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Population modelling in veterinary medicine : an introduction

This presentation provides an introduction to population pharmacokinetic/pharmacodynamic analysis in veterinary medicine, explaining concepts and illustrating with examples. Topics include variability, covariates, and the use of population PK/PD modeling to optimize dosing regimens and make recommendations in veterinary practice.

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Population modelling in veterinary medicine : an introduction

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  1. Population modelling in veterinary medicine : an introduction Pierre-Louis Toutain Royal veterinary College London & project officer at the ENV of Toulouse Wuhan University October 2017

  2. Ojectives of the presentation • To explain the main concepts related to population PK/PD investigations • To illustrate with some examples how this approach may be useful in veterinary medicine:

  3. Objectives of the presentation It is not to learn population PK/PD analysis…

  4. POP PK analysis : reviews, textbooks and regulatory guidelines

  5. Pharmacokinetic-Pharmacodynamic Modeling and Simulation.PL Bonate;. 2011 second edition . New York: Springer • This book is written for the kineticist who performs PK/PD modeling • It is expected the reader has basic knowledge of PK and simple PD models. • The reader is also expected to have had a 1-year introductory course in statistics that covers basics of probability, regression, and analysis of variance. • A 1-semester course in matrix algebra is desired but not needed.

  6. Reviews for an introduction to Pop PK/PD (open access)

  7. Publications in population PK: reviews

  8. Guidelines: EMA 2007

  9. Guidance FDA 1999

  10. POP PK: definition

  11. Population PK/PD: generic definition • Study of the variability in drug concentration or pharmacological effect between individuals when standard dosage regimens are administered A. Arons Br. Clin. Pharmacol. 1991, 32: 669

  12. Goal of Population kinetic • To identify the sources (factors or covariates) of PK and PD variability in the target animal population as well as the magnitude of that variability, in field or clinical condition (not in lab condition) and to explain variability by covariates to make recommendations

  13. Ultimate goal of population PK/PD • Adjust the dosing regimen for a given patient or a group of patients (e.g. for a given breed) taking into account relevant covariates • And also to make recommendations: management issues e.g. size of a pen to reduce BSV , withdrawal time and health status etc,

  14. The difference between optimal population and optimal individual dose The range of dose-responses for efficacy ( green) and adverse effects (blue) in a population is shown, with the optimal dose selected to provide the best efficacy without too many adverse effects. However, patient A (orange curves) experiences many adverse effects at the population dose yet responds well to a lower dose, whilst patient B ( purple) experiences little efficacy at the population dose but can tolerate a higher dose.

  15. The tool for pop PKPD NONMEMNon-LinearMixedEffectModel A statistical model non-linear in the regression parameters and non-linear in random effects

  16. 1-Population PK to investigate variability

  17. Variability is a biological fact of interest

  18. Variability is a biological fact …..

  19. Veterinary medicine can face huge sources of variability between animals due to the existence of breeds, collective treatments….

  20. Sources of variability PK PD well documented • species • food • age • sex • diseases Effect BODY Receptor Dose Plasma concentration Often ignored Subpopulations/responders/non-responders; health status….

  21. Sources of variability in drug response

  22. Sources of Intersubject Variability • Demographic • Age, Body Weight or Surface Area, gender, race • Genetic: • CYP2D6, CYP2C19 • Environmental: • Diet, temperature (fish)… • Physiological/Pathophysiological: • Renal (Creatinine Clearance) or Hepatic impairment, Disease State • Behavior associated to collective treatments • Social, food behavior… • Concomitant Drugs

  23. Two types of covariates • Continuous • Age, BW, creatinine…. • Categorical • Sex, breed, polymorphism, formulation, pain score

  24. Age as covariate: bioavailability of Cefadroxil in foal POP modeling: continuous covariate Duffee JVPT 1997 20 427

  25. Polymorphism: COX-2 inhibitors POP modeling: categorical covariate

  26. Variability vs. noise

  27. Should be suppressed (bias) or minimized (precision) Should be: recognized measured & Explained by covariables

  28. Experimental vs. population approach:the status of variability • Experimental • viewed as a nuisance that has to be overcome • Observational Population • recognized as an important feature that should be identified, measured and explained (covariates)

