k a – K

AUC ( oral ) ⁄ Dose ( oral )


f = -------------------------------------------------------------- (EQ 5-19)
AUC ( iv ) ⁄ Dose ( iv )

AUC ( generic ) ⁄ Dose ( generic ) -


CB = ------------------------------------------------------------------------------------- (EQ 5-20)
AUC ( inovator ) ⁄ Dose ( inovator )

ln ( k a ⁄ K )
t p = ----------------------- (EQ 5-21)
( ka – K )

X
-----a- = K ⋅ AUC ∞ – ( C p + K ⋅ AUC t ) (EQ 5-22)
v

where CB = the comparative bioavailability

f = the absolute bioavailabilty; the fraction of dose which ultimately reaches sys-
temic circulation (which is made up of the fraction of the dose which is absorbed
times the fraction which gets past the liver (first pass effect))

ka = absorption rate constant.

7.1.2 UTILIZATION

Basic Pharmacokinetics REV. 99.4.25 7-3


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Oral Dosing

Ampicillin (Problem 5 - 17)

The following information is available for ampicillin: 90% is excreted unchanged and a 250 mg IV bolus dose yields an
AUC of 11 mic/mL*hr. The following blood level profile has been reported for two brands of ampicillin which were
given as 500 mg oral capsules.

TABLE 4-7

µg
MEAN SERUM LEVEL --------
Time (hr) mL
LEDERLE BRISTOL
0.5 0.37 0.38
1.0 1.97 1.91
1.5 2.83 2.49
2.0 3.15 3.11
3.0 2.73 2.79
4.0 1.86 1.95
6.0 0.43 0.49

Find the following:.


a. k for both products.
b. k a for both products.

c. k u for both products.

d. AUC for both products.


e. f for both products.

f. t max for both products.

g. Cl

h. Vd

i Cp 0 for a 250 mg IV dose.

j. Cp max

k. Are these two products bioequivalent? Why or why not?


l. What infusion rate would be necessary to maintain a serum

Basic Pharmacokinetics REV. 99.4.25 7-4


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Oral Dosing

plasma concentration of 2mcg/mL

The data was plotted as above with the best fit line drawn. From the graph the fol-
lowing parameters were derived:

TABLE 4-8 Comparison of Ampicillin

Lederle Bristol Ratio (L/B)


–1 0.688 0.635
K ( hr )
–1 0.858 0.831
K a ( hr )

T max ( hr ) 1.74 1.8 0.97

( C p ) max ( µg ⁄ mL ) 3 2.9 1.03

AUC (trapaziodal) 11.4 11.6 0.98

2) In a clinical study (DiSanto & DeSante, JPS 64:100,1975) prednisone was


administered to 22 adult healthy volunteres (average weight 64.5 kg) either as one
50 mg tablet (product A) or as ten 5 mg tablets (product B). The following data
was observed:

Time (hours) Concentration (mic/100ml plasma)

A B

Basic Pharmacokinetics REV. 99.4.25 7-5


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

0.5 40.8 57.3

1 70.0 77.1

2 79.5 82.3

3 80.7 69.4

4 68.6 60.6

6 49.4 48.0

8 35.0 33.7

12 15.3 17.4

24 2.1 3.0

Find ka's for both products.

Calculate peak time and Cp max and AUC for both products.

Can you conclude that these products are bioequivalent ?

(Reasons should include discussion of rate and extent of absorption)

Answer:

Basic Pharmacokinetics REV. 99.4.25 7-6


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Product A Product B Ratio (A/B)

Ka (hr^-1) 1.19 1.8

Tmax (hr) 2 1.52 1.31

Cmax (mcg/100mL)83.2 82.8 1.00

AUC (trapazoidal)676.52 688.81 0.976

Can you conclude that these products are bioequivalent ?

No, Time to peak (Tmax) is outside guidelines.

3) Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthy


volunteers in a four way crossover design of four dosage forms containing 300 mg
of cimetadine. The following data was obtained:

Basic Pharmacokinetics REV. 99.4.25 7-7


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

A B C D

A.U.C. (mic/ml x hr)------ 5.2 5.4

% recovered in urine intact77.177.147.149.0

Peak serum conc.(mic/ml)------ 1.53 1.44

Onset (hr) 0 0.34 0.65

Duration (hr) 4.5 4.0 4.2 4.4

Time to peak (hr)0 1.0 2.0

A = IV bolus B = IM inj. C = Oral Liq. D = Oral Tab.

