1

Rationale for the effective use of pharmacokinetics and

pharmacodynamics in drug development

P.L. Toutain

ECOLENATIONALEVETERINAIRE

T O U L O U S E

Update: 09/10//2010

2

Objective of the presentation

• To show non-kineticists that PK can be a

very useful tool to document drug safety

and efficacy

• To understand the meaning and utility of the

main PK parameters

3

PHARMACOLOGY

Pharmacokinetics

Pharmacodynamics

Clinical pharmacology

Action of animal on drug

Action of drug on animal

Study of drug in a clinical context

4

Clinical trialsvs.

PK/PD trials

5

Dose titration

Dose ResponseBlack box

PK/PD

Dose

PK PD

Plasmaconcentration

surrogateResponse

6

Dose effect vs. concentration effect relationship

DOSE AUC = (Dose/Cl)

EFFECT EFFECT

Less variance must be expected in the AUC/effect than in the dose/effect relationship

External dose Internal dose

8

Acute toxicity of anticancer drugshuman versus mouse

0

2

4

6

8

10

12

14

0-1 0.4-0.6 0.6-1.2 2.0-3.0 >4 0

2

4

6

8

10

12

14

0-1 0.4-0.6 0.6-1.2 2.0-3.0 >4

Dose RatioExternal dose

AUC Ratio Internal dose

Fre

qu

ency

9

Digoxin levels in toxic and nontoxic patients

* From smith TW and haber E. J clin invest 1970;49:2377-86.

Non toxic (131)

Toxic (48)

10

The concentration principle in drug development:

Extrapolations

• From in vitro to in vivo

• From experimental to target species

11

PK/PD: in vitro vs. in vivo

ResponsePlasmaconcentration

Body

Medium concentration Test system

effet

In vivo

In vitro

Extrapolation in vitro in vivo

13

The concentration principle in drug development: mechanistic approach

14

PK/PD: mechanistic approach

PK/PD

DoseResponse

PK PD

Plasmaconcentration

Plasma concentration

Drug receptor interaction

TransductionDose

Response

Drug specificity, affinity &intrinsic efficacy

System specificity

18

Dose vs. plasma concentration profile as independent variable

Dose

Mass(no biological information)

Dose F%Clearance

Time

Concentration profile

X

(biological information)

19

PK vs. PD variability

i.e. the 2 main sources of variability

21

PK and PD variability

well documented– species– food– age– sex– diseases

PK PD

Dose

Plasma concentration

EffectBODY Receptor

Generally ignoredbut usually more

pronounced than PK variabilities (for a given

species)

22

Coefficient of variation (%)

PK PD

Clearance Vss EC50 EC50

antipyretic anti-inflammatory

Nimesulide 17 20 49 62

Tolfenamic Ac. 28 9.5 47 48

Prednisolone 12 15 49

PK/PD variability for anti-inflammatory drugs

T. Haake, 1997

23

Definition of the main pharmacodynamic drug properties

• Efficacy– Drug action, drug effect, drug response– efficiency

• Potency– Power

• Sensitivity• Selectivity• Specificity

24

The 3 structural parameters of the dose-effect relationship

Emax ED50slope

shallow

steep

ED502

Emax 1

Efficacy Potency Sensitivity

Emax 2

1

2

12

ED501

Range of useful concentrations Selectivity

2

1

25

Efficacy vs. potency and selectivity

• Efficacy, potency and selectivity therapeutic effect

side effect

A more potent than BA = B for efficacyB is preferable to A in a clinical context for its selectivity

A B

Concentration

Eff

ect 100

80

26

PK/PD variabilitiy

• Consequence for dosage adjustmentPK PD

Dose

Plasma concentration

EffectBODY Receptor

Kidney functionLiver function...

