Alflutinib (AST2818) is a third-generation epidermal growth factor receptor (EGFR) inhibitor that inhibits both EGFR-sensitive mutations and T790M mutations. Previous study has shown that after multiple dosages, alflutinib exhibits nonlinear pharmacokinetics and displays a time- and dose-dependent increase in the apparent clearance, probably due to its self-induction of cytochrome P450 (CYP) enzyme. In this study, we investigated the CYP isozymes involved in the metabolism of alflutinib and evaluated the enzyme inhibition and induction potential of alflutinib and its metabolites. The data showed that alflutinib in human liver microsomes (HLMs) was metabolized mainly by CYP3A4, which could catalyze the formation of AST5902. Alflutinib did not inhibit CYP isozymes in HLMs but could induce CYP3A4 in human hepatocytes. Rifampin is a known strong CYP3A4 inducer and is recommended by the FDA as a positive control in the CYP3A4 induction assay. We found that the induction potential of alflutinib was comparable to that of rifampin. The E_max of CYP3A4 induction by alflutinib in three lots of human hepatocytes were 9.24-, 11.2-, and 10.4-fold, while the fold-induction of rifampin (10 μM) were 7.22-, 19.4- and 9.46-fold, respectively. The EC₅₀ of alflutinib-induced CYP3A4 mRNA expression was 0.25 μM, which was similar to that of rifampin. In addition, AST5902 exhibited much weak CYP3A4 induction potential compared to alflutinib. Given the plasma exposure of alflutinib and AST5902, both are likely to affect the pharmacokinetics of CYP3A4 substrates. Considering that alflutinib is a CYP3A4 substrate and a potent CYP3A4 inducer, drug–drug interactions are expected during alflutinib treatment.

阿氟替尼 (AST2818) 是第三代表皮生长因子受体 (EGFR) 抑制剂，可抑制 EGFR 敏感突变和 T790M 突变。先前的研究表明，多次给药后，阿氟替尼表现出非线性药代动力学，并表现出时间和剂量依赖性的表观清除率增加，这可能是由于其细胞色素 P450 (CYP) 酶的自诱导作用。在本研究中，我们研究了阿氟替尼代谢中涉及的CYP同工酶，并评估了阿氟替尼及其代谢物的酶抑制和诱导潜力。数据显示，阿氟替尼在人肝微粒体（HLM）中主要通过CYP3A4代谢，CYP3A4可以催化AST5902的形成。阿氟替尼不会抑制 HLM 中的 CYP 同工酶，但可以诱导人肝细胞中的 CYP3A4。利福平是一种已知的强效 CYP3A4 诱导剂，被 FDA 推荐作为 CYP3A4 诱导测定中的阳性对照。我们发现阿氟替尼的诱导潜力与利福平相当。在三批人肝细胞中，阿氟替尼诱导 CYP3A4 的E _{max分别为 9.24、11.2 和 10.4 倍，而利福平 (10 μM) 的}诱导倍数分别为 7.22、19.4 和 9.46 倍。阿氟替尼诱导CYP3A4 mRNA表达的EC ₅₀为0.25 μM，与利福平相似。此外，与阿氟替尼相比，AST5902 表现出弱得多的 CYP3A4 诱导潜力。鉴于阿氟替尼和 AST5902 的血浆暴露，两者都可能影响 CYP3A4 底物的药代动力学。考虑到阿氟替尼是 CYP3A4 底物和有效的 CYP3A4 诱导剂，因此在阿氟替尼治疗期间预计会出现药物相互作用。