Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu, China.
Chengdu Gencore Pharmaceutical Technology Co., Ltd., Chengdu, China.
Eur J Pharm Sci. 2022 Oct 1;177:106258. doi: 10.1016/j.ejps.2022.106258. Epub 2022 Jul 12.
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 (k), 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 (AUC) 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.
布瓦西坦（BRV）是第三代抗癫痫药物（AED），主要在体内通过酰胺水解和 CYP2C19 介导的羟化作用代谢。本研究利用基于生理的药代动力学（PBPK）模型，根据 CYP2C19 遗传多态性，探讨 BRV 的药代动力学和 BRV 与利福平（RIF）（CYP2C19 诱导剂）之间的药物相互作用。通过调整催化速率常数（k），在一般人群和不同 CYP2C19 表型个体中建立了 BRV 的 PBPK 模型，并使用观察到的临床数据对模型进行了验证。然后，将该模型外推至预测不同 CYP2C19 表型个体（有无联合 RIF 用药）的 BRV 稳态血浆浓度。该模型充分描述了上述人群中 BRV 的暴露情况。与纯合子广泛代谢者（EMs）相比，杂合子广泛代谢者（hEMs）和弱代谢者（PMs）的预测稳态 AUC 增加 20%和 55%。当与 RIF 联合使用时，模型预测 EMs 中药物相互作用（DDI）的幅度最大，而 PMs 中 BRV 的暴露变化最小。参考治疗药物监测（TDM）的推荐浓度，我们得出结论，无论 CYP2C19 多态性如何，以及是否与 RIF 联合使用，目前 BRV 的临床维持剂量都是可以接受的。
