How to extrapolate a dose Within between species

How to extrapolate a dose? (Within & between species and from in vitro to in vivo) Pierre-Louis Toutain Visiting Professor Royal Veterinary College , London 6 July 2018 Australian & New Zealand College of Veterinary Scientists QT Gold Coast, Surfers Paradise Australia

To extrapolate from major to minor species All animal species, which are not considered major, are as a consequence, by default, classed as minor species.

To extrapolate within species : size, age, status… Young to adult Ruminant/preruminant Adult to adult

Dose extrapolation within a given species

Dose individualisation in dogs Size matters ! Dose /kg BW?

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

Lefebvre HP. Etude KINDO (unpublished- BW influence not correctly taken into account (allometric rules) 2. 8 ± 0. 4 kg Body Weight 54. 2 ± 6. 1 kg

Lefebvre HP American College of Veterinary Internal Medicine. 28 th Annual Forum, Anaheim, USA, June 9 -12, 2010. Etude KINDO Beagle N=11 12. 9± 2. 9 kg 2. 9± 0. 5 m. L/min/kg Suggests that breed has an impact in addition to BW ! Thus POP PK Great Dane N=7 54. 2± 6. 1 kg 2. 8± 0. 3 m. L/min/kg

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

The current practice of using BSA in dosing anticancer agents was implemented in clinical oncology more than half a century ago for between species extrapolation not within species extrapolation https: //www. ncbi. nlm. nih. gov/pubmed/27323883

BSA is not directly measured but estimated with allometric equations (Meeh 1879) Plumb’s Veterinary Drug Handbook 7 th Ed 2011 Meeh K. Oberflächenmessungen des menschlichen Körpers. Z. Biol. 15, 425– 485 (1879)

https: //www. ncbi. nlm. nih. gov/pubmed/7879983 ECVPT-2009 12

1 Pinkel D. The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Res. 1958; 18: 853 -856. https: //www. ncbi. nlm. nih. gov/pubmed/13573353

There is no fatality to have b=0. 66 or b=0. 75 or b=1 including between species Cox 2007 J. vet. Pharmacol. Therap. 30, 381– 386 https: //www. ncbi. nlm. nih. gov/pubmed/17803728

Population PK has to replace the outdated BSA law Power (B) 1 0. 66 0. 75 Experimental Appoaches The usual scaling per Kg BW Surface law Metabolic BW POP PK

Body weight or body surface area? • No scientific background for BSA • Many examples for which BSA is not appropriate in human medicine • Conclusion: There is no advantage using BSA over BW https: //www. ncbi. nlm. nih. gov/pubmed/9686387 17

https: //www. ncbi. nlm. nih. gov/pubmed/17766650 Despite the lack of basic fundamentals, BSA-based dosing still seems “untouchable” in clinical oncology. Even when alternatives are shown to be indisputably better, many hurdles will probably have to be overcome before physicians will be willing to discard BSA-based dosing.

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

What is exactly is a Dose?

A fundamental relationship For linear kinetics, clearance this is a scaling parameter between dose and plasma concentration The Dose can be determined rationally using a PK/PD concept 21

Plasma clearance controls internal exposure • For IV administration, Clearance is the only parameter controlling internal exposure i. e. AUC

Application of the clearance concept for interspecies dose extrapolation 23

Interspecies dose extrapolation using the clearance concept • Goal : to obtain the same exposure (AUC) for the 2 species Dose = AUC x Cl 24

What is the Morphine dose in dogs and cats Species Human Dogs Cats Usual dose (mg/kg) 0. 17 0. 5 - 2 0. 05 – 0. 2 Clearance (m. L/kg/min) 14. 7 85 8. 6 Computed dose (mg/kg) 1 0. 1

Interspecies dose extrapolation using clearance Which dose of ketoprofen is suitable for the goat ? : 3 mg/kg/24 h ; Cl = 0. 17 L/kg/h : Cl = 0. 74 L/kg/h Dosegoat = 13 mg/kg 26

Vet Clin North Am Exot Anim Pract 21 (2018) 183– 194 https: //www. ncbi. nlm. nih. gov/pubmed/29655466

Principles of doses extrapolation when clearance is not known in the target species but is known in several other species: the allometric approach

Range of body size in mammals Shrew 2 g Blue whale: >108 g Allometry is the study of size and its consequences • Interspecies allometric scaling is based on the assumption that there anatomical, physiological and biochemical similarities among animals which can be described by simple mathematical models 29

Many allometric relationships have been established between body size and organ weight as well as body size and physiological process b Y = a. BW 30

Cardiac output in mammals In m. L per minute Body Weight in kg 31

Physiological model of plasma (blood) clearance Heart Clbody = Q x E Clearing organs (liver, kidney, …) o E o Q = cardiac output = 180 BW-0. 19 with BW= kg et Q= ml/kg/min E = overall extraction ratio o 32

Assuming similar extraction ratio (E) , Simple allometric relationship is expected for plasma clearance log. Y=log a +b log BW b=slope Y=a. BWb log a is the Y-intercept

Ampicillin Riviere et al. J. vet. Pharmacol. Therap. 1997 20, 453 -463,

Oxytetracycline Riviere et al. J. vet. Pharmacol. Therap. 20, 453 -463, 1997.