The plasma concentration - time profile for product A is as follows:

time(hrs) (ug/ml) time(hrs) (ug/ml)

1 1.79 6 0.45

2 1.36 12 0.08

4 0.78

a} Using linear regression, find K & Cp0.

b} What is the absolute bioavailability (f) of the liquid.

c} How does that correlate with % recovered intact in the urine?

d} Would you consider the oral forms bioequivalent?

Why/Why not?

Basic Pharmacokinetics REV. 99.4.25 7-8


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

f} What infusion rate would you suggest to maintain a plasma concentration of


0.75 mic/ml ?

g} How long would it take that infusion rate to attain a therapeutic plasma con-
centration of 0.5 mic/ml ?

Answer:

IV Bolus Parameters:

Cp max2.4 mic/mL

AUC 8.5

K 0.283 hr^-1

Basic Pharmacokinetics REV. 99.4.25 7-9


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

a} Using linear regression, find K & Cp0. (graph)

b} What is the absolute bioavailability (f) of the liquid.

5/2/8.5 = 0.61

c} How does that correlate with % recovered intact in the urine?

Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that to
show up in the urine because only 77% of the IV dose shows up in the urine
(.61*.77=.47).

d} Would you consider the oral forms bioequivalent? (No)

Why/Why not? Ratio of peak times ouside guidelines.

e} What infusion rate would you suggest to maintain a plasma concentration of


0.75 mic/ml ?

Q = Cpss * K * V = 0.75 mg/L * 0.283 hr^-1 * 125 L = 26.54 mg/hr

f} How long would it take that infusion to attain a therapeutic plasma concentra-
tion of 0.5 mic/ml ?

Cp = Q/(K*V)(1-exp(-K*T) = 0.5 = 26.54/(0.283*125)*(1-exp(-0.283*T)) --> 3.9


hr

4) LYSERGIC ACID DIETHYLAMIDE (LSD) was given to human volunteers at


the dose of 150 mic orally. (Impregnated blotter dosage form.) The following data
was obtained:

Basic Pharmacokinetics REV. 99.4.25 7-10


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Time Cp (ng/ml) Time Cp (ng/ml)

0.25 1.75 2.0 4.6

0.5 2.9 3.0 4.1

0.75 3.7 4.0 3.3

1.0 4.2 6.0 2.1

1.5 4.6 8.0 1.4

a) Find ka

b) An IV dose of 100 mic resulted in an AUC of 20.4 ng/ml*hr. Find f.

c) The volunteers ability to concentrate as measured by their ability to do standard


tasks was also monitored. (100% control means no drug interference.) The fol-
lowing data was obtained:

Cp (ng/ml) % Control Cp (ng/ml) % Control

5.5 33 1.5 65

4.1 40 1.1 80

2.9 52

If 100 mic dose were given by IV bolus, how long would it be before the volunteer
would regain 80% of his control?

Answwer:

Basic Pharmacokinetics REV. 99.4.25 7-11


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Evaluation of the graph of Concentration vs. time yields:

Cpmax 4.63 ng/mL

T max 1.7 hr

AUC (trap)30.07

K 0.225 hr^-1

Basic Pharmacokinetics REV. 99.4.25 7-12


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

m (-K) -0.225 hr^-1

Ka 1.22 hr^-1

f (AUCoral/Doseoral)/(AUCiv/Doseiv) = .98

Evaluation of the graph of response vs ln(concentration) yields:

dR/dln(c) = 27.86

Multiplying dR/dln(c) * dln(c)/dt (m of the previous graph) yields dR/dt = 27.86 *


-0.225 = 6.26%/hr

100 mic dose IV yields Cp0 of (Cp0 =AUC * K = 20.4 * 0.225) 4.59ng/mL.

The response of a 100 mic dose is (R = 27.86*ln(4.59)+19.9) 62.3%

Response = Response at t=0 - dR/dt * t

20% = 62.3% - 6.26%/hr * t hours

T = 6.76 hours

5. The following data was collected from a double blind cross over study between
500 mg dose of cloxacillin made by Bristol (Tegopen@) and a generic product
which you might want to put in your store.

