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Biopharmaceutics and
Clinical Pharmacokinetics
MILO GIBALDI, PH. D.
Dean, School of Pharmacy
Associate VicePresident,
Health Sciences
University of Washington
Seattle, Washington
FOURTH EDITION
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Library of Congress Cataloging-in-Publication Data
It Gibaldi, Mile.
Biopharmaceutics and clinical pharmacokinetics / Milo Gibaldi.—
4th ed.
p. cm.
o Includes bibliographical references.
I- ISBN 0-8121-1346-2
1. Biopharmaceutics. 2. Pharmacokinetics. 1. Title
'P
[DNLM: 1. Biopharmaceutics. 2. Pharmacokinetics. QV 38 G437b]
RM301.4.G53 1990
615'. 7—dc20
j1.
DNLM/DLC
for Library of Congress 90-5614
CIP
The use of portions of the text of USP XX-NF XV is by permission of the USP Convention. The Convention
is not responsible for any inaccuracy of quotation or for false or misleading implication that may arise
from separation of excerpts from the original context or by obsolescence resulting from publication of a
supplement.
Reprints of chapters may be purchased from Lea & Febiger in quantities of 100 or more.
Copyright © 1991 by Lea & Febiger. Copyright under the International Copyright Union. All Rights Reserved. This
book is protected by copyright. No part of it may be reproduced in any manner or by any means without written permission
from the publisher.
Print no.: 4 3 2 1
Contents
Introduction to Pharmacokinetics
Gastrointestinal Absorption—
Biologic Considerations 24
A Gastrointestinal Absorption—
Physicochemical Considerations 40
Gastrointestinal Absorption—
Role of the Dosage Form 61
6. Nonoral Medication 80
g Bioavailability 146
ix
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Contents
.V
I 272
13. Pharmacokinetic Variability—Disease
Index 381
1
Introduction to Pharmacokinetics
Advancements in biopharmaceutics have come a rate constant (k). The magnitude of the rate con
about largely through the development and appli stant determines how fast the transfer occurs.
cation of pharmacokinetics. Pharmacokinetics is The transfer of drug from blood to extravascular
i
the study and characterization of the time course fluids (i.e., extracellular and intracellular water) i
of drug absorption, distribution, metabolism, and and tissues is called distribution. Drug distribution
excretion, and the relationship of these processes is usually a rapid and reversible process. Fairly
to the intensity and time course of therapeutic and quickly after intravenous (iv) injection, drug in the
toxicologic effects of drugs. Pharmacokinetics is plasma exists in a distribution equilibrium with
used in the clinical setting to enhance the safe and drug in the erythrocytes, in other body fluids, and
effective therapeutic management of the individual in tissues. As a consequence of this dynamic equi
patient. This application has been termed clinical librium, changes in the concentration of drug in
pharmacokinetics. the plasma are indicative of changes in drug level
in other tissues including sites of pharmacologic
effect (bioreceptors).
DISTRIBUTION AND ELIMINATION The transfer of drug from the blood to the urine
The transfer of a drug from its absorption site or other excretory compartments (i.e., bile, saliva,
to the blood, and the various steps involved in the and milk), and the enzymatic or biochemical trans
distribution and elimination of the drug in the body, formation (metabolism) of drug in the tissues or
are shown in schematic form in Figure 1-1. In the plasma to metabolic products, are usually irre
blood, the drug distributes rapidly between the versible processes. The net result of these irre
plasma and erythrocytes (red blood cells). Rapid versible steps, depicted in Figure 1-1, is called
distribution of drug also occurs between the plasma drug elimination. Elimination processes are re
proteins (usually albumin but sometimes ctj-acid sponsible for the physical or biochemical removal
glycoproteins and occasionally globulin) and of drug from the body.
plasma water. Since most drugs are relatively small The moment a drug reaches the bloodstream, it
molecules they readily cross the blood capillaries is subject to both distribution and elimination. The
and reach the extracellular fluids of almost every rate constants associated with distribution, how
organ in the body. Most drugs are also sufficiently ever, are usually much larger than those related to
lipid soluble to cross cell membranes and distribute drug elimination. Accordingly, drug distribution
in the intracellular fluids of various tissues. throughout the body is usually complete while most
Throughout the body there is a distribution of drug of the dose is still in the body. In fact, some drugs
between body water and proteins or other macro- attain distribution equilibrium before virtually any
molecules that are dispersed in the body fluids or of the dose is eliminated. In such cases, the body
are components of the cells. appears to have the characteristics of a single com
The body can be envisioned as a collection of partment.
