emea london 2008 - 1 pharmacokinetic- pharmacodynamic integration in veterinary drug development: an...

EMEA London 2008 - 1

Pharmacokinetic-pharmacodynamic integration in

veterinary drug development: an overview

Pharmacokinetic-pharmacodynamic integration in

veterinary drug development: an overview

P.L. Toutain National Veterinary School ;Toulouse France

EMEA : Focus group meeting on PK/PD

London 24 September 2008

NATIONALVETERINARYS C H O O L

T O U L O U S E


What is PK/PD?

• PK-PD modeling is a scientific tool to quantify, in vivo, the key PD parameters of a drug, which allow to predict the time course of drug effects under physiological and pathological conditions (intensity and duration)


What is the main goal of a PK/PD trial

It is an alternative to dose-titration studies to discover an optimal dosage regimen


An overview on the concept of PK/PD


Dose titration

Dose ResponseBlack box

PK/PD

Dose

PK PD

Plasmaconcentration

surrogateResponse


Why is plasma concentration profile a better explicative (independent)

variable than dose for determining a dosage regimen ?


Dose vs. plasma concentration profile as independent variable

Dose

Mass(no biological information)

Dose F%Clearance

Time

Concentration profile(biological information)

X


PK/PD applications

1. in vitro to in vivo extrapolation

2. Measure in vivo key PD parameters (efficacy, potency, selectivity, affinity…)

3. predict dosage regimen

4. sources (PK or PD) variability in drug response (antibiotics)


Application of PK/PD modelling in veterinary medicine

• Antibiotics

• NSAIDs

• ACEI

• Hormones

• others


An example of application of PK/PD to determine a dosage

regimen for a NSAID in cat


As for a conventional dose titration, PK/PD investigations generally require a relevant

experimental model (here a kaolin inflammation model)

Possibility to perform PK/PD in patient

EMEA London 2008 - 12Measure of vertical forces exerted on force plate

• To measure the vertical forces, a corridor of walk is used with a force plate placed in its center.

• The cat walks on the force plate on leach.

Video

As for a conventional dose titration, PK/PD investigations require to measure some

relevant endpoints


• The measure of vertical force and video control are recorded

Vertical forces (Kg)

Video

Measure of vertical forces exerted on force plate


withdrawal time: timer stopped when cat withdraws its paw

Surrogate endpoint for pain


Measure of pain with analgesiometer

• Cat is placed in a Plexiglas box.

• A light ray is directed to its paw to create a thermal stimulus.

• The time for the cat to withdraw its paw of the ray is measured.

withdrawal time of the paws (second)

Video


dRdt

= Kin (1- ) - Kout R Imax + Cn

IC50n + Cn

PK/PD results: analgesic effect

-200

-150

-100

-50

0

50

100

150

0 4 8 12 16 20 24 28 32 36

Time after meloxicam administration (h)

Pai

n sc

ore

(%)

0

200

400

600

800

1000

1200

1400

1600

Mel

oxic

am c

once

ntra

tion

(ng/

mL)

Observed response

Fitted response

Observed concentration

Fitted concentration-200

-150

-100

-50

0

50

100

150

0 4 8 12 16 20 24 28 32 36


Pai

n sc

ore

(%)

0

200

400

600

800

1000

1200

1400

1600

Mel

oxic

am c

once

ntra

tion

(ng/

mL)

Observed response

Fitted response


Fitted concentration-200

-150

-100

-50

0

50

100

150

0 4 8 12 16 20 24 28 32 36


Pai

n sc

ore

(%)

0

200

400

600

800

1000

1200

1400

1600

Mel

oxic

am c

once

ntra

tion

(ng/

mL)

Observed response

Fitted response


Fitted concentration

•Emax/Imax•EC50•Slope

The 3 structural PD parameters: Dose titration (DT) vs. PK/PD

Emax ED50/EC50

SlopeSensitivity

shallow

steep

ED502

Emax 1

Efficacy Potency• Range of useful

concentrations

• Selectivity

Emax 2

1

2

12

ED501

DT & PK/PD: Same Emax

ED50 vs EC50 Only PK/PD


Simulated dose-response: Drug xxx: analgesic effect

-250

-200

-150

-100

-50

0

50

100

0 4 8 12 16 20 24

Time (h)

