PL Toutain UMR 181 Physiopathologie et Toxicologie Expérimentales INRA, ENVT

1. ECOLE NATIONALE VETERINAIRE T O U L O U S E Festschrift in honour of Professor Peter LeesPK/PD modelling of NSAIDs in domestic animalsThe Royal Veterinary College Camden Campus: 22nd July 2010 PL Toutain UMR 181 Physiopathologie et Toxicologie Expérimentales INRA, ENVT

2. 1795: Rev Edward Stone described the antipyretic properties of the willow 1897 • 1982 Nobel Prize for Medicine for his research on mechanism of action of NSAID (prostaglandins).

4. Modern history of veterinary NSAIDS:1971 and beyond

5. Brander & Pugh (1977)No chapter on NSAIDs Originally these drugs (PBZ…) were synthesized in the days of antiseptic surgery as derivatives of phenol which might be capable of exerting internal antisepsis

6. Veterinary Pharmacology & Therapeutics No chapter on NSAIDs 1982

7. Veterinary Pharmacology & Therapeutics (Ninth Ed.) 2009

8. Historically, aspirin was not (appropriately) used in veterinary medicine • Historically too expansive for large animals • The doses recommended for small animals are too high. • Such recommendations for salicylates were rather constant in veterinary pharmacology handbooks in e.g. Germany, USA, Russia and Spain from 1900 up to the 70’s. • The fallacy of the allometric rule

9. The fallacy of allometric scaling for Aspirin • Extrapolation from man to animal using the Surface Law and Metabolic Body Weight was popular.

10. Simple allometry: the log-log transformation Plasma Half-life Y=aBWb Body weight

11. The fallacy of allometric scaling for Aspirin • The principal reason for this lack of universal applicability is that allometry deals only with size; specifically, it does not address metabolic differences among species.

12. Half-life (h) Body Weight (KG) A double log plot of salycilate half-life in different species

13. The Lloyd E. Davis’ paper (1972) • Introduction: “We believed that information relevant to the biotransformation and rates of disappearance from blood of several drugs in a series of large domestic animals might prove of value”

14. The Lloyd E. Davis’ paper on salicylate (1972)

15. The Lloyd E. Davis’ paper (1972) • Conclusion: “the present data indicate the futility of extrapolating dose and dosage regimens from one species to another, as has been done in the past, in the treatment of domestic animals”

16. PK : Concepts and practice 1977

17. The main limiting factors to conduct PK studies in the late 1970’s • During the 70's, most chemical separations were carried out using paper chromatography and thin-layer chromatography • Only in the late 1970's, reverse phase liquid chromatography allowed for improved separation between very similar compounds

18. The main limiting factors to conduct PK studies in the late 1970’s • By the 1980's HPLC was commonly used for the separation of chemical compounds. New techniques improved separation, identification, purification and quantification far above the previous techniques.. Improvements in type of columns and thus reproducibility were made as such terms as micro-column, affinity columns, and Fast HPLC began to immerge

19. The main limiting factors to conduct PK & PK/PD studies in the late 1970’s 1976 1984 1994 Late 70’: Analog computer

20. Computer: The main limiting factors to conduct PK & PK/PD studies From Lisboa (2003) to Toulouse (2009)

21. Why to investigate NSAIDs in the early eighties

22. Why to investigate NSAIDS • All domestic species suffer pain and controlling pain is a priority issue for veterinary pharmacologist • Inflammation is a major source of pain • Acute (e.g. infectious) or chronic (e.g. osteoarthritis) • To determine an adequate dosage regimen • Efficacy • Safety • Selectivity (COX1 vs. COX2)

23. Peter’s work from 1981 to 2010 2009 1982

24. The first Peter’s paper on PK of NSAIDs (1981)

25. Lack of allometric relationship for different NSAIDS in domestic species

27. Condition of the GI tract and oral PBZ absorption The presence of food in the stomach can have a marked and often unpredictable effect on drug absorption 16 Concentration (µg/ml) 12 8 8 4 4 0 8 0 4 12 24h 12 24h Hay at the time of administration and 5 h after Hay 5 h before and at the time of oral administration

28. The today most cited Peter’s paperand the second most cited RVC paper

29. PD PK

30. PK/PD modelling of NSAIDs in domestic animals

31. Peter’s first PK/PD paper

32. 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)

33. What is PK/PD modeling? • PK/PD modeling is a versatile tool which is mainly used in veterinary medicine to select rational dosage regimens (dose, dosing interval) for confirmatory clinical testing.

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

35. 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

36. What kind of data for PK/PD modeling

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

38. Biomarker definition • A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention  Markers of drug response  Markers of disease or physiological function

39. EC50 in vivo effect EC50action whole blood assay Inhibition of PGE2 production Suppression of lameness Inhibition of COX NSAID plasma concentration Requires 95% PGE2 inhibition EC50 response Which dependent variable for PK/PD modeling ? EC50 response >> EC50 effect

40. Biomarkers and surrogates in drug development NSAID Drug development Binding affinity Screening Biomarkers COX inhibition Learning Demonstrate the likely chance of efficacy/safety PGs production Internal decision making Local temperature Pain modulation Surrogate Confirming Demonstrate therapeutic response Lameness Registration dossier Field clinicaloutcome Wellbeing/Demeanor

41. Ex Vivo biomarker investigation:The tissue cage model

43. Development of equine models of inflammation (1987)

44. The tissue cage model • PK investigations • Plasma: shallow compartment • Tissue cage: Deep compartment (size effect) • Influence of inflammation on local concentration of NSAIDs • PD investigations

45. Flunixin plasma, exudate & transudate concentrations after an IV flunixin administration (1.1mg/kg) Exudate Transudate

46. The tissue cage model • PK investigations • PD investigations • Biological liquids for in vitro assays (transudat, exudates) • Ex vivo investigations (PK/PD integration) • In vivo investigation ( PK/PD modeling)

47. The tissue cage model: possible in vivo PK/PD modeling using tissue cage as a surrogate of biophase

48. PK/PD: in vitro vs. in vivo In vivo Response Body Plasma concentration Extrapolation in vitro  in vivo Mechanism-based PK/PD In vitro Medium concentration Response Test system

49. Robenacoxib selectivity