Alflutinib (AST2818), primarily metabolized by CYP3A4, is a potent CYP3A4 inducer

Authors: Xiao-yun Liu1,2, Zi-tao Guo1, Zhen-dong Chen1,2, Yi-fan Zhang1, Jia-lan Zhou1, Yong Jiang3, Qian-yu Zhao3, Xing-xing Diao1,2, Da-fang Zhong1,2
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Shanghai Allist Pharmaceuticals Inc., Shanghai 201203, China
Correspondence to: Xing-xing Diao:, Da-fang Zhong:,
DOI: 10.1038/s41401-020-0389-3
Received: 2 November 2019
Accepted: 20 February 2020
Advance online: 31 March 2020


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 Emax 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.
Keywords: alflutinib; AST5902; CYP3A4; metabolism; enzyme induction; drug–drug interaction

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