Time (Conc. mic/ml) Time (Conc. mic/ml)

TEGOPEN GENERIC TEGOPEN GENERIC

Basic Pharmacokinetics REV. 99.4.25 7-13


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

0.25 .41 0.1 1.5 6.93 7.75

0.5 8.56 6.39 2 4.95 5.16

0.75 11.97 11.44 3 2.19 2.29

1 11.28 11.42 4 1.48 1.30

1.25 9.57 9.64

Calculate the comparative bioavailability.

Would you consider these products bioequivalent? Why/Why not?

Answer:

Basic Pharmacokinetics REV. 99.4.25 7-14


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Evaluation of the above graphs yields:

Tegopen GenericRatio (G/T)

Cpmax (mic/mL)10.8 9.94 0.92

T max (hr) 0.74 0.89 1.20

AUC (trap) 21.7 21.06 0.97

K (hr^-1) 0.72 0.8

ka (hr^-1) 4.3 2.69

Actual evaluation of ka and peak time is dificult because of the pucity of data at
early time points however all relavent parameters meet guidlines.

7. The F.D.A. reported the following data submitted to be consideration regarding


the equivalence of Mylan Pharmaceuticals' Tetracycline with that of Lederle and
an intervenous bolus dose. (Dose 250 mg).

Time(hrs) Conc.(mcg/ml) Time(hrs) Conc.(mcg/ml)

Lederle Mylan I.V. Lederle Mylan I.V.

0.5 0.55 0.20 5.2 4 2.70 2.60 2.9

1 1.80 1.35 4.8 6 2.20 1.80 2.1

1.5 2.11 1.75 4.4 9 1.35 1.25 1.26

2 2.35 2.10 4.0 12 0.83 0.74 0.76

Basic Pharmacokinetics REV. 99.4.25 7-15


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

3 2.65 2.25 3.4 15 0.50 0.45 0.46

Would you consider Mylan to be bioequivalent to the Lederle product ?

Calculate the absolute bioavailability of Lederle Tetracycline.(.77)

f) Calculate the volume of distribution of tetracycline. (44.3 L)

g) Tetracycline has a pKa of 9.7. Tetracyclines tend to localize in the dentin and
enamel of developing teeth causing hypoplasia and permanent discoloration of
teeth. Would you recomend tetracyline for a 110 pound lactating mother ?

Support your argument with the dose of the child. (Child's weight 11 lbs. and he
eats 2 oz of milk every 2 hours. Mom's average plasma concentration is main-
tained at 3 mic/ml by taking 250 qid. pH of the milk is 6.1, pH of blood is 7.4)

Answer:

Basic Pharmacokinetics REV. 99.4.25 7-16


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Pharmacokinetic parameters:

Lederle Mylan IV

Cpmax (mic/mL)2.75 2.42 5.65

Tmax (hr) 3.04 3.08 0

AUC 26.4 23.3 31.4

k (hr^-1) 0.165 0.161 0.167

Ka (hr^-1) 0.684 0.729

Ratio of bioequivalence parameters (Cpmax, Tmax and AUC) are all within guide-
lines. So, the would be considered bioequivalent.

Absolute bioavailability f (= (AUCoral/DOSEoral)/(AUCiv/DOSEiv) = (26.4/


250)/(31.4/250) is 0.84.

Basic Pharmacokinetics REV. 99.4.25 7-17


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Volume of Distribution (Dose/Cp0 = 250 mg/ 5.65 mg/mL) is 44.2 L

The ratio of milk to blood is about 200.

r(m/b) = (10^(pKa-pH) + 1)milk / (10^(pKa-pH) + 1)blood

= (10^(9.7-6.1)+1)/(10^(7.4-6.1)+1) = 10^3.6/10^1.3 = 10^2.3 = 200

Dose the kid gets is mom's plasma concentration * Ratio(M/b) * volume of milk /
day = 3 mic/mL * 200 * 60cc * 12 feedings = 432 mg.day

Mom gets 1000 mg/day

Ratio of dose on a mg/kg basis (kid/mom) = (432/5)/1000/50) = 4.32 - Kid's get-


ting more than mom.

