目的:本研究旨在评估激酶抑制剂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-药物相互作用(DDI)潜力。
方法:使用体外CYP探针底物混合物测定法研究了15种激酶抑制剂对CYP2C9,3A,1A2。然后,使用机械静态和基于生理的药代动力学(PBPK)模型进行DDI预测。
结果:林西替尼,马赛替尼,Regorafenib,Tozasertib,曲美替尼,和vatalanib被鉴定为竞争性CYP2C9抑制剂(Ki=1.4、1.0、1.1、3.8、0.5和0.1μM,分别)。Masitinib和vatalanib是竞争性CYP3A抑制剂(Ki=1.3和0.2μM),和vatalanib非竞争性抑制CYP1A2(Ki=2.0μM)。此外,linsitinib和tozasertib是CYP3A时间依赖性抑制剂(KI=26.5和400.3μM,kinact=0.060和0.026min-1)。只有林西替尼显示CYP1A2的时间依赖性抑制(KI=13.9μM,kinact=0.018min-1)。机械静态模型确定了林西替尼和瓦他尼与(S)-/(R)-华法林的可能DDI风险,和马赛替尼与(S)-华法林。PBPK模拟进一步证实,vatalanib可能会增加(S)和(R)华法林暴露4.37和1.80倍,分别,而林西替尼可能会使(R)-华法林暴露量增加3.10倍。机制静态模型预测激酶抑制剂与阿哌沙班或利伐沙班之间DDI的风险较小。预测厄洛替尼与阿哌沙班和利伐沙班的组合的最大AUC增加(1.50-1.74)。Linsitinib,马赛替尼,预计vatalanib对阿哌沙班和利伐沙班AUC的影响较小(AUCR1.22-1.53)。预测没有激酶抑制剂增加依度沙班暴露。
结论:我们的结果表明,几种激酶抑制剂,包括Vatalanib和linsitinib,可引起CYP介导的药物与华法林的药物相互作用,在较小程度上,阿哌沙班和利伐沙班.这项工作提供了对激酶抑制剂和抗凝剂之间DDI风险的机械见解,可用于在临床中避免可预防的DDI。
OBJECTIVE: 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).
METHODS: 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.
RESULTS: Linsitinib, masitinib, regorafenib, tozasertib, trametinib, and vatalanib were identified as competitive CYP2C9 inhibitors (Ki = 1.4, 1.0, 1.1, 3.8, 0.5, and 0.1 μM, respectively). Masitinib and vatalanib were competitive CYP3A inhibitors (Ki = 1.3 and 0.2 μM), and vatalanib noncompetitively inhibited CYP1A2 (Ki = 2.0 μM). Moreover, linsitinib and tozasertib were CYP3A time-dependent inhibitors (KI = 26.5 and 400.3 μM, kinact = 0.060 and 0.026 min-1, respectively). Only linsitinib showed time-dependent inhibition of CYP1A2 (KI = 13.9 μM, kinact = 0.018 min-1). 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.
CONCLUSIONS: 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.