separate compartments, each containing some frac This simplification, however, may not be applied
tion of the administered dose. The transfer of drug to all drugs. For most drugs, concentrations in
from one compartment to another is associated with plasma measured shortly after iv injection reveal a
) 1
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•J 2 Biopharmaceutics and Clinical Pharmacokinetics
•ft
w. Drug in Urine
k4
Drug at
4 > Drug in Blood
^5
Metabolite(s)
n Absorption Site
^6
^1 ^2 k_ 2
Drug in Other
Excretory Fluids
Drug in
Other Fluids
k3 , Drug in
of Distribution k_3 Tissues
:•
distinct distributive phase. This means that a meas The proportionality constant relating amount and
urable fraction of the dose is eliminated before concentration is called the apparent volume of dis
attainment of distribution equilibrium. These drugs tribution (V). In most situations, V is independent
impart the characteristics of a multicompartment of drug concentration. Doubling the amount of
system upon the body. No more than two com drug in the body (e.g., by doubling the iv dose)
partments are usually needed to describe the time usually results in a doubling of drug concentration
course of drug in the plasma. These are often called in plasma. This is called dose proportionality; it
the rapidly equilibrating or central compartment is often used as an indicator of linear pharmaco
and the slowly equilibrating or peripheral com kinetics.
partment. The apparent volume of distribution is usually a
characteristic of the drug rather than of the biologic
PHYSICAL SIGNIFICANCE OF DRUG system, although certain disease states and other
CONCENTRATION IN PLASMA factors may bring about changes in V. The mag
Blood samples taken shortly after intravenous nitude of V rarely corresponds to plasma volume,
administration of equal doses of two drugs may extracellular volume, or the volume of total body
show large differences in drug concentration de water; it may vary from a few liters to several
spite the fact that essentially the same amount of hundred liters in a 70-kg man. V is usually not an
each drug is in the body. This occurs because the anatomic volume but is a reflection of drug distri
degree of distribution and binding is a function of bution and a measure of the degree of drug binding.
the physical and chemical properties of a drug and Acid drugs, such as sulfisoxazole, tolbutamide,
may differ considerably from one compound to or warfarin, are often preferentially bound to
another. plasma proteins rather than extravascular sites. Al
At distribution equilibrium, drug concentrations though these drugs distribute throughout body wa
in different parts of the body are rarely equal. There ter, they have small volumes of distribution ranging
may be some sites such as the central nervous sys from about 10 to 15 L in man. A given dose will
tem or fat that are poorly accessible to the drug. result in relatively high initial drag concentrations
There may be other tissues that have a great affinity in plasma.
for the drug and bind it avidly. Drug concentrations On the other hand, many basic drugs including
at these sites may be much less than or much greater amphetamine, meperidine, and propranolol are
than those in the plasma. more extensively bound to extravascular sites than
Despite these complexities, once a drug attains
to plasma proteins. The apparent volumes of dis
distribution equilibrium its concentration in the
tribution of these drugs are large, ranging from 4
plasma reflects distribution factors and the simple
to 8 times the volume of total body water (i.e..
relationship between amount of drug in the body
180 to 320 L in a 70-kg man). The frequently small
(A) and drug concentration in the plasma (C) shown
doses and large distribution volumes of these drugs
in Equation 1-1 applies:
often make their quantitative detection in plasma
A = VC (1-1) difficult.
I Introduction to Pharmacokinetics 3
k = k4 + kj + k5 (1-3) •
PHARMACOKINETIC CONSIDERATIONS OF
DRUG CONCENTRATIONS IN PLASMA Dimensional analysis of Equation 1-2 indicates
that the units of k are reciprocal time (i.e., day
The plasma contains measurable quantities of
hr1, or mhr1).
many endogenous chemicals. In healthy individ
Since there is a relationship between the amount
uals these biochemicals are present in concentra
of drug in the body and the drug concentration in
tions that are reasonably constant, and it is appro
the plasma (Eq. 1-1), we may rewrite Equation
priate to speak of creatinine or bilirubin levels in
, 1-2 as
the plasma. Drug levels or concentrations in the
plasma are rarely level. One usually finds different d(VC) dC
= -V— = k(VC)
concentrations of drug in the plasma at different dt dt
times after administration. These changes reflect
the dynamics of drug absorption, distribution, and or
elimination (Fig. 1-2). dC
— = kC (1-4)
I
dt
Intravenous Administration
Absorption need not be considered when a drug Integrating this expression between the limits t =
is given by rapid iv injection. As soon as the drug 0 and t = t yields
is administered it undergoes distribution and is sub kt
ject to one or more elimination pathways. The log C = log C0 (1-5)
2.303
amount of drug in the body and the drug concen
tration in plasma decrease continuously after in
jection. At the same time, there is continuous for
Equation 1-5 indicates that a plot of log C versus
t will be linear once distribution equilibrium is
is
mation of metabolites and continuous excretion of reached. The term C0 is the intercept on the log
drug and metabolites. Eliminated products accu concentration axis, on extrapolation of the linear
mulate while drug levels in the body decline. segment to t = 0.
Most drugs distribute rapidly so that shortly after
iv injection, distribution equilibrium is reached.
Figure 1-3 shows the average concentration of
a semisynthetic penicillin in the plasma as a func I
Drug elimination at distribution equilibrium is usu tion of time after an intravenous injection of a 2-g
ally described by first-order kinetics. This means dose. The concentration values are plotted on a log
that the rate of the process is proportional to the scale; the corresponding times are plotted on a lin
amount or concentration of substrate (drug) in the ear scale. The semilogarithmic coordinates make
system. As drug concentration falls, the elimina- it convenient to plot first-order kinetic data for they
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Introduction to Pharmacokinetics 5
• I
since all other terms are known. This estimate may
I
be less than accurate but it is always better than
that provided by Equation 1-6.
Z The maximum or peak drug concentration in
o c plasma is always lower after intravenous infusion L
H O
than after bolus injection of the same dose. The
< c T'
when distribution equilibrium is essentially reached sufficiently small so that the elimination rate ex
by the end of the infusion. A semilogarithmic plot ceeds the absorption rate (i.e., dAE/dt > dAA/dt),
of C (post-infusion drug concentration in plasma) the amount of drug in the body and the drug con
11 *
versus t' yields a straight line, from which the half- centration in the plasma decrease with time. The
III I
life and elimination rate constant can be estimated. maximum or peak concentration after drug admin i; i
The entire drug concentration-time profile during istration occurs at the moment the absorption rate 'M
and after a short-tenn infusion is shown in Figure equals the elimination rate (i.e., dAA/dt = dAE/dt).
1-4. The faster a drug is absorbed, the higher is the
Equation 1-11 may be arranged to calculate V, maximum concentration in plasma after a given
I
6 Biopharmaceutics and Clinical Pharmacokinetics i
Many drugs have no demonstrable pharmaco a form that results in slow or incomplete absorp
logic effect or do not elicit a desired degree of tion. U
it
pharmacologic response unless a minimum con
centration is reached at the site of action. Since a BIOAVAILABILITY
f.
distribution equilibrium exists between blood and The bioavailability of a drug is defined as its rate
tissues, there must be a minimum therapeutic drug and extent of absorption. Rapid and complete ab ;
'
concentration in the plasma that corresponds to, sorption is usually desirable for drugs used on an
though may not equal, the minimum effective con- acute or "as needed" basis for pain, allergic re-
8 Biopharmaceutics and Clinical Pharmacokinetics
stant. This area must be added to the area calculated Constant Rate Infusion
from time zero to t* to obtain the total area under
It is convenient to consider first the simpler case
the curve.
of continuous administration of a drug by intra
The total area under the drug level-time curve
venous infusion; this method of drug administration
for drugs eliminated by first-order kinetics is given
results in a plasma concentration-time profile that
by
is similar in many ways to that found on intermit
Amount of drug reaching tent repetitive dosing. Figure 1-8 illustrates the
the bloodstream time course of drug concentration in plasma during
AUC - (1-22)
k • V and after infusion at a constant rate. At the outset,
drug concentration increases gradually but at a di
It follows that the bioavailability (F) of a drug from
minishing rate. If infusion is continued, drug con •;
f
'•<
10 Biopharmaccutics and Clinical Pharmacokinetics
I•1
Infusion
i
16n
\ VTime-4 x Half-life
12-
E
2
ill O
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Is H
4:1 8-
1:i (T
1— ^ T i m e=1XHalf-life
2
LU
o H a l f - l i f e , 1. 7 h r
y
Z
•Vl O 4-
O
i i
; 8 16 24 32
TIME, hr
Fig. 1-8. Drug concentration in plasma during and after prolonged constant rate Intravenous infusion. (From Gibaldi,
M., and Levy, G.: Pharmacokinetics in clinical practice. II. Applications. JAMA, 235:1987, 1976. Copyright 1976,
American Medical Association.)
cmax
3CH
—c
o>
z
E
r\ \
\
mm
O
20-
H
<
a:
z
LLI
O
z
o 10-
o
I
2 3 4
1
TIME, days
maximum (C m a ,),
Fig. 1-9. Drug concentratio n in plasma during repetitive oral administratio n of 250 mg every 5 hr. The
(C ), and average (C) drug concentratio ns at steady state are noted. (From Gibaldi, M., and Levy, G.: Phar
minimum mm
American Medical Associa-
macokinetic s in clinical practice. II. Applications . JAMA, 235:1987, 1976. Copyright 1976,
tion.)
at steady state to that after the first dose. Dividing but they are given either several times a day or
Equation 1-28 by Equation 1-29 yields once a day. Drug accumulation may be substantial.
When appropriate, it has become increasingly
common to administer a drug once every half-life.
Accumulation = (Cmin)ss/Cmin (1-30) The current use of theophylline, procainamide,
= 1/[1-exp( k T ) ] phenytoin, and tricyclic antidepressants reflects
this trend.
Therefore, by merely knowing the elimination rate
Average Drug Concentration at Steady State
constant (k) or half-life of a drug we can predict
the degree of accumulation for a given dosing reg An alternative and simpler way of describing
imen. If a drug is given every half-life (T = t^) steady state is to consider the average drug con
the accumulation at steady state will be about 2-fold centration (Css), which is analogous to the steady-
relative to the first dose. state concentration during continuous infusion. If
Some drugs, including the penicillins and ceph drug concentration during each dosing interval is
alosporins, are given less frequently than once viewed in terms of an average concentration, we
every half-life. These drugs have half-lives in the can express the intermittently administered dose in !
order of 1 hr, but are usually given every 6 to 8 tenns of an average dosing rate. For example, 100
hr. Virtually no accumulation is observed on re mg given every 4 hr can be viewed as a 25 mg/hr I* U
peated administration. Many drugs, such as diaz average dosing rate. When based on these consid
:
erations, Equation 1-26 for a constant rate intra
ih
epam, amiodarone, phenobarbital, and digoxin, are
given more frequently than once every half-life. venous infusion can be applied to the intermittent f
For these drugs the half-life is greater than one day oral administration of a drug with one additional llli
111
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lit
12 Biopharmaceutics and Clinical Pharmacokinelics
provision; allowance must be made for the possi for those drugs which distribute slowly or to which
bility that absorption of the drug is less than com patients become accustomed only gradually. Cau
plete. Then, tion should be applied at all times. With digoxin
or digitoxin therapy, loading (or digitalization) is
Css = F(average dosing rate)/Vk (1-31)
almost always carried out with 3 or 4 divided doses
over the first 1 or 2 days of therapy.
where F is the fraction of the administered dose
Treatment of epileptic patients with phenytoin
that actually reaches the bloodstream. The prop
is often initiated with a regular maintenance dose.
erties and usefulness of Css are discussed in greater
divided or single, of 300 to 400 mg daily. When
detail in Chapter 2.
phenytoin therapy is begun in this manner, steady-
Loading Dose state plasma phenytoin levels are achieved after 7
to 10 days. Some clinicians believe, however, that
Whether a drug is given by continuous intra
in the patient with frequent seizures a delay in
venous infusion or by repetitive oral administra reaching the therapeutic steady-state phenytoin
tion. it usually requires about 4 times the half-life plasma level may be detrimental because attacks
of the drug to reach an average concentration within may occur before the drug develops its full anti
10% of the steady-state concentration. In some in convulsant effect. Several clinical investigators
stances, this may represent too long a period to have suggested initial loading of selected patients
wait for optimum drug effects, and an initial load with phenytoin.12 In one study,2 61 patients re
ing dose is used. ceived a 1-g loading dose of phenytoin followed
Assuming that it is clinically acceptable to do by a constant daily maintenance dose of 300 to 400
this in a single dose, one can estimate a loading mg. Seizure control was obtained promptly in all
dose based on the usual maintenance dose and elim patients who responded to the drug. Patients tol
ination rate constant of the drug as follows: erated the loading doses well, and therapeutic
phenytoin levels were achieved rapidly. Studies in
Maintenance dose
(1-32) children have confirmed the efficacy but have
Loading dose =
1 - exp( - k T ) raised questions regarding the safety of this ap
proach.3
This loading dose will provide a drug concentration It is well recognized that more than a week of
T hr after administration that is equal to the mini treatment with a given maintenance dose of gua-
mum drug concentration at steady state following nethidine may be required to produce the maximum
repetitive administration of the maintenance dose. antihypertensive effect of this dose. This results
If a drug is administered every half-life, the ap from the fact that elimination of the dmg from the
propriate loading dose is 2 times the maintenance body is slow (average half-life about 5 days). A
dose. Therapy with tetracycline (t^ = 8 hr) is often regimen has been devised for achieving the phar
initiated with a 500-mg loading dose followed by macologic effects of guanethidine relatively rap
250 mg every 8 hr. idly, using the concept of loading and maintenance
The difference between loading dose and main doses based on the kinetics of guanethidine elim
tenance dose depends on the dosing interval and ination.4 This regimen was tested in 6 hypertensive
the half-life of the drug. Digoxin, which has a half- patients. Reduction of blood pressure was achieved
life of about 44 hr but is administered once a day. with individualized divided loading doses of 150
is typically given as a loading dose of 1.0 to 1.5 to 525 mg guanethidine administered over a period
mg followed by daily doses of 0.125 to 0.5 mg; of 1 to 3 days. Maintenance doses ranging from
the ratio of loading dose to maintenance dose is 20 to 65 mg per day were calculated from the
about 3 or 4. The half-life of digitoxin is about 6 loading dose by assuming a daily loss of about one
days; typically digitoxin therapy is initiated with a seventh of the body stores of drug. Satisfactory
loading dose of up to 1.6 mg followed by daily control of blood pressure was maintained following
doses of 0.1 to 0.2 mg; the ratio of loading dose the guanethidine load, without side effects.
to maintenance dose is usually about 10. The
Dosing Interval
smaller the ratio of dosing interval to half-life, the
larger is the ratio of loading dose to maintenance The frequency of dosing is often based on tra
dose. dition and usage (e.g., the t.i.d. orq.i.d. regimen).
Loading of drugs may be hazardous, particularly From a pharmacokinetic point of view, however.
Inlroduction to Pharmacokinetics 13
a rational dosing interval for most drugs approxi men because it was easier to remember or easier 3
mates the biologic half-life. Thus, it has been found to take and more convenient.'0 J
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that the traditional 3-times-a-day dose of pheny Less frequent dosing may not be feasible with
toin, a drug with an average half-life of about one some rapidly absorbed drugs that produce high
day, is unnecessary in many patients and that the peak concentrations in the plasma, resulting in
total daily dose can often be administered once a adverse effects. This problem may be overcome
day.5 by using slow-release dosage fonns. Thus, slow-
Similar conclusions have been reached with re- release forms may be rational even for some drugs
spect to dosing of griseofulvin. Comparable steady- with long biologic half-lives. Presumably, once-a- 1
day dosing of griseofulvin and certain phenytoin
state plasma levels of griseofulvin are achieved
products is well tolerated because these drugs are
whether the drug is given in doses of 125 mg 4
absorbed rather slowly. High doses of most neu
times a day or in a single daily dose of 500 mg.6
roleptics and tricyclic antidepressants tend to sedate
Apparently, treatment with griseofulvin can be
and, for most patients, late evening administration
simplified to once-a-day administration with no
of the total dose is preferable. This may offer the
loss of efficacy or safety.
additional advantage of avoiding the need for a
Many neuroleptics and tricyclic antidepressants hypnotic drug.
have rather long biologic half-lives. Almost from i
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