Fifty miligrams of ketameperidine was given by IV bolus. The following urinary


profile was obtained for the only metabolite N-methyl-ketameperidine:

Collection period (hr) Mean urinary excretion rate (mg/hr)

0.0 - 0.5 2.26

0.5 - 1.5 5.83

1.5 - 2.5 5.43

2.5 - 3.5 4.60

3.5 - 5.0 2.36

Basic Pharmacokinetics REV. 99.4.25 7-18


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

5.0 - 7.0 1.47

7.0 -10.0 0.96

10.0 -18.0 0.44

Calculate K, km and ku.

What Percent of ketameperidine was metabolized?

Answer:

With only one data point in the early time points, the larger rate constant is in ques-
tion. The terminal slope is assumed to be K. The AUC will yield the amount of
ketameperidine which was metabolized (dXmu/dt * t = Xmu).

K (hours^-1) 0.216

AUC (mg)30.3

30.3 mg showed up as metabolite = 60.6% of 50 mg dose.

km = 60.6% * K = 0.131 hours^-1

Basic Pharmacokinetics REV. 99.4.25 7-19


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

kr = K - km = 0.085 hours^-1

Aminophylline consists of THEOPHYLLINE (85% W/W) & Ethylene diamine


(15% W/W)

THEOPHYLLINE is the active compound measured in blood.

THEOPHYLLINE has a volume of distribution of 0.45 l/kg.

THEOPHYLLINE is 10% excreted unchanged and 90% metabolized to inactive


metabolites.

THEOPHYLLINE has a therapeutic range between 20 and 10 mg/l.

AUC FROM 0 to infinity for THEOPHYLLINE (given as 400 mg AMINPHYL-


LINE) is 120 mg/l x hr.

The average plasma concentration of THEOPHYLLINE given as 400 mg of AMI-


NOPHYLLINE is as follows:

time conc. time conc.

(hrs) (mg/L) (hrs) (mg/L)

0.5 7.24 4.0 8.06

1.0 9.56 6.0 6.89

2.0 10.00 8.0 5.57

3.0 8.84 10.0 4.53

Find f, K, ka, Vd,total body clearance.

Find the infusion rate necessary to maintain a plasma concentration of 15 mg/l.

Basic Pharmacokinetics REV. 99.4.25 7-20


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Answer:

AUC (mg/L)*hr117.8

K (hr^-1) 0.096

ka (hr^-1) 2.11

f = (AUCoral/DOSEoral)/(AUCiv/DOSEiv) =

= (117.8 / 400 )/(120 / 400 ) = 0.98

Vd

AUC * K = Cp0iv

120 * 0.096 = 11.52 mg/L

Vd = Dose/Cp0 = (400mg*0.85)/11.52 = 29.5 L

TBC = K * Vd = 0.096/hr * 26.5L = 2.83 L/hr

Basic Pharmacokinetics REV. 99.4.25 7-21


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Infusion rate = Q = Cpss * TBC = 15 mg/L * 2.83 L/hr = 42.45 mg/hr Theophyl-
line = 42.45/.85 = 50 mg/hr Aminophylline

Abbott labs has provided the following data conserning their ORETIC tablets
(hydrochlorthiazide tablets U.S.P.) Dose given was 50 mg.

time conc. time conc.

(hrs) (mg/L) (hrs) (mg/L)

0.5 0.05 3.0 0.31

1.0 0.21 4.5 0.23

1.5 0.27 6.0 0.18

2.0 0.31 8.0 0.12

a Find K, ka, Cmax,

Answer:

Basic Pharmacokinetics REV. 99.4.25 7-22


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

The data is plotted both without (first figure) and with (second figure) a lag-time
which is associated with the release of the drug from the delivery system. Note
that the addition of the lag-time improves the fit.

The parameters obtained from each fit are:

WithoutWith

Cpmax (mg/L)0.22 0.31

Tmax (hr) 3.45 2.28

AUC (mg/L*hr)2.2 2.26

K (hr^-1) 0.216 0.201

ka (hr^-1) 0.380 1.10

t lag (hr) 0.0 0.393

Basic Pharmacokinetics REV. 99.4.25 7-23


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

It takes the tablet about 20 minutes to release the drug!

Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthy volun-


teers in a four way crossover design of four dosage forms containing 300 mg of
cimetadine. The following data was obtained: A B C D

AUC(mic/ml x hr) --- --- 5.2 5.4

recovered in urine intact77.177.1 54.9 55.8

Peak serum conc.(mic/ml)--- --- 1.53 1.44

Onset (hr) 0 0.34 0.65

Duration (hr) 4.5 4.6 4.2 4.4

Time to peak (hr) 0 1.0 2.0

A = IV Bolus B=IM injection C = Oral liquid D= Oral tablet

The plasma concentration vs. time profile for product A is as follows:

time (hrs) conc.(ug/ml)

1 1.79

2 1.36

4 0.78

6 0.45

12 0.08

a} find K, Cp0.

Both can be found from the graph. K = .283/hr Cp0 = 2.36 mic/ml

Basic Pharmacokinetics REV. 99.4.25 7-24


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

b} What is the absolute bioavailability (f) of the liquid.

5.2/8.5 = 0.61

c} How does that correlate with % recovered intact in the urine?

Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that
to show up in the urine because only 77% of the IV dose shows up in the urine
(0.61 * .77 = .47).

d} How can you explain the variation in % recovered intact in the urine?

e} Would you consider the oral forms bioequivalent ? Why/Why not?

No. The ratio of peak times is outside the guidelines.

f} What infusion rate would you suggest to maintain a plasma concentration of


0.75 mic/ml?

Q = Cpss * K * V = 0.75 mg/L * 0.283/hr * 125L = 26.54 mg/hr

g} How long would it take that infusion rate to attain a therapeutic plasma concen-
tration of 0.5 mic/ml ?

Cp = Q/(K * V)(1-exp(-K*T) = 0.5 = 26.54/(0.283 *125)*(1-exp(-0.283 * T)) -


> 3.9 hr

Roxane labs of Columbus, Ohio offers the following data for your review of their
Quinidine Sulfate tablets (Dose 200 mg). It is compared against the reference
standard by Ely Lilly and company at the same dose.

Basic Pharmacokinetics REV. 99.4.25 7-25


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Time (hours)Concentration (mcg/ml)

Roxane Lilly

1 .42 .58

2 .73 .77

3 .71 .74

4 .61 .66

6 .45 .52

8 .32 .34

12 .20 .22

a) Calculate the comparative bioavailability.

b) Would you consider Roxane Quinidine Sulfate to be bioequivalent to the Lilly


product ?

Answers

Basic Pharmacokinetics REV. 99.4.25 7-26


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Basic Pharmacokinetics REV. 99.4.25 7-27


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Roxane labsEli Lilly

w/o w w/o w Rw/o(R/L)Rw(R/L)

Cpmax (mcg/mL)0.650.740.740.76 0.88 0.97

AUC (mcg/mL*hr)6.086.236.756.84 0.90 0.91

Tmax (hr) 2.69 2.05 2.33 2.10 1.15 0.98

T lag (hr) 0.0 0.70 0.0 0.36

Yes. Ratios are within guidelines.

Shand et al. offers the following data for propranolol : Answers:

Time Concentration (ng/ml)

(hours) 10 mg I.V. 80 mg oral

0.5 -- 50

1 -- 77

1.5 -- 100

2 29 100

3 24 90

4 18 78

5 15 59

6 11 45

7 9 32

Basic Pharmacokinetics REV. 99.4.25 7-28


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

a) find ka

b) Calculate the absolute bioavailability of propranolol.

c) Calculate TBC

Basic Pharmacokinetics REV. 99.4.25 7-29


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

IV data Oral Data

w/o w

AUC (ng/mL*hr)201.3562.8 540

Cpmax (ng/mL) 47.7 97.8 99.7

Tmax (hr) 0 2.0 2.1

K (hr^-1) 0.239 0.324 0.421

ka (hr^-1) --- 0.715 0.548

T lag 0.0 0.02

Absolute bioabailability = (AUCoral/DOSEoral)/(AUCiv/DOSEiv)

= (562.8/80) /(201.3/10) = 0.35 or using lag time data

(540 / 80) /(210.3/10) = 0.335

TBC = Dose / AUC = 10,000 mic/ 201.3 mic/L*hr = 50 L/hr or

0.35*80,000mic /562.8 mic/L*hr = 50 L/hr

Niazi et al. offers the following data for meperadine :

Meperidine : is 95% metabolized

has an absolute bioavailability of 0.4

has a hepatic plasma extraction ratio of 0.6

has a volume of distribution of 100 L.

has a half life of 3.5 hours.

