EMEA London 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

EMEA London 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)

EMEA London What is the main goal of a PK/PD trial  It is an alternative to dose- titration studies to discover an optimal dosage regimen

EMEA London An overview on the concept of PK/PD

EMEA London Dose titration DoseResponse Black box PK/PD Dose PKPD Plasma concentration surrogateResponse

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

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

EMEA London 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)

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

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

EMEA London 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 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

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

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

EMEA London 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

EMEA London 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

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 ED 50 1 DT & PK/PD: Same Emax ED 50 vs EC 50 Only PK/PD

EMEA London Simulated dose-response: Drug xxx: analgesic effect

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

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

EMEA London 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

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

EMEA London 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

EMEA London PK Variability n = 215 Doxycycline

EMEA London MIC distribution Pasteurella multocida (n=205) 0 MIC (  g/mL) Pathogens % SUSCEPTIBLE

EMEA London 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

EMEA London 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

EMEA London 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

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

EMEA London 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 +++

EMEA London PK/PD modeling Modelling issues: Need professional skill

EMEA London 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.

EMEA London 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