1. PK/PD integration/modelling of drugs in veterinary pharmacology Mario GIORGI ChemD MsPharmacol Pharmacology & Toxicology Division Veterinary Teaching Hospital 24h, Department of Veterinary Sciences UNIVERSITY of PISA, ITALY

2. OUTLINE 1 2 PK/PD studies in veterinary medicine Examples of recent PK/PD studies

3. Peculiarity of the vet med Veterinary medicine faces the unique challenge of having to treat many types of domestic animal species, including mammals, birds, and fishes Excluding a few cases, active ingredients employed in veterinary medicine derive from the ones used in human medicine Develop in rodents Transfer to humans Extrapolation to animals 1 2 3

4. 1 PK/PD studies

5. Concepts: PK vs PD Pharmacokinetics (PK) describes the time course of drug concentrations in plasma (and sometimes in other fluids and tissues) resulting from a particular dosing regimen Pharmacodynamics (PD) expresses the relationship between drug concentrations in plasma (and sometimes in other fluids and tissues) and a resulting pharmacological effect

6. Concepts: PK vs PD t1 t2 delay ― ― Conc -- -- Effect For most drugs concentration and effect are not in phase

7. Concepts: PK vs PD Hysteresis loop = “coming late” Prosteresis clockwise loop = “coming early” 1 3 2 4 5 6 7 Anticlockwise hysteresis loop > > > > >

8. When PK/PD modelling is undertaken? Single study PK+PD Mechanistic GoalClinic Goal Enables documentation of the pharmacological profile of the drug Assists the establishment of a rational dosage regimen What is the main goal of a PK/PD trial? It is an alternative to dose-titration studies to discover an optimal dosage regimen in different animal species

9. Rough way to assess the dosage regimen

10. Dose titration Dose Response Black box Response (no biological information) Dose

11. PD: hysteresys loop Plasma concentration PK/PD PK PD Drug disposition Biophase/ receptors Response surrogate Concentration Time Plasma concentration Response Replace the dose by the plasma concentration profile Response

12. 1. In vitro to in vivo extrapolation 2. Predict dosage regimen 3. Drug translation between species PK/PD applications

13. PK/PD studies 2

14. 1.PK/PD to determine a dosage regimen for a NSAID in the cat 2.PK/PD of the novel COX-2 selective inhibitor CIMICOXIB in horses 3. PK/PD of the novel atypical opioid TAPENTADOL in turtles

15. 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 Swelling paw In the cat unlikely to rodent models it’s appropriate to administered NSAID after rather than before the inflammation (at least 4 days)

16. Kinds of endpoints Paw volume (ml) Skin temperature (°C) anti-inflammatory activity Lameness score Body temperature (°C) antipyretic activity Overall locomotion variable (%) (climbing, descending, creeping) Pain score (%) analgesic activity

17. Measure of vertical forces exerted on force plate Animals are accustomed and trained for 4 weeks before trials 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 leash As for a conventional dose titration, PK- PD investigations require to measure some relevant endpoints

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

19. Withdrawal time: timer stopped when cat withdraws its paw Surrogate endpoint for pain

20. 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 out of the ray is measured withdrawal time of the paws (second) (Giraudel et al., 2005 Br J Pharmacol)

21. dR dt = K in (1- ) - K out R I max x C n IC 50 n + C n PK-PD results: analgesic effect Emax/Imax EC 50 Slope drug Hill equation Drug concentration at time n First order rate loss of inflammation (pain) Constant rate of inflammation (pain) production Rate of variation dR/dt in the response variable R

22. Measure of PK/PD antipyretic effect (Giraudel et al., 2005 Br J Pharmacol) First order rate constant for heat loss Body temperature (°C) before drug admin Maximum response attributed to the drug (°C) Drug concentration at time n Drug plasma concentration producing half the maximum stimulation of the heat loss Measured response

23. 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 Log Drug conc

24. Simulated dose-response Drug xxx: analgesic effect Once the three PD parameters have been established, the dose effect and the time-to-effect relationship corresponding to different possible PK profiles, can easily be explored

25. Simulations drug xxx: once vs twice a day Mean effect  32% Mean effect  52% Mean effect  96% No need to run other animal experiments. No additional time or cost during drug development

26. CIMICOXIB Cimicoxib is a novel and the latest coxib to be released for veterinary use. The recommended dose is (2 mg/kg) in the dog. Washout 1-week PK PD FED FASTED 5 mg/kg

27. CIMICOXIB  Fasted 5 mg/kg  Fed 5 mg/kg  Fasted 2 mg/kg  Fed 2 mg/kg

28. CIMICOXIB TBX marker for COX-1 PGE2 marker for COX-2 CIMICOXIB works as a tNSAID in horses

29. TAPENTADOL 5 mg/kg IM Blood collections and TWL: 0-1-2-4-6-8-10 and 24 h Saline IM Washout 2 weeks PK

30. TAPENTADOL Plantar Test (Hargreaves Apparatus)

31. TAPENTADOL PD evaluationPK evaluation

32. TAPENTADOL PK/ PD evaluation

33. 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

34. -Grazie -Thank you - Dziekujemy -Muchas Gracias -Obrigado -Merci Beaucoup -Diolch yn Fawr -Xie Xie -Gamsahamnida -Danyavad با تشکر mgiorgi@vet.unipi.it