Recent allometric dose estimates for antimicrobials https: //www. ncbi. nlm. nih. gov/pubmed/27596044 36

Body (Plasma) BPA clearance in man (or the target species) is unknown and we wish to estimate it https: //www. ncbi. nlm. nih. gov/pubmed/27596044 37

Allometric estimation of plasma clearance in man from 6 species Cl. BPA (L/min)=0. 0390 x BW 0. 9014 BPA clearance (L/min) 10 1 0. 1 Rhesus monkey (6. 56 kg) 0. 01 Allometry: Cl. BPA = 32. 4 m. L/(kg. min) Experimental (from Doerge et al 2010) 38 m. L/kg/min 0. 001 0. 1 1 10 Body weight (kg) 1000 38

Allometric estimation of plasma clearance in man Cl. BPA (L/min)=0. 0440 x BW 0. 8645 BPA clearance (L/min) 10 1. 0 0. 1 Man 0. 01 Cl. BPA = 24. 7 m. L/(kg. min) or 103 L/h for a 70 kg BW 0. 001 Prediction interval [9. 3 -66. 0] 0. 0001 0. 01 Collet et al Unpublished results 0. 1 1 10 Body weight (kg) 1000 39

Historically, aspirin was not (appropriately) used in veterinary medicine • Historically too expensive 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 40

The Lloyd E. Davis’ paper on salicylate (1972) https: //www. ncbi. nlm. nih. gov/pubmed/5022404 41

Half-life (h) A double log plot of salicylate half-life in different species Body Weight (KG) 42

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” 43

Extrapolation of bioavailability 44

First pass effect (oral route) Gut Lumen Gut Wall CYP P-Gp Portal vein Gut Metabolism To faeces Liver To site of measurement Hepatic Metabolism

Bioavailability in man: prediction from rodents, primates & dogs From Grass ADDR 2002 pp 433 https: //www. ncbi. nlm. nih. gov/pubmed/11922957

Oral bioavailability of amoxicillin • Amoxicillin has an oral bioavailability of about 5% in adult horses , 36% in 1 -week-old foals , 28 to 33% in pigs , 64 to 77% in dogs and 93% in humans

Bioavailability of Cefadroxil in foal Age 0. 5 1 2 3 5 F% 99. 6 67. 6 35. 1 19. 5 14. 4 Tmax (h) 2. 1 1. 60 0. 96 0. 90 (months) Duffee JVPT 1997 20 427 https: //www. ncbi. nlm. nih. gov/pubmed/9430765

For more information, consult the Mahmood’ book ECVPT-2009 49

Interspecies pharmacodynamic scaling

Allometry of pharmacokinetics and pharmacodynamics of the muscle relaxant metocurine in mammals https: //www. ncbi. nlm. nih. gov/pubmed/7840343

https: //www. ncbi. nlm. nih. gov/pubmed/15305849 ♥ ECVPT-2009 52

Extrapolation from in vitro data

A more advanced use of the clearance concept for dose extrapolation from in vitro data : the case of hepatic cleared drugs

Clearances are additive Clbody = Clrenal + Clhepatic + Clother 55

Clearance for hepatic cleared drug

Model for hepatic clearance (Clh) Eh fu : free fraction Clint : intrinsic clearance

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

Dose for a hepatic cleared drug with a low hepatic ER and complete absorption The plasma protein binding and metabolism activity are the major determinants for the elimination of low hepatic clearance drugs; therefore it is not expected to have a good allometric relationship with BW across species for this kind of drug

The efficacious concentration is known from in vitro measurements: antibiotics, insecticides…

Computation of the dose for an AMD with point estimates (mean clearance, F%, MIC 90) PK/PD breakpoint to achieve MIC 90 Bioavailability

Computation of the dose for an AMD using Monte Carlo simulation (point estimates are replaced by distributions) Log normal distribution: 9± 2. 07 m. L/Kg/h Observed distribution BP metaphylaxis Dose to POC=0. 9 Uniform distribution

The tick blood meal: From a living animal or from a silicone membrane? Cumulative mortality of Ixodes ricinus females feeding on bovine blood through a silicone membrane with dimethylsulfoxide (DMSO) added (placebo) and with increasing doses of fipronil in DMSO.

Fipronil dose in sheep • In vitro efficacious concentration : about 100 ng/m. L over 7 days • Plasma clearance : about 2 m. L/kg/min • Dose : 288 µg/kg/Day

In silico approach Physiologically based pharmacokinetic model (PBPK) 3/1/2021

https: //www. ncbi. nlm. nih. gov/pubmed/27653238 ECVPT-2009 67

Conclusion • Many approaches • Some are outdated (BSA for oncology) • Some are rather new (in silico)