Physiologically based pharmacokinetic modeling of brivaracetam and its interactions with rifampin based on CYP2C19 phenotypes

Brivaracetam (BRV), a third-generation antiepileptic drug (AED), is primarily metabolized through amidase hydrolysis and CYP2C19-mediated hydroxylation in vivo. This study utilized physiologically based pharmacokinetic (PBPK) modeling to explore the pharmacokinetics of BRV and drug interactions between BRV and rifampin (RIF), a CYP2C19 inducer, based on CYP2C19 genetic polymorphisms. A PBPK model of BRV was developed in the general population and in individuals with different CYP2C19 phenotypes by adjusting catalytic rate constants (kcat), and the model was validated with observed clinical data. The model was then extrapolated to predict BRV steady-state plasma concentration in individuals with different CYP2C19 phenotypes, with or without coadministration of RIF. The developed model adequately described BRV exposure in the abovementioned populations. The predicted steady-state area under the curve (AUCτ-ss) increases by 20% in heterozygous extensive metabolizers (hEMs) and 55% in poor metabolizers (PMs), compared to homozygous extensive metabolizer (EMs). When coadministered with RIF, the model predicted the most significant magnitude of drug-drug interaction (DDI) in EMs, while the exposure change of BRV was minimal in PMs. Referencing the recommended concentration for therapeutic drug monitoring (TDM), we concluded that the current clinical maintenance dose of BRV is acceptable regardless of CYP2C19 polymorphisms and coadministration with RIF.