Application of a Bayesian approach to physiological modelling of mavoglurant population pharmacokinetics
| Autor: | Leon Aarons, Kayode Ogungbenro, Thierry Wendling, Swati Dumitras |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Indoles Bayesian probability Population Administration Oral Population pharmacokinetics Pharmacology Models Biological Drug Administration Schedule chemistry.chemical_compound Pharmacokinetics Oral administration Humans Medicine Mavoglurant Computer Simulation Drug Interactions Tissue Distribution Child education Clinical Trials as Topic education.field_of_study Models Statistical business.industry Continuous flow Age Factors Brain Bayes Theorem Markov Chains Ketoconazole chemistry Child Preschool Administration Intravenous Female business Excitatory Amino Acid Antagonists Monte Carlo Method medicine.drug |
| Zdroj: | Journal of Pharmacokinetics and Pharmacodynamics. 42:639-657 |
| ISSN: | 1573-8744 1567-567X |
| DOI: | 10.1007/s10928-015-9430-4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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