Leon Aarons

Manchester Pharmacy School

University of Manchester

Population Pharmacokinetics

and Pharmacodynamics

as a Tool in Drug Development

Pharmacokinetics

and

Pharmacodynamics

Clinical Pharmacokinetics

DosageRegimen

PlasmaConcentration

Site ofAction Effect

Pharmacokinetics Pharmacodynamics

Models

The type of model to be developed should be

driven by the available information and the

goal of the simulations

Empirical

models

Semi-mechanistic

models

Mechanistic

models

Descriptive

Explanatory Rich

“Poor”

Extrapolation in

complex and

variable environment

Interpolation in

simple and

stable environment

Information

needed Goal

Days Months Years

Category

0.01

0.1

1

10

100

0 2 4 6 8 10

time

co

nc

en

tra

tio

n

1 2t t1 2C( t ) C e C e

1 2

k12

k21

k10

11 12 1 1 10 1 1 21 2 2

22 12 1 1 21 2 2

( )( ) ( ) ( )

( )( ) ( )

dC tV k V C t k V C t k V C t

dt

dC tV k V C t k V C t

dt

PBPK MODEL

Pharmacokinetic

Study Design

Sparse Data

Tobramycin study

Objective: to establish dosage regimen guidelines to

maintain maximum efficacy (Cmax > 6

mg/L) and minimum toxicity (Cav < 4

mg/L) in a majority of patients

Patients: n 97 (after pruning)

body weight (kg) 42-120

age (yr) 16-85

sex (M/F) 52/45

creatinine clearance 10-166

(ml/min)

indication variety of infection

Study design: no design - routine TDM

dosage - 20 to 140 mg every 8 to 24 hr

number of concentrations per individual 1-9

(median 2)

duration of therapy - 14 to 520 hr

Why? It seeks to obtain relevant pharmacokinetic

information in patients who are representative

of the target population to be treated with the

drug

It recognizes variability as an important feature

that should be identified and measured during

drug development and evaluation

It seeks to explain variability by identifying

factors of demographic, pathophysiological,

environmental or drug-related origin that may

influence the pharmacokinetic behavior of a

drug

It seeks to quantitatively estimate the magnitude

of the unexplained variability in the patient

population

Summary

• PK/PD is model driven

• PK/PD models aid the interpretation of

pharmacological data and can be used

prospectively to design subsequent studies

learning/confirming

• Nonlinear mixed effects modelling allows data

from a variety of unbalanced, sparse designs to be

analysed

• Software for nonlinear mixed effects modelling is

now widely available -

even for amateurs!