Pai

n s

core

(%

)

0.1 mg/kg

0.2 mg/kg

0.3 mg/kg

0.4 mg/kg

0.5 mg/kg

1 mg/kg


Simulations drug xxxx: once vs. twice a day

Mean effect 32 % Mean effect 52 %

Simulated time course of pain

0

10

20

30

40

50

60

70

80

90

100

0 4 8 12 16 20 24

Time (h)

Pai

n (%

)

5 mg/kg

2 x 2.5 mg/kg

5 mg/kg split in 12

Mean effect 96 %


Why to prefer a PK/PD approach to a classical

dose-titration?


ED50 - is a hybrid variable (PK and PD)

- is not a genuine PD drug parameter

PD

1. ED50 vs EC50

A variable vs. a parameter

ilityBioavailab

ECclearancePlasmaED 50

50

_

PK

EC50 is a PD parameter allowing extrapolation•Between formulations•Between physiological status (renal failure)•Between species


Why to prefer a PK/PD approach to a classical dose-titration?

2.The separation of PK and PD variability


PK/PD variability

• Consequence for dosage adjustment

PK PD

Dose

Plasma concentration

EffectBODY Receptor

Kidney functionLiver function...

Clinical covariables• disease severity or duration

• pathogens susceptibility (MIC)

PK/PD population approach


PK Variability

n = 215

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

-5 0 5 10 15 20 25 30

Time (h)

Con

cent

ratio

ns m

g/m

L

Doxycycline


MIC distributionPasteurella multocida (n=205)

0

MIC (g/mL)

5

10

15

20

25

30

35

40

0.06250.125 0.25 0.5 1 2 4

Pat

ho

gen

s %

SUSCEPTIBLE


Dosage regimen: application of PK/PD concepts

The 2 sources of variability : PK and PDPK: exposure PD: MIC

Distribution of PK/PD surrogates (AUC/MIC)

Monte-Carlo approach

AUC [0, 24 h] Distribution

0

2

4

6

8

10

12

14

16

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20AUC (µg.h.mL-1)

Fréq

uenc

es (%

)

0

MIC (g/mL)

5

10

15

20

25

30

35

40

0.06250.125 0.25 0.5 1 2 4P

ath

og

ens

%

SUSCEPTIBLE

0

MIC (g/mL)

5

10

15

20

25

30

35

40

0.06250.125 0.25 0.5 1 2 4P

ath

og

ens

%

SUSCEPTIBLE


Metaphylaxis: dose to achieve a POC of 90% i.e. an AUC/MIC of 80 h

(Drug xxxx: empirical antibiotherapy)

Dose distribution

The main limits of the PK/PD modeling

The main limits of the PK/PD modeling:

Clinical validity of surrogates


Biomarker and surrogate for NSAID

EC50 in vivo effect

Plasma concentration

Inhibition of COX

Inhibition of PGE2

production

Suppression of lameness

Requires 95% PGE2 inhibition

EC50 responseEC50 response >> EC50 effect

EC50actionWhole blood assay

Clinical endpoint vs. surrogate/biomarkers

• True clinical endpoints are patient feeling, wellbeing, survival rate etc.– because therapeutic endpoints may

be unavailable, impossible to evaluate, time taking…

biomarkers & surrogates


Measuring responsee.g.: ACE inhibitors

biomarker

surrogate

Clinical outcome

Binding affinity

ACE inhibition

Renin/angiotensin aldosterone modulation

Blood pressure

Survival timeWell-being

Continuity Objectivity Sensitivity

reproducibility

Validity +++


PK/PD modeling Modelling issues:

Need professional skill


PK / PD modelling CONCLUSION

• A powerful tool for many applications

• Requires clear understanding of theoretical background and computer software

• Veterinary pharmacologists should be encouraged to consider PD, and not only PK.


PK / PD modelling CONCLUSION

• The pharmaceutical industry must not hesitate to introduce state-of-art science and technology into its R&D, due to concerns about regulatory impacts

emea london 2008 - 1 pharmacokinetic- pharmacodynamic integration in veterinary drug development: an...

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