Predictive value of PK/PD drug modelling: application to analgesic drugs

1. ECOLE NATIONALE VETERINAIRE T O U L O U S E Predictive value of PK/PD drug modelling: application to analgesic drugs PL Toutain UMR 181 Physiopathologie et Toxicologie Expérimentales INRA, ENVT Satellite symposium: Validity and Quality of Animal Models for Measurement of Pain

2. Objectives of the presentation • Overview on the concept of PK/PD • Predictive value of PK/PD modeling for analgesics

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

4. What are the main practical applications of a PK/PD trial • Preclinical investigations: It is an alternative to dose-titration studies to discover a dosage regimen • Clinical setting: • It is a tool to optimize dosage regimen in a clinical setting (pop PK/PD)

5. 1-An overview on the concept of PK/PD

6. Dose titration Dose Response Black box PK/PD Response PK PD Dose Plasma concentration

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

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

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

10. PD PK The determination of an ED50 or any ED% ED50 = ED50 - is a hybrid parameter (PK and PD) - is not a genuine PD drug parameter Clearancextarget EC50 Bioavailability

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

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

13. PK/PD variability • Consequence for dosage adjustment PK PD Effect BODY Receptor Dose Plasma concentration Kidney function Liver function ... • Clinical covariables • Pain severity or duration PK/PD population approach

14. 2-Predictive value of PK/PD for analgesics

15. Predictive value of PK/PD modeling rely on: • The question: • Mechanistic question vs. Clinical drug development • Selection of a pain model & In life validation of the selected model • Appropriate study design & conduct • Appropriate PK & PD data • Appropriate PK/PD modeling • Population PK/PD (clinical setting)

16. The question: a mechanistic question Drug discovery

17. Questions for a veterinary rational drug development: find an optimal dosage regimen for a target species • What is the typical Dosage regimen • Time information and decision • Onset of drug action: fentanyl vs. morphine • Duration of drug action: time of remedication ( Dosage interval) • Extrapolation • Between species • assumption of the same PD parameters • Within the same species: between route of administration • Assumption: different PK profile but same qualitative metabolic profile • Dosage adjustment • Population investigations

18. 2-Selection of a pain model: experimental pain models vs. clinical pain for PK/PD investigations

20. Pain model selection for PK/PD investigation: value & validity • Validity: • to be discussed by the pain’ specialist • refers to whether a study is able to scientifically answer the questions it is intended to answer • Regarding the ultimate objective: • To investigate neurophysiologic mechanisms of pain or complicate drug mechanism of action • Preclinical determination of a dosage regimen • Simple but reproducible antinociceptive model are often sufficient • Validityof a model =capacity to find a useful dose • Value: • to be demonstrated by the PK/PD trialist

21. Pain model selection for PK/PD investigation: value & validity • Validity • Value • Ethical • Metrological performances • Reliable • Sensitive • Robust & transferable • Convenience • Etc.

22. Models using pressure noxious stimulus or thermal noxious stimulus are considered as valuable in veterinary medicine to approximate a starting dose

23. Inflammatory pressure noxious stimulus. (here a kaolin inflammation model)

24. 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

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

26. Measure of pain with analgesiometer • The time for the cat to withdraw its paw of the ray is measured. • withdrawal time of the paws (second) • Sensitive and specific model to activate C-fibers Video

27. Validation of the selected model

28. Validation of the model • A priori validation makes sure the method is suitable for its intended use • When developing a new method • In life validation (routine validation for any new trial) • Animal selection • Investigator skill • Reproducibility & repeatability of selected animals • etc

29. Validation of the model is tedious

30. Predictive value of PK/PD modeling rely on: • The question: • Selection of a pain model & In life validation of the selected model • Appropriate study design & conduct • Crossover design and placebo period • Appropriate PK & PD data • Appropriate PK/PD modeling • Population PK/PD (clinical setting)

31. 4-Appropriate data for PK/PD modeling

32. Full concentration time curve experimental setting Cmax , Cmin Clinical setting Biomarkers Surrogate Clinical outcomes Measuring variables in PK/PD trials Measuring drug exposure Measuring drug response

33. Measuring exposure • Generally straightforward. • May be more complicate if: • presence of an active metabolite • Tramadol • Racemates • Profens

34. Tramadol plasma concentration (ng/mL) vs. time (min) after an IM administration of tramadol (circa 8 mg/kg);

35. pharmacokinetics of (±)-trans-T and M1 are stereoselective in vivo • Trans-tramadol [(±)-trans-T] hydrochloride is a chiral compound • (+)-, (-)-Trans-T take as the action mainly through inhibiting the reuptake of serotonin and norepinephrine, respectively • The drug is metabolized in the liver to form five phase I metabolites, with the main pathways (in man and rats) being O-demethylation to O-demethyltramadol (M1) • Among the metabolites, M1 is an only active metabolite, and (+)-M1 has a high affinity to the opioid receptor

37. Pharmacodynamic parameters of tramadol in the rat

38. Tramadol and tramadol metabolite M1 concentration (ng/mL) vs. time (min) in 8 dogs after an IM administration of tramadol (circa 8 mg/kg) ; Spaghetti plot; semilogarithmic scale No CYP2D6 in dogs but an ortholog i.e CYP2D15

39. Plasma concentrations of R- and S-ketoprofen after intramuscular administration of ketoprofen ( 6 mg/kg)

40. Time development of the plasma concentration of ketoprofen and the mechanical nociceptive thresholds before kaolin injection (negative control), after kaolin injection (positive control) and after ketoprofen administration R-keto S-Keto Kaolin Nociception EC50 R-keto=2.0±05 µg/mL S-ket=38.8±10.8 T. K. FOSSE et al JVPT in press

41. Full concentration time curve AUC Cmax , Cmin Biomarkers Surrogate Clinical outcomes Measuring variables in PK/PD trials Measuring drug exposure Measuring drug response

42. EC50 in vivo effect EC50action whole blood assay Inhibition of PGE2 production Suppression of lameness Inhibition of COX NSAID plasma concentration Requires 90% PGE2 inhibition EC50 response Which dependent variable for PK/PD modeling ? EC50 response >> EC50 effect

43. 5-PK/PD modelling

44. Modeling options regarding presence or not of a delay between PK and PD time development Emax x Cobserved EC50 + Cobservedl No PK modeling E = NO Emax x C(t)model EC50 + C(t)model PK modeling E = PK and PD delay Effect compartment model PK origin YES Indirect response model PD origin

45. Thermal threshold Plasma Fentanyl • No hysteresis for fentanyl • Direct incorporation of plasma fentanyl concentration in an Emax model

46. hysteresis loop IV Oral ΔT(ºC) Buprenorphine concentration

47. Modeling strategies when there is a delay of PK origin

48. The “effect compartment model” Dose Cp(t) Effect(t) Ce(t) Ke0 Ke0 Effect Concentration Effect effect Time Ce Time K10 3:PD model Parametric (Emax, Hill) Non parametric (spline) 1:PK model Parametric (Exponential) Non parametric (Spline) 2:Link model Ke0 Estimation of EC50 and Ke0

49. A mechanistic class of PK/PD models

50. An example of dose determination using a PK/PD modeling approach:Tramadol in dogs