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

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 (NSCLC). Although in vitro experiments and molecular docking suggested its potential as a CYP450 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 (C max ) and area under the plasma concentration-time curve (AUC) 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, a second generation ALK-TKI, 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 DDI of ensartinib in clinic. Therefore, the first ensartinib PBPK 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.