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

文献类型：期刊论文

作者Zhu, Yun-ting2; Zhang, Yi-fan2; Jiang, Jin-fang1; Yang, Yong1; Guo, Li-xia2; Bao, Jing-jing3; Zhong, Da-fang2
刊名INVESTIGATIONAL NEW DRUGS
出版日期2021-01-27
页码8
关键词Alflutinib Rifampicin CYP3A4 AST5902 Drug-drug interaction
ISSN号0167-6997
DOI10.1007/s10637-021-01071-z
通讯作者Zhang, Yi-fan(yfzhang@simm.ac.cn) ; Zhong, Da-fang(dfzhong@simm.ac.cn)
英文摘要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 AUC(0-infinity) and C-max, respectively, as well as 17% decrease in AST5902 AUC(0-infinity) and 1.09-fold increase in AST5902 C-max. The total active ingredients (alflutinib and AST5902) exhibited 62% and 39% decreases in AUC(0-infinity) and C-max, 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 . The registration No. is CTR20191562, and the date of registration is 2019-09-12.
资助项目National Natural Science Foundation of China[81521005] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050306]
WOS研究方向Oncology ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000612243900001
出版者SPRINGER
源URL[http://119.78.100.183/handle/2S10ELR8/295992]  
专题新药研究国家重点实验室
通讯作者Zhang, Yi-fan; Zhong, Da-fang
作者单位1.HQ Biosci Co LTD, Suzhou, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
3.Shanghai Allist Pharmaceut Co Ltd, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zhu, Yun-ting,Zhang, Yi-fan,Jiang, Jin-fang,et al. Effects of rifampicin on the pharmacokinetics of alflutinib, a selective third-generation EGFR kinase inhibitor, and its metabolite AST5902 in healthy volunteers[J]. INVESTIGATIONAL NEW DRUGS,2021:8.
APA Zhu, Yun-ting.,Zhang, Yi-fan.,Jiang, Jin-fang.,Yang, Yong.,Guo, Li-xia.,...&Zhong, Da-fang.(2021).Effects of rifampicin on the pharmacokinetics of alflutinib, a selective third-generation EGFR kinase inhibitor, and its metabolite AST5902 in healthy volunteers.INVESTIGATIONAL NEW DRUGS,8.
MLA Zhu, Yun-ting,et al."Effects of rifampicin on the pharmacokinetics of alflutinib, a selective third-generation EGFR kinase inhibitor, and its metabolite AST5902 in healthy volunteers".INVESTIGATIONAL NEW DRUGS (2021):8.

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来源：上海药物研究所

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