Dose extrapolation from in vitro to in vivo and across species

1. Dose extrapolation from in vitro to in vivoand across species Pierre-Louis Toutain Royal veterinary College London & project officer at the ENV of Toulouse Wuhan University October 2017

2. How to determine a dose?Experimentally: The dose-titration trialNon experimentally: by extrapolation

3. Selected dose Dose determination: The parallel design Response NS • Complicate • Costly • Ethical aspect (experimetal model) * * Dose 1 2 3 Placebo

4. Many major and minor species in veterinary medicine Impossible to determine experimentally a dose for all species

5. Range of body size within species require extrapolation Adult to adult Young to adult

6. As it is impossible to determine an experimental dose for all species and breeds , how to extrapolate a dose from an other species or within a given species or from in vitro data?

7. The different possible extrapolations to determine a dose • Using In vivo data • Between species • From rat/man to dogs • Within species • From preruminant calf to adult cow • From in vitro (or ex vivo) to in vivo

8. Dose extrapolation within a given species

9. Dose individualisation in pets Dose /kg BW Size matters !

10. Scaling dose per Kg body weight for the within species extrapolation is routinely used in veterinary medicine Is it always appropriate ?

11. Is dose normalisation per kg BW sufficient? • Assessment of GFR in a large healthy canine population 582 pure-breeddogs • 49 breeds • Plasma exogenouscreatinine clearance test • IV bolus : 40 mg/kg • BS: 0, 5, 10 min, 1,2,4,6,8 h • Assay: enzymaticmethod (Vitros 250) Lefebvre HP. Etude KINDO

12. Lefebvre HP. Etude KINDO BW influence not correctly taken into account (allometric rules) Body Weight 2.8 ± 0.4 kg 54.2 ± 6.1kg

13. Beagle N=11 12.9±2.9 kg 2.9±0.5 mL/min/kg Great Dane N=7 54.2±6.1 kg 2.8±0.3 mL/min/kg Lefebvre HP American College of Veterinary Internal Medicine. 28th Annual Forum, Anaheim, USA, June 9-12, 2010. Etude KINDO Suggests that breed has an impact in addition to BW !

14. Scaling using the body surface area (BSA) as an alternative to the scaling by body weight

15. Cancer Res 1958 28 853-856 it was seen that the doses per unit of body weight of mechlorethamine, methotrexate, actinomycin D, and TSPA are greater in smaller animals than in larger ones, and higher in children than in adults. The doses per unit of surface area are nearly similar for all species and for all ages of humans.

16. Methotrexate dosage

17. Introduction of BSA in veterinary medicine for oncology

18. BSA is not directly measured but estimated with allometric equations

20. Body weight or body surface area? • No scientific background • Many examples for which BSA is not appropriate in human medicine • Conclusion: There is no advantage using BSA over BW

21. Population PK has to replace the outdated BSA law

22. Dose extrapolation: from empiric (scaling) to mechanistic (physiological) approaches

23. What is exactly a Dose?

24. Dose titration Dose Response Black box A dose is a PK/PD variable PK/PD Response PK PD Dose Plasma concentration

25. A fundamental relationship For a linear kinetic , clearance is a scaling parameter between a dose and plasma concentration ! A osecan be determined rationally using a PK/PD concept

26. 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

27. What is plasma clerance? • Clearance is the PK parameter expressing capacity of a body (or an organ) to eliminate a drug

28. plasma clearance control internal exposure • For an IV administration, Clearance is the only parameter controlling internal exposure i.e. AUC

29. Application of the clearance concept for Interspecies dose extrapolation

30. Interspecies dose extrapolation using the clearance concept • Goal : to obtain the same exposure (AUC) for the 2 species Dose = AUC x Cl

31. Interspecies dose extrapolation using clearance Dose species2 x Cl species1 Cl species2 Dose species1 =

32. Whatis the Morphine dose in dogs and cats

33. Interspecies dose extrapolation using clearance Which dose of ketoprofen in goat ? :3 mg/kg/24 h ; Cl = 0.17L/kg/h : Cl = 0.74 L/kg/h Dosegoat = 13 mg/kg

34. The goat has often a high drug clearance • A browser not grazingwith a high metabolism for an efficient first-passeffect • This enhanced metabolism is thought to be an adaptation to enable detoxification for toxic plant and has the potential to render some drugs unsuitable for use in goat.

35. A more advanced used of the clearance concept for dose extrapolation: the use of the overall extraction ratio

36. It happens that the clearance for the target species is unknown:Q: how to estimate this unknown clearance from the one of the known species ?A: by using the extraction ratio computed from the known species

37. Physiological model of plasma (blood) clearance Heart Clearing organs (liver, kidney,…) o Clbody = Q x E E o Q = cardiac output = 180 BW-0.19 with BW= kg et Q= ml/kg/min E = overall extraction ratio o

38. The extraction ratio Body clearance (blood) Cardiac output Ebody =

39. What is the Penicillin G extraction ratio in horses • cardiac output: 55 mL/kg/min • extraction ratio: 15.4% • body clearance 8.5mL/kg/min

40. Extraction ratio (ER) for antibiotics • Q: what is the body clearance of cefazolin in camel? • A: the cardiac output in camel x the cefazolin ER

41. Cardiac output in mammals In mL per minute Body Weight in kg

42. Plasma clearance (per minute) of cefazoline in camel (250kg BW)

43. What is the dose of cefazolin in camel extrapolated from dogs Dose dogsx Cl camel Cl dogs Dose camel=

44. What is a dose of cefazolin in camel ? Camel Cardiac output (L per day) Horse ER per day

45. A more advanced used of the clearance concept for dose extrapolation: the case of hepatic cleared drug

46. Clearances are additive Clbody = Clrenal + Clhepatic + Clother

47. Clearance for hepatic cleared drug

48. Model for hepatic clearance (Clh) Eh fu : free fraction Clint : intrinsicclearance

49. Hepatic Clint : in vitro For a low extraction drug, Km>Cfree

50. Model for hepatic clearance (Clh) for a low extraction drug Eh fu : free fraction Clint : intrinsicclearance