  29. Experimental vs POP PK/PD trial Experimental PK & PD Population (POP) PK & PD • Objective: document mean and variability of PK/PD data for THE whole population • Hence the term “Population” • This implies to study a representative sample of this population • Individuals are randomly sampled in the population • Objective: test one hypothesis (e.g. fed/unfed, pionneer/generic) • Hence consider interindividual variability as a nuisance that should be reduced • This implies to select homogenous subjects • Individuals may not be considered as randomly sampled in the population Simultaneous analysis of subjects altogether Analysis subject per subject; two stages approach

  30. Experimental vs. observational population studies and the inference space ? ?

  31. Variability is often viewed as a nuisance Variability can be viewed as a nuisance rather than a valuable information and may be deliberately suppressed : • e.g.: healthy animals rather than patients • e.g.: beagle dogs rather than mongrel dog

  32. Why to suppress variability? • There is advantage (for statistical reasons) in limiting or even suppressing sources of variability when performing a laboratory study • Question: what is the universality (relevance) of the conclusion generated under these conditions ? (question of the inference space)

  33. Variability is a biological and relevant fact, not a noise • There is sometime advantage (for statistical reasons) in limiting or even suppressing sources of variability when performing a study • Bioequivalence trial (only the formulation factor is investigated) • There is often disadvantageto suppress variability • e.g.: healthy animals rather than patients • e.g.: beagle dogs rather than mongrel dog • Question: what is the universality of the conclusion generated under these conditions

  34. An example of biological variability to explain :What are covariates able to explain between subject variability of doxycycline exposure in pigs when doxycycline is given as a mass medication in feed?

  35. PK variability of doxycycline administered to pigs • 215 pigs (30-110 kg) • 12- 15 pigs/pen (15 m2) • Doxycyclinegiven in mealstwice a day at 5mg/kg/meal • PK : large interindividual variability Plasma concentrations AUC0-24h distribution Del Castillo et al. (2006)

  36. Doxycycline concentration variability: population vs. experimental trial 1.5 1.0 Number of data points Trial Population n=215 Experimental n=15 to 19 DOXYCYCLINE (µg/mL) 0.5 0.0 0 4 6 12 24 Time (h)

  37. Doxycycline concentration variability: population vs. experimental trial for time 6h post-administration 1.5 Number of data points 1: Population n=215 2: Experimental n=16 3: Experimental n=64 1.0 DOXYCYCLINE (µg/mL) 0.5 0.0 2 3 0 1

  38. Doxycycline : sex effect Sexe 0 Sexe 1 Doxycycline Time (h)

  39. Variability analysis: AUC vs. body weight

  40. Doxycycline : diseaseeffect healthy diseased Concentrations (µg/mL) Time (h)

  41. Doxycycline : body temperatureeffect Doxycycline Rectal temperature

  42. PK doxycycline variability analysis: conclusions • No observed covariable was able to explain variability • Social behaviour (food behaviour, hierarchy etc. is likely the most important factor of variability

  43. Pharmacokinetic variability of fosfomycin administered to pigs in food and water: impact of social rank

  44. Effect of social ranking on fosfomycin exposure • Fosfomycin given in food or drinking water • Feed and water consumption was recorded. Animals were identified using a system of video cameras (equipped with night vision and wide-angle lens) Fosfomycin given in feed Fosfomycin given in water R=0.53 R=0.63 Fosfomycin AUC Fosfomycin AUC Hierarchy level Hierarchy level

  45. Variabilidad concentraciones plasmáticas ATB administrado en el alimento

  46. Variabilidad concentraciones plasmáticas ATB administrado en el agua

  47. Veterinary examples of Population PK to investigate variability

  48. Examples of questions to document using POP PK In pigs: Does the same dose of an antibiotic should be given for prophylaxis, metaphylaxis or for curative treatment? In cattle for susceptibility testing: what is the PK/PD breakpoint for a new antibiotic; what is the withdrawal time for an extralabel use of a drug In cats: do we have to adapt the dosage regimen in case of a mild renal failure? In dogs oncology: the body surface area matter ? In horses: what is the appropriate withdrawal time for doping control fish: what is the influence of water temperature on an antibiotic exposure

  49. POP PK in dogs & cats

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