Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China; Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland; Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland.
Eur J Pharm Sci. 2024 Dec 1;203:106884. doi: 10.1016/j.ejps.2024.106884. Epub 2024 Aug 30.
This study aimed to evaluate the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of kinase inhibitors with warfarin and direct oral anticoagulants (DOACs).
An in vitro CYP probe substrate cocktail assay was used to study the inhibitory effects of fifteen kinase inhibitors on CYP2C9, 3A, and 1A2. Then, DDI predictions were performed using both mechanistic static and physiologically-based pharmacokinetic (PBPK) models.
Linsitinib, masitinib, regorafenib, tozasertib, trametinib, and vatalanib were identified as competitive CYP2C9 inhibitors (K = 1.4, 1.0, 1.1, 3.8, 0.5, and 0.1 μM, respectively). Masitinib and vatalanib were competitive CYP3A inhibitors (K = 1.3 and 0.2 μM), and vatalanib noncompetitively inhibited CYP1A2 (K = 2.0 μM). Moreover, linsitinib and tozasertib were CYP3A time-dependent inhibitors (K = 26.5 and 400.3 μM, k = 0.060 and 0.026 min, respectively). Only linsitinib showed time-dependent inhibition of CYP1A2 (K = 13.9 μM, k = 0.018 min). Mechanistic static models identified possible DDI risks for linsitinib and vatalanib with (S)-/(R)-warfarin, and for masitinib with (S)-warfarin. PBPK simulations further confirmed that vatalanib may increase (S)- and (R)-warfarin exposure by 4.37- and 1.80-fold, respectively, and that linsitinib may increase (R)-warfarin exposure by 3.10-fold. Mechanistic static models predicted a smaller risk of DDIs between kinase inhibitors and apixaban or rivaroxaban. The greatest AUC increases (1.50-1.74) were predicted for erlotinib in combination with apixaban and rivaroxaban. Linsitinib, masitinib, and vatalanib were predicted to have a smaller effect on apixaban and rivaroxaban AUCs (AUCR 1.22-1.53). No kinase inhibitor was predicted to increase edoxaban exposure.
Our results suggest that several kinase inhibitors, including vatalanib and linsitinib, can cause CYP-mediated drug-drug interactions with warfarin and, to a lesser extent, with apixaban and rivaroxaban. The work provides mechanistic insights into the risk of DDIs between kinase inhibitors and anticoagulants, which can be used to avoid preventable DDIs in the clinic.
本研究旨在评估与华法林和直接口服抗凝剂（DOACs）的细胞色素 P450（CYP）介导的药物相互作用（DDI）潜力的激酶抑制剂。
使用体外 CYP 探针底物鸡尾酒测定法研究了十五种激酶抑制剂对 CYP2C9、3A 和 1A2 的抑制作用。然后，使用基于机制的静态和基于生理的药代动力学（PBPK）模型进行 DDI 预测。
鉴定出林替替尼、马替替尼、regorafenib、托扎替尼、曲美替尼和瓦他拉尼为竞争性 CYP2C9 抑制剂（K = 1.4、1.0、1.1、3.8、0.5 和 0.1 μM）。马替替尼和瓦他拉尼为竞争性 CYP3A 抑制剂（K = 1.3 和 0.2 μM），而瓦他拉尼非竞争性抑制 CYP1A2（K = 2.0 μM）。此外，林替替尼和托扎替尼为 CYP3A 时间依赖性抑制剂（K = 26.5 和 400.3 μM，k = 0.060 和 0.026 min）。只有林替替尼对 CYP1A2 显示出时间依赖性抑制作用（K = 13.9 μM，k = 0.018 min）。基于机制的静态模型确定了林替替尼和瓦他拉尼与（S）/（R）-华法林以及马替替尼与（S）-华法林之间可能存在 DDI 风险。PBPK 模拟进一步证实，瓦他拉尼可能使（S）-和（R）-华法林的暴露量分别增加 4.37-和 1.80-倍，而林替替尼可能使（R）-华法林的暴露量增加 3.10-倍。基于机制的静态模型预测激酶抑制剂与阿哌沙班或利伐沙班之间发生 DDI 的风险较小。与阿哌沙班和利伐沙班联合使用时，厄洛替尼的 AUC 增加最大（1.50-1.74）。林替替尼、马替替尼和瓦他拉尼对阿哌沙班和利伐沙班 AUC 的影响预计较小（AUCR 1.22-1.53）。没有激酶抑制剂被预测会增加依多沙班的暴露量。
我们的研究结果表明，包括瓦他拉尼和林替替尼在内的几种激酶抑制剂可能会引起 CYP 介导的与华法林的药物相互作用，并且在较小程度上与阿哌沙班和利伐沙班发生药物相互作用。该研究工作提供了激酶抑制剂与抗凝剂之间发生 DDI 的机制见解，可用于避免临床中发生可预防的 DDI。
