Effects of rifampicin on the pharmacokinetics of alflutinib, a selective third-generation EGFR kinase inhibitor, and its metabolite AST5902 in healthy volunteers.

Background Alflutinib is a novel irreversible and highly selective third-generation EGFR inhibitor currently being developed for the treatment of non-small cell lung cancer patients with activating EGFR mutations and EGFR T790M drug-resistant mutation. Alflutinib is mainly metabolized via CYP3A4 to form its active metabolite AST5902. Both alflutinib and AST5902 contribute to the in vivo pharmacological activity. The aim of this study was to investigate the effects of rifampicin (a strong CYP3A4 inducer) on the pharmacokinetics of alflutinib and AST5902 in healthy volunteers, thus providing important information for drug-drug interaction evaluation and guiding clinical usage. Methods This study was designed as a single-center, open-label, and single-sequence trial over two periods. The volunteers received a single dose of 80 mg alflutinib on Day 1/22 and continuous doses of 0.6 g rifampicin on Day 15-30. Blood sampling was conducted on Day 1-10 and Day 22-31. The pharmacokinetics of alflutinib, AST5902, and the total active ingredients (alflutinib and AST5902) with or without rifampicin co-administration were respectively analyzed. Results Co-administration with rifampicin led to 86% and 60% decreases in alflutinib AUC0-∞ and Cmax, respectively, as well as 17% decrease in AST5902 AUC0-∞ and 1.09-fold increase in AST5902 Cmax. The total active ingredients (alflutinib and AST5902) exhibited 62% and 39% decreases in AUC0-∞ and Cmax, respectively. Conclusions As a strong CYP3A4 inducer, rifampicin exerted significant effects on the pharmacokinetics of alflutinib and the total active ingredients (alflutinib and AST5902). The results suggested that concomitant strong CYP3A4 inducers should be avoided during alflutinib treatment. This trial was registered at http://www.chinadrugtrials.org.cn . The registration No. is CTR20191562, and the date of registration is 2019-09-12.

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

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.