title: Reduction of a Whole-Body Physiologically Based Pharmacokinetic Model to Stabilise the Bayesian Analysis of Clinical Data.
abstract: Whole-body physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development for their ability to predict drug concentrations in clinically relevant tissues and to extrapolate across species, experimental conditions and sub-populations. A whole-body PBPK model can be fitted to clinical data using a Bayesian population approach. However, the analysis might be time consuming and numerically unstable if prior information on the model parameters is too vague given the complexity of the system. We suggest an approach where (i) a whole-body PBPK model is formally reduced using a Bayesian proper lumping method to retain the mechanistic interpretation of the system and account for parameter uncertainty, (ii) the simplified model is fitted to clinical data using Markov Chain Monte Carlo techniques and (iii) the optimised reduced PBPK model is used for extrapolation. A previously developed 16-compartment whole-body PBPK model for mavoglurant was reduced to 7 compartments while preserving plasma concentration-time profiles (median and variance) and giving emphasis to the brain (target site) and the liver (elimination site). The reduced model was numerically more stable than the whole-body model for the Bayesian analysis of mavoglurant pharmacokinetic data in healthy adult volunteers. Finally, the reduced yet mechanistic model could easily be scaled from adults to children and predict mavoglurant pharmacokinetics in children aged from 3 to 11 years with similar performance compared with the whole-body model. This study is a first example of the practicality of formal reduction of complex mechanistic models for Bayesian inference in drug development.
authors.affiliation: Manchester Pharmacy School, The University of Manchester, Manchester, UK. thierry.wendling@manchester.ac.uk.|Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel, Switzerland. thierry.wendling@manchester.ac.uk.
authors.forename: Thierry
authors.initials: T
authors.lastname: Wendling
authors.affiliation: Manchester Pharmacy School, The University of Manchester, Manchester, UK.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Tsamandouras
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Swati
authors.initials: S
authors.lastname: Dumitras
authors.affiliation: Pharmacometrics, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Etienne
authors.initials: E
authors.lastname: Pigeolet
authors.affiliation: Manchester Pharmacy School, The University of Manchester, Manchester, UK.
authors.forename: Kayode
authors.initials: K
authors.lastname: Ogungbenro
authors.affiliation: Manchester Pharmacy School, The University of Manchester, Manchester, UK.
authors.forename: Leon
authors.initials: L
authors.lastname: Aarons
mesh_terms: D000328:Adult; D000465:Algorithms; D001499:Bayes Theorem; D001921:Brain / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008390:Markov Chains; D008954:Models, Biological; D015233:Models, Statistical; D009010:Monte Carlo Method; D010599:Pharmacokinetics; D011153:Population
chemical_list: D007211:Indoles; C581397:mavoglurant
keywords: Bayesian population approach; PBPK extrapolation; mavoglurant; physiologically based pharmacokinetic models; proper lumping