1. EMEA London 2008 - 1 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 NATIONAL VETERINARY S C H O O L T O U L O U S E

2. EMEA London 2008 - 2 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)

3. EMEA London 2008 - 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. EMEA London 2008 - 4 An overview on the concept of PK/PD

5. EMEA London 2008 - 5 Dose titration DoseResponse Black box PK/PD Dose PKPD Plasma concentration surrogateResponse

6. EMEA London 2008 - 6 Why is plasma concentration profile a better explicative (independent) variable than dose for determining a dosage regimen ?

7. EMEA London 2008 - 7 Dose vs. plasma concentration profile as independent variable Dose Mass (no biological information) Dose F% Clearance Time Concentration profile (biological information) X

8. EMEA London 2008 - 8 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)

9. EMEA London 2008 - 9 Application of PK/PD modelling in veterinary medicine Antibiotics NSAIDs ACEI Hormones others

10. EMEA London 2008 - 10 An example of application of PK/PD to determine a dosage regimen for a NSAID in cat

11. EMEA London 2008 - 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. EMEA London 2008 - 12 Measure 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

13. EMEA London 2008 - 13 The measure of vertical force and video control are recorded  Vertical forces (Kg) Video Measure of vertical forces exerted on force plate

14. EMEA London 2008 - 14  withdrawal time: timer stopped when cat withdraws its paw Surrogate endpoint for pain

15. EMEA London 2008 - 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. EMEA London 2008 - 16 dR dt = K in (1- ) - K out R I max + C n IC 50 n + C n PK/PD results: analgesic effect Emax/Imax EC50 Slope

17. The 3 structural PD parameters: Dose titration (DT) vs. PK/PD Emax ED 50 /EC 50 Slope Sensitivity shallow steep ED 50 2 Emax 1 Efficacy Potency Range of useful concentrations Selectivity Emax 2 1 2 1 2 ED 50 1 DT & PK/PD: Same Emax ED 50 vs EC 50 Only PK/PD

18. EMEA London 2008 - 18 Simulated dose-response: Drug xxx: analgesic effect

19. EMEA London 2008 - 19 Simulations drug xxxx: once vs. twice a day Mean effect  32 %Mean effect  52 % Mean effect  96 %

20. EMEA London 2008 - 20 Why to prefer a PK/PD approach to a classical dose-titration?

21. EMEA London 2008 - 21 E D 50 - is a hybrid variable (PK and PD) - is not a genuine PD drug parameter PD 1.ED 50 vs EC 50 A variable vs. a parameter PK EC 50 is a PD parameter allowing extrapolation Between formulations Between physiological status (renal failure) Between species

22. EMEA London 2008 - 22 Why to prefer a PK/PD approach to a classical dose-titration? 2.The separation of PK and PD variability

23. EMEA London 2008 - 23 PK/PD variability Consequence for dosage adjustment PKPD Dose Plasma concentration Effect BODY Receptor Kidney function Liver function... Clinical covariables disease severity or duration pathogens susceptibility (MIC) PK/PD population approach

24. EMEA London 2008 - 24 PK Variability n = 215 Doxycycline

25. EMEA London 2008 - 25 MIC distribution Pasteurella multocida (n=205) 0 MIC (  g/mL) 5 10 15 20 25 30 35 40 0.06250.1250.250.5124 Pathogens % SUSCEPTIBLE

26. EMEA London 2008 - 26 Dosage regimen: application of PK/PD concepts The 2 sources of variability : PK and PD PK: exposure PD: MIC Distribution of PK/PD surrogates (AUC/MIC) Monte-Carlo approach

27. EMEA London 2008 - 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. EMEA London 2008 - 30 Biomarker and surrogate for NSAID EC 50 in vivo effect Plasma concentration Inhibition of COX Inhibition of PGE2 production Suppression of lameness Requires  95% PGE2 inhibition EC 50 response EC 50 response >> EC 50 effect EC 50 action Whole blood assay

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. EMEA London 2008 - 32 Measuring response e.g.: ACE inhibitors biomarker surrogate Clinical outcome Binding affinity ACE inhibition Renin/angiotensin aldosterone modulation Blood pressure Survival time Well-being Continuity Objectivity Sensitivity reproducibility Validity +++

33. EMEA London 2008 - 33 PK/PD modeling Modelling issues: Need professional skill

34. EMEA London 2008 - 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. EMEA London 2008 - 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