Clinical covariables• disease severity or duration • pathogens susceptibility

Population approach

28

Kinetic population vs. classical approach

• Subjects

• Location of study

• Sampling

• Subject homogeneity

• Controlled variable

• Inference space

Classical

Few (healthy)

laboratory

intensive

yes

yes

narrow

Population

Many (patient)

hospital

sparse

no

no (but documented)

large

29

What is the usefulness of PK

A scientific toolR & D

Scientific critical mass of the company

Can be very sophisticated

A requirement for regulatory affairs

Guidelines

Very basic

Drug monitoring

Human medicine

Drug submissionDrug discovery and

developmentDrug prescription

30

Usefulness of PK

1-Drug prescription

31

Drug candidates for Therapeutic Drug Monitoring (TDM)

• Low therapeutic index

• No physiologic or therapeutic endpoints to guide dosage

• Pharmacokinetics vary widely between individuals

• Need to monitor adherence ?

32

Effect of adherence rate on outcome in HIV infected patients

From: Paterson DL, et al. Ann Intern Med 2000;133:21-30.

33

Usefulness of PK

2-Drug discovery

34

Drug discovery and PK

• The success rate of New Chemical Entities (NCE) is low (1/5000)

• The main reasons for failure were :

– unacceptable clinical efficacy

–Historically poor PK (40%) but much better now

35

Why compounds fail or slow down in development

37

Drug discovery strategies

• Researchers have concentrated on maximizing potency and selectivity (specificity) against a biological target

but

• a good candidate requires a balance of potency, safety and PK properties

now:

• drug metabolism and PK in drug discovery process is accepted

41

Hierarchical in vitro screening sequences

New compound(s)

In vitro binding against target receptor

In vitro binding against selectivity receptors

Functional activity against target receptor

In vitro intrinsic clearance in hepatocytes

In vitro permeability in Caco-2 cells

In vitro protein binding

In vivo pharmacokinetic and pharmacodynamic evaluation

Physiochemical analysis; measured or computed

Roberts S.A. Current opinion, Drug Disc. Dev. 2003,6: 66-80

42van de Waterbeemd & Gifford, Nature Reviews Drug Discovery 2, 192, 2003Predictive models ADME processes Predictive models ADME processes

43

Clearance

HepaticRenal

Metabolic Biliary

CYP450 Others

Polymorphism 1A2;2C9;2C19;2D6;3A4

IR

InductionInhibition

CAR

AHRPXR

Sulfate

GlucuronideAmino-acid

44

• PK (clearance determination) is the bottleneck

cocktail approach

and

cassette dosing

• Objectives– 200 compounds per week for 2 scientists

Pharmacokinetics and combinatorial chemistry

48

Possible Impacts of MW

Size or molecular weight of a potential drug affects:

1. stability, ease of synthesis?2. solubility, transport across membranes3. bioavailability 4. Biliary excretion (interspecific differences)5. Safety (antigenicity)6. success in clinical trials 7. FDA approval!

52

Usefulness of PK

3-Regulatory pharmacokinetics

53

Regulatory pharmacokinetics

• Purpose

– Necessity to understand the role of regulatory authorities

– The role of the authorities is to ensure that marketed drug products are safe and effective

– The authority requires basic PK information to understand the features of the drug and factor variation

55

Regulatory pharmacokinetics

• Guideline vs. science driven PK– the PK guidelines were written to provide regulatory

people with the minimal information required to make a judgment and not to provide companies with an optimal drug development procedure

– Some companies have forgotten the true purpose of PK studies and too often PK data appear to have been generated with a "checklist" for regulatory authorities in mind rather than a scientific approach to efficacy

56

In a company, is PK conducted as :

A regulatory requirement

or

For rationale drug development

57

If PK is scientifically conducted

10 critical PK and PD parameters should be determined for each new drug

58

Hierarchy of pharmacokinetic parameters

R & D• Clearance• Effective concentration range• Extent of bioavailability• Fraction of the available dose excreted

unchanged• Blood / plasma concentration ratio• Half-life• Toxic concentration• Extent of protein binding• Volume of distribution• Rate of availability

Regulatory• Absorption• Distribution• Metabolism• Elimination

Benett, 1993

59

Hierarchy of pharmacokinetic parameters

R & D

• Independent

• Have a physiological meaning

• Clearance, distribution

Regulatory affairs

• Hybrid

• Only descriptive

• t 1/2, Cmax, Tmax