Pharmacokinetics: Concepts and Examples, Lecture notes of Pharmacokinetics

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Basic Concepts

of Pharmacokinetics

Achiel Van Peer, Ph.D.

Clinical Pharmacology

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Some introductory Examples

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Prediction of drug plasma concentrations

before the first dose in a human

NOAEL in female rat

NOAEL in male rat NOAEL in female dog

NOAEL in male dog

First dose 5 mg Fabs 100%Fabs 50%Fabs 20%

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Allometric Scaling

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Definition of Pharmacokinetics?

Pharmacokinetics is the science describing drug

absorption from the administration site distribution to

„

tissues,

„

target sites of desired and/or undesired activity

metabolism excretion

PK= ADME

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We will cover

Some introductory Examples Model-independent Approach Compartmental Approaches Drug Distribution and Elimination Multiple-Dose Pharmacokinetics Drug Absorption and Oral Bioavailability Role of Pharmacokinetics

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C

max

, T

max

and AUC in

Bioavailability and Bioequivalence Studies

Absolute bioavailability (Fabs)

„

compares the amount in the systemic circulationafter intravenous (reference) and extravascular (usually oral) dosing

Fabs = AUC

po

/AUC

iv

for the same dose

„

between 0 and 100% (occasionally >100%)

Relative bioavailability (Frel)

„

compares one drug product (e.g. tablet)relative to another drug product (solution)

Bioequivalence (BE):

a particular Frel

Two drug products with the same absorption rate (Cmax, Tmax)and the same extent (AUC) of absorption

(90% confidence intervals for Frel between 80-125%)

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Absolute oral bioavailability

flunarizine,

J&J data on file

Other example: nebivolol:

10% in extensive metabolisers; 100% in poor metabolisers

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Elimination half-life?

Half-life (t1/2) : time the drug concentration

needs

to decrease by 50%

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Elimination half-life?

visual inspection

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From

Whole-Body Physiologically

based

Pharmacokinetics to

Compartmental

Models

Poggesi et al., Nerviano Medical Science

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Compartmental Approach

One-compartment PK model

Body

compartment

Drug

Absorption

Drug Elimination

drug distributes very rapidly to all tissuesvia the systemic circulation an equilibrium is rapidly established between the bloodand the tissues, the body behaves like

one (lumped) compartment

does not mean that the concentrations in the differenttissues are the same

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Intravenous dose of 0.2 mg Levocabastine

(J&J data on file)

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Depending on rate of equilibration with

the systemic circulation, lumping tissues together,

and simplification is possible

Multi-Tissue or Multi-Compartment Whole Body Pharmacokinetic model

Tri-compartment model

Two-compartment model

One-compartment model