Pharmacokinetic-pharmacodynamic integration in veterinary drug development: an overview

1. Pharmacokinetic-pharmacodynamic integration in veterinary drug development: an overview NATIONAL VETERINARY S C H O O L T O U L O U S E P.L. Toutain National Veterinary School ;Toulouse France EMEA : Focus group meeting on PK/PD London 24 September 2008

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

3. What is the main goal of a PK/PD trial • It is an alternative to dose-titration studies to discover an optimal dosage regimen

4. An overview on the concept of PK/PD

5. Dose titration Dose Response Black box PK/PD Response surrogate PK PD Dose Plasma concentration

6. Why is plasma concentration profile a better explicative (independent) variable than dose for determining a dosage regimen ?

7. Dose vs. plasma concentration profile as independent variable F% Clearance Time Dose Dose X Mass (no biological information) Concentration profile (biological information)

8. PK/PD applications • in vitro to in vivo extrapolation • Measure in vivo key PD parameters (efficacy, potency, selectivity, affinity…) • predict dosage regimen • sources (PK or PD) variability in drug response (antibiotics)

9. Application of PK/PD modelling in veterinary medicine Antibiotics NSAIDs ACEI Hormones others

10. An example of application of PK/PD to determine a dosage regimen for a NSAID in cat

11. 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

12. Measure of vertical forces exerted on force plate As for a conventional dose titration, PK/PD investigations require to measure some relevant endpoints • 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

13. Measure of vertical forces exerted on force plate • The measure of vertical force and video control are recorded • Vertical forces (Kg) Video

14. Surrogate endpoint for pain • withdrawal time: timer stopped when cat withdraws its paw

15. 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

16. Imax+Cn IC50n + Cn dR dt = Kin (1- ) - Kout R PK/PD results: analgesic effect • Emax/Imax • EC50 • Slope

17. The 3 structural PD parameters: Dose titration (DT) vs. PK/PD Slope Sensitivity ED50/EC50 Emax 1 1 Emax 1 2 2 Emax 2 shallow steep ED501 ED502 • Range of useful concentrations • Selectivity Potency Efficacy DT & PK/PD: Same Emax ED50 vs EC50 Only PK/PD

18. Simulated dose-response: Drug xxx: analgesic effect

19. Simulations drug xxxx: once vs. twice a day Mean effect  96 % Mean effect  32 % Mean effect  52 %

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

21. ED50 vs EC50A variable vs. a parameter ED50 - is a hybrid variable (PK and PD) - is not a genuine PD drug parameter PD PK • EC50 is a PD parameter allowing extrapolation • Between formulations • Between physiological status (renal failure) • Between species

22. Why to prefer a PK/PD approach to a classical dose-titration? • The separation of PK and PD variability

23. PK/PD variability • Consequence for dosage adjustment PK PD Effect BODY Receptor Dose Plasma concentration Kidney function Liver function ... • Clinical covariables • disease severity or duration • pathogens susceptibility (MIC) PK/PD population approach

24. PK Variability Doxycycline n = 215

25. 40 35 30 Pathogens % 25 20 15 10 SUSCEPTIBLE 5 0 0.0625 0.125 0.25 0.5 1 2 4 m MIC ( g/mL) MIC distributionPasteurella multocida (n=205)

26. Dosage regimen: application of PK/PD concepts The 2 sources of variability : PK and PD PD: MIC PK: exposure Distribution of PK/PD surrogates (AUC/MIC) Monte-Carlo approach

27. Metaphylaxis: dose to achieve a POC of 90% i.e. an AUC/MIC of 80 h (Drug xxxx: empirical antibiotherapy) Dose distribution

28. The main limits of the PK/PD modeling

29. The main limits of the PK/PD modeling:Clinical validity of surrogates

30. Biomarker and surrogate for NSAID EC50action Whole blood assay EC50 in vivo effect Inhibition of PGE2 production Plasma concentration Suppression of lameness Inhibition of COX Requires 95% PGE2 inhibition EC50 response EC50 response >> EC50 effect

31. 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

32. Measuring responsee.g.: ACE inhibitors Binding affinity Continuity Objectivity Sensitivity reproducibility biomarker ACE inhibition Renin/angiotensin aldosterone modulation surrogate Blood pressure Survival time Well-being Validity +++ Clinical outcome

33. PK/PD modeling Modelling issues:Need professional skill

34. 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.

35. 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