Relative contributions of the major human CYP450 to the metabolism of icotinib and its implication in prediction of drug-drug interaction between icotinib and CYP3A4 inhibitors/inducers using physiologically based pharmacokinetic modeling

被引:19
|
作者
Chen, Jia
Liu, