Ivan N.

Tanodra, MD, RPh

Bio=Pharmaceutics
Life

general area of study concerned with the formulation, manufacture, stability and effectiveness of pharmaceutical dosage forms

Biopharmaceutics
study of the factors influencing the bioavailability of a

drug in man and animals and the use of this information to optimize pharmacological or therapeutic activity of drug products in clinical application

Biopharmaceutics
Interrelationship of the physicochemical properties of

the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of drug absorption

Biopharmaceutics
Study of the relationship of the physicochemical

properties and in vitro behavior of the drug & drug product on the delivery of the drug to the body under normal or pathologic conditions

 PHARMACOKINETICS a process of how the body

deals with the drug, what your body does to your drug

PHARMACODYNAMICS a process of how your drug

deals with the body, what your drug does to your body

Pharmacokinetics
Deals with the changes of drug concentration in a drug

product inside the human or animal body following administration

Pharmacokinetics
Involves the kinetics of drug absorption, distribution,

metabolism and elimination

Pharmacodynamics
Relationship between the drug concentration at the

site of action (receptor) and pharmacologic response including the biochemical and physiologic effects that influence their interaction Initiation of sequence of molecular events resulting in pharmacologic or toxic response

Drug Product
Finished dosage form that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredient (vehicle)
Formulation or matrix in which the drug is contained Term may also include a dosage form that does not contain an active ingredient intended to be used = placebo

Physicochemical properties of drug product

Pharmacologic/clinical effect

Factors
Stability of the drug within a drug product
The release of the drug from the drug product Rate of dissolution/release of the drug at the

absorption site The systemic absorption of the drug

Rationale
Apply biopharmaceutic principles in developing a

rational design of a drug product which would enhance the delivery of active drug and provide optimal therapeutic efficacy of the drug in the patient

AIM:
To deliver the right amount of drug that is EFFECTIVE and SAFE at the right place (site of action) and at the right time (oral, SL or IV/ fast or slow-release)

In-vivo & in-vitro methods

Be able to assess the impact of the physical and

chemical properties of the drug, drug stability and large-scale production of the drug and drug product on the biologic performance of the drug

 Mometasone cream AND Mometasone (Nasonex)

nasal spray Methylprednisolone tablet AND Fluticasone spray Salbutamol nebules, Salbutamol MDI and Salbutamol syrup Nitroglycerin patch AND Nitroglycerin spray Lactacyd facial wash AND Lactacyd feminine wash Atropine eyedrops AND Atropine ampule Lidocaine spray, Epinephrine ampule and Lidocaine:Epinephrine carpule

Drug disposition
Description of drug distribution and elimination

Lets discuss the disposition of a drug

DOSAGE FORM
ROUTE OF ADMINISTRATION

Bioavailability of the drug (active ingredient) is the primary concern of biopharmaceutics - Remember you AIM

LADMERT

How do you measure the bioavailability of a drug?

How do you measure the bioavailability of a drug?

1.
2. 3.

4.

Blood = plasma level concentration Urine Feces reflect a drug that has not been absorbed after an oral dose or a drug that has been biliary secreted after systemic absorption Clinical outcome/Pharmacologic effect/pharmacodynamic effect

Which is the most direct measurement?

Plasma Level Time Curve

Plasma level (mg/mL)

Time (mins.)

Identify.
Peak plasma level (cmax) max drug concentration

related to the dose & the rate constants for absorption & elimination of the drug AUC (Area Under the Curve)- related to the amount of drug absorbed systemically Time of peak plasma level (tmax) time of max drug conc. in plasma roughly proportional to the average rate of drug absorption

Determine the route of administration

IV
Oral

Higher plasma level concentration = ___________? bioavailability

Bioavailability = Therapeutic Efficacy ???

Establish
Minimum effective concentration (MEC)
Minimum toxic concentration (MTC)

Let us go back to the plasma-level time curve

You will be able to determine.

Onset time of action
Duration of action Intensity of drug action

Higher plasma concentration of a drug = Therapeutic Efficacy ???

Most of the time..

Plasma level concentration of a drug = concentration of drug at the receptor sites = intensity of a pharmacologic effect

Is measuring plasma concentrations of a drug enough to determine its therapeutic efficacy?

Pharmacodynamic Response
Digoxin = ECG tracings
Warfarin = Prothrombin time Insulin = Blood glucose levels Simvastatin = Blood cholesterol levels Nifedipine (anti-hypertensive) =

___________________ Paracetamol = ___________________

Plasma drug concentrations do not accurately predict pharmacodynamic response

Action of warfarin is dependent on the clotting factors II, VII, IX & X

Having the same trend of plasma level concentration of Warfarin..

Will the intensity of the activity of Warfarin in a

hemophiliac be the same with a normal person?