Basic Pharmacokinetics REV. 99.4.25 7-30


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

a) Calculate TBC

TBC = K * V = (0.198/hr)(100L) = 19.8 L/hr

b) Calculate the intrinsic hepatic plasma clearance of meperidine.

19.8 L/hr * .95 = 18.8 L/hr

c) Calculate the effect on total body clearance in a patient with viral hepititis (FI =
0.3).

Clh*/Clh = (.3)(1)/1 + .6(.3 - 1) = .3/.58 = .517

(.517)(18.8) = 9.72

TBC = 1 + 9.72 = 10.72

d) Calculate the effect on total body clearance in a patient with stenosis (FR = 0.3).

Clr*/Clr = (1)(.3)/.3 + .6(1 - .3) = .3/.72 = .417

TBC = 18.8 + .417 = 19.22

e) Comment on which patient might need modification in therapy and why.

The patient with viral hepatitis would need modification in therapy. Because
of the decrease in TBC, we can see that the drug is staying the body much
longer than normal, therefore the dosage regimen should be decreased.

Chlorthalidone is used to treat high blood pressure. The following information is


offered regarding a generic

and a brand name chlorthalidone 50 mg tablet:

Time Conc. (mcg/ml)

Basic Pharmacokinetics REV. 99.4.25 7-31


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

(hours) Hygroton@Generic

.5 0.14 0.15

1 0.51 0.64

2 1.23 1.67

3 1.94 2.48

4 2.20 2.91

6 2.64 3.49

8 2.86 3.52

12 3.43 3.82

24 3.22 3.38

48 2.45 2.74

72 1.53 1.91

96 1.20 1.40

120 0.76 0.77

Pharmacokinetic parameters

Cpmax (mg) 3.73 4.62

Time to peak (hr) 13.810.8

AUC (0 to Inf)293 336

Xu inf (mg)18.3 22.1

Ka (hr^-1)0.168 0.253

Ke (hr^-1)0.019 0.019

Basic Pharmacokinetics REV. 99.4.25 7-32


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

Average mean83.1 84.5

blood presure

a) Calculate the comparative bioavailability.

(336/50mg)/(293/50mg) = 1.15

b) Would you consider the generic product to be bioequivalent to the USV


(Hygroton@) product? Prepare a short statement that you would tell a patient
regarding why you would or would not make a generic substitution for this drug.

No. The maximum concentration the generic is too much greater than that of
the brand name product.

They are not considered to be bioequivalent.

R(G/H)

Cpmax (mg) 1.23 outside

Time to peak (hr)0.78outside

AUC (0 to inf)115 ok

Buspirone is a new anxiolytic agent that has been found to be effective for the
treatment of generalized anxiety disorder at a mean dose of approximately 20 mg/
day orally in divided doses. Buspirone is metabolized almost entirely. Less than
0.1% is found intact in the urine. The following data has been presented by Gam-
mans (Am J Med:80(supp 3b),41-51;1986):

Time (hours)Concentration (ng/ml)

(hours) 1 mg I.V.20 mg oral

Basic Pharmacokinetics REV. 99.4.25 7-33


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

0.25 -- 1.07

0.50 4.33 1.76

1.0 3.75 2.45

2 2.80 2.51

3 2.10 2.05

4 1.57 1.60

6 0.8 0.91

a) find ka

b) Find Oral Peak Time and Oral Cmax.

c) Calculate the absolute bioavailability of buspirone.

answer:

Basic Pharmacokinetics REV. 99.4.25 7-34


Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Oral Dosing

IV Oral

Cpmax (ng/mL) 5.0 2.6

AUC (0 to inf)17.4 13.9

Tmax (hr) 0