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

作　　者：Lu Liu Wei Li Le Yang Zi-tao Guo Hao Xue Ning-jie Xie Xiao-yan Chen 

机构地区：[1]Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [2]University of Chinese Academy of Sciences,Beijing,100049,China

出　　处：《Acta Pharmacologica Sinica》2022年第4期1082-1090,共9页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(Grant 82073924)。

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 (Cmax) and the plasma exposure (AUC0–t) of almonertinib were increased by 56.3% and 2.38-fold, respectively, whereas the Cmax and AUC0–t of HAS-719 were reduced by 86.8% and 71.8%, respectively. Co-administration with rifampicin reduced the Cmax and AUC0–t of almonertinib by 79.3% and 92.6%, but the AUC0–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.

关 键 词：almonertinib itraconazole RIFAMPICIN drug metabolism drug interaction CYP3A P-GP PHARMACOKINETICS 

分 类 号：R96[医药卫生—药理学]