Application of a Bayesian approach to physiological modelling of mavoglurant population pharmacokinetics

Thierry Wendling, Swati Dumitras, Kayode Ogungbenro, Leon Aarons*

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Mavoglurant (MVG) is an antagonist at the metabotropic glutamate receptor-5 currently under clinical development at Novartis Pharma AG for the treatment of central nervous system diseases. The aim of this study was to develop and optimise a population whole-body physiologically-based pharmacokinetic (WBPBPK) model for MVG, to predict the impact of drug–drug interaction (DDI) and age on its pharmacokinetics. In a first step, the model was fitted to intravenous (IV) data from a clinical study in adults using a Bayesian approach. In a second step, the optimised model was used together with a mechanistic absorption model for exploratory Monte Carlo simulations. The ability of the model to predict MVG pharmacokinetics when orally co-administered with ketoconazole in adults or administered alone in 3–11 year-old children was evaluated using data from three other clinical studies. The population model provided a good description of both the median trend and variability in MVG plasma pharmacokinetics following IV administration in adults. The Bayesian approach offered a continuous flow of information from pre-clinical to clinical studies. Prediction of the DDI with ketoconazole was consistent with the results of a non-compartmental analysis of the clinical data (threefold increase in systemic exposure). Scaling of the WBPBPK model allowed reasonable extrapolation of MVG pharmacokinetics from adults to children. The model can be used to predict plasma and brain (target site) concentration–time profiles following oral administration of various immediate-release formulations of MVG alone or when co-administered with other drugs, in adults as well as in children.

Original languageEnglish
Pages (from-to)639-657
Number of pages19
JournalJournal of Pharmacokinetics and Pharmacodynamics
Volume42
Issue number6
DOIs
Publication statusPublished - 1 Aug 2015
Externally publishedYes

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