Prediction of Drug-Drug Interactions with Ensartinib as a Time-Dependent CYP3A Inhibitor Using Physiologically Based Pharmacokinetic Model

Xiaowen Wang; Yiqun Yu; Hongrui Liu; Fengjiao Bu; Chunying Shen; Qingfeng He; Xiao Zhu; Pin Jiang; Bing Han; Xiaoqiang Xiang

doi:10.1124/dmd.123.001373

Prediction of Drug-Drug Interactions with Ensartinib as a Time-Dependent CYP3A Inhibitor Using Physiologically Based Pharmacokinetic Model

Drug Metab Dispos. 2023 Nov;51(11):1515-1526. doi: 10.1124/dmd.123.001373. Epub 2023 Aug 29.

Authors

Affiliations

¹ Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China (X.W., Q.H., X.Z., P.J., X.X.); Department of Pharmacy, Minhang Hospital, Fudan University, Shanghai, China (X.W., Y.Y., H.L., C.S., B.H.); Department of Pharmacy, Eye and ENT Hospital, Fudan University, Shanghai, China (F.B.); and Shanghai Medicilon Inc., Shanghai, China (P.J.).
² Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China (X.W., Q.H., X.Z., P.J., X.X.); Department of Pharmacy, Minhang Hospital, Fudan University, Shanghai, China (X.W., Y.Y., H.L., C.S., B.H.); Department of Pharmacy, Eye and ENT Hospital, Fudan University, Shanghai, China (F.B.); and Shanghai Medicilon Inc., Shanghai, China (P.J.) xiangxq@fudan.edu.cn hbshcn@163.com.

PMID: 37643879
DOI: 10.1124/dmd.123.001373

Abstract

Ensartinib (X-396) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of ALK-positive patients with locally advanced or metastatic non-small cell lung cancer. Although in vitro experiments and molecular docking suggested its potential as a cytochrome P450 inhibitor, no further investigation or clinical trials have been conducted to assess its drug-drug interaction (DDI) risk. In this study, we conducted a series of in vitro experiments to elucidate the inhibition mechanism of ensartinib. Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed based on in vitro, in silico, and in vivo parameters, verified using clinical data, and applied to predict the clinical DDI mediated by ensartinib. The in vitro incubation experiments suggested that ensartinib exhibited strong time-dependent inhibition. Simulation results from the PBPK model indicated a significant increase in the exposure of CYP3A substrates in the presence of ensartinib, with the maximal plasma concentration and area under the plasma concentration-time curve increasing up to 12-fold and 29-fold for sensitive substrates. Based on these findings, it is evident that co-administration of ensartinib and CYP3A substrates requires careful regulatory consideration. SIGNIFICANCE STATEMENT: Ensartinib was found to be a strong time-dependent inhibitor of CYP3A for the first time based on in vitro experiments, but there was no research conducted to estimate the risk of drug-drug interaction (DDI) of ensartinib in clinic. Therefore, the first ensartinib physiologically based pharmacokinetic model was developed and applied to predict various untested scenarios. The simulation result indicated that the exposure of CYP3A substrate increased significantly and urged the further clinical DDI study.