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Itraconazole and rifampicin, as CYP3A modulators but not P-gp modulators, affect the pharmacokinetics of almonertinib and active metabolite HAS-719 in healthy volunteers

文献类型：期刊论文

作者Liu, Lu1,2; Li, Wei1; Yang, Le1,2; Guo, Zi-tao1; Xue, Hao1; Xie, Ning-jie1,2; Chen, Xiao-yan1,2
刊名ACTA PHARMACOLOGICA SINICA
出版日期2021-07-15
页码9
关键词almonertinib itraconazole rifampicin drug metabolism drug interaction CYP3A P-gp pharmacokinetics
ISSN号1671-4083
DOI10.1038/s41401-021-00710-8
通讯作者Chen, Xiao-yan(xychen@simm.ac.cn)
英文摘要Almonertinib is a novel third-generation EGFR tyrosine kinase inhibitor. It is mainly metabolized by CYP3A in vitro, and N-desmethylated almonertinib (HAS-719) is the major active metabolite in human plasma. In this study, we investigated the effects of CYP3A inhibitor itraconazole and CYP3A inducer rifampicin on the pharmacokinetics of almonertinib and HAS-719 in 64 healthy volunteers. We found that when co-administered with itraconazole, the maximal plasma concentration (C-max) and the plasma exposure (AUC(0-t)) of almonertinib were increased by 56.3% and 2.38-fold, respectively, whereas the C-max and AUC(0-t) of HAS-719 were reduced by 86.8% and 71.8%, respectively. Co-administration with rifampicin reduced the C-max and AUC(0-t) of almonertinib by 79.3% and 92.6%, but the AUC(0-t) of HAS-719 was unexpectedly decreased by 72.5%. In vitro assays showed that both almonertinib and HAS-719 were substrates of CYP3A and P-gp. Co-administration of rifampicin in Beagle dogs reduced the fecal recovery of almonertinib and HAS-719, and markedly increased the levels of metabolites derived from further metabolism of HAS-719, which was consistent with human plasma data, suggesting that although rifampicin was also a potent inducer of P-gp, the pharmacokinetic alternation of HAS-719 was mainly due to its further metabolism but not excretion changes. Moreover, we revealed that almonertinib was a moderately sensitive substrate of CYP3A in vivo. Special attention should be paid to the interaction between almonertinib and drugs or food affecting CYP3A activity in the clinical application of almonertinib.
WOS关键词ACQUIRED-RESISTANCE ; EGFR
资助项目National Natural Science Foundation of China[82073924] ; Hansoh Pharmaceutical Group Co. Ltd.
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000674427800002
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/296768]  
专题中国科学院上海药物研究所
通讯作者Chen, Xiao-yan
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Lu,Li, Wei,Yang, Le,et al. Itraconazole and rifampicin, as CYP3A modulators but not P-gp modulators, affect the pharmacokinetics of almonertinib and active metabolite HAS-719 in healthy volunteers[J]. ACTA PHARMACOLOGICA SINICA,2021:9.
APA Liu, Lu.,Li, Wei.,Yang, Le.,Guo, Zi-tao.,Xue, Hao.,...&Chen, Xiao-yan.(2021).Itraconazole and rifampicin, as CYP3A modulators but not P-gp modulators, affect the pharmacokinetics of almonertinib and active metabolite HAS-719 in healthy volunteers.ACTA PHARMACOLOGICA SINICA,9.
MLA Liu, Lu,et al."Itraconazole and rifampicin, as CYP3A modulators but not P-gp modulators, affect the pharmacokinetics of almonertinib and active metabolite HAS-719 in healthy volunteers".ACTA PHARMACOLOGICA SINICA (2021):9.

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来源：上海药物研究所

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