Pharmacodynamic response OR Plasma level concentration????

IQ
A 64 year-old male, diabetic patient with a poor creatinine clearance is being given Gentamycin 80mg (aminoglyocside) IV once daily as a treatment for sepsis. Which is important: a. Blood culture and sensitivity to determine his response to treatment b. Plasma level concentration to determine the blood level of the drug c. A and B Why?

Pharmacokinetic Models
Drugs are in a dynamic state within the body
It is a hypothesis conceived using mathematical terms Describe drug concentrations in the body as a function

of unit time

Pharmacokinetic Models
Concentration of drug in the tank would be governed by two parameters which are CONSTANT: 1. Fluid volume of the tank 2. Elimination of drug per unit of time

Let us correlate the LADMER System with Pharmacokinetic Models

Pharmacokinetic Models
If a known set of drug concentrations in the tank were determined at various intervals volume of fluid in the tank & rate of drug elimination would be established

Pharmacokinetic Models

A compartment is a tank containing a volume of fluid In the human body, a fraction of drug is continually eliminated as a function of time

Pharmacokinetic Models

Concentration of drug in the tank (compartment) after a given dose (Ab) is governed by two parameters: 1. Fluid volume of the tank (Vd) 2. Elimination of drug per unit of time (kel, CL) this could be established by knowing a set of drug concentrations in the tank (Cp) at various time intervals

Pharmacokinetic Models
The number of parameters needed to describe the

model depends on: 1. Complexity of the process (ADME) 2. route of drug administration

Uses of Pharmacokinetic Models

Predict plasma, tissue and urine drug levels with any

dosage regimen Calculate the optimum dosage regimen for each patient individually Estimate possible accumulation of drug and/or metabolites Correlate drug concentrations with pharmacologic or toxicologic activity

Uses of Pharmacokinetic Models

Evaluate differences in the rate or extent of availability

between formulations (bioequivalence) Describe how changes in physiology or disease affect the absorption, distribution and elimination of the drug Explain drug interactions

Pharmacokinetic Models
A. Compartment Model (Mammillary Model)
B. Physiologic Pharmacokinetic Model (Flow Model)

Compartment (Mammillary) Model

One or more peripheral compartment connected to a

central compartment like satellites DRUG IN THE BODY = CENTRAL COMPARTMENT + TISSUE COMPARTMENT

Compartment (Mammillary) Model

Compartment is not a real physiologic or anatomic

region Used when there is little information known about the tissues ASSUMPTION: Compartment group of tissues that have a similar blood flow and drug affinity Within each compartment, drug is uniformly distributed OPEN drugs move in & out of the compartment (dynamic)

Compartment (Mammillary) Model

ASSUMPTION: Drug has an equal probability of leaving the compartment

Compartment Models
Rate constants (ka & ke) represents the overall rate

processes of drug entry into and exit from the compartments

Compartment Model
FUNCTIONS: Enables the pharmacokineticist to write different equations to drug concentration changes inside each compartment Visual representation of rate processes Shows how many pharmacokinetic constants are necessary to describe the process adequately

Compartment Models
Open-one compartment model
Open-two compartment model Compartment model for IV and oral

Compartment Model
Can a drug concentration data be obtained directly

from each compartment??? In open two compartment data in the peripheral compartment cannot be obtained tissues are not easily sampled & may not contain homogenous concentration of the drug only estimated mathematically (from amount of drug absorbed & eliminated per unit time)

Compartment Model
DISADVANTAGES: NOT REALISTIC because everything is based on presumption and mathematical concept Cannot be extrapolated to humans

Physiologic Pharmacokinetic Model

Blood flow or perfusion model Based on known anatomic and physiologic data MORE REALISTIC Actual tissue volume is used Experimentally determined in ANIMALS extrapolated to humans No data fitting required On model if theres no perfusion, organ is excluded (e.g. brain)

Construct the model.

IV injection, Venous blood, Arterial blood, Heart,

Muscle, Slowly equilibrating tissue (SET), Rapidly equilibrating tissue (RET), Kidney, Liver, ke, km, Perfusion (Q) Qh, Qm, Qs, Qr, Qk, Ql, Urine

Physiologic Pharmacokinetic Model

DISADVANTAGE:
1. Data can be experimentally difficult to obtain 2. Data can be affected by pathophysiologic conditions

Factors Affecting Design of a Drug Product

DRUG Dosage form Dose (mg/kg) Physicochemical properties Route of administration BODY Physiologic factors (e.g. age, body mass) Pathologic factors (e.g. liver and renal disease)

Application of Biopharmaceutics
Generic equivalency
Drug availability Therapeutic efficacy Drug substitution

Bioequivalence
Achieved if the extent and absorption of a drug

product are not statistically significantly different from the standard when administered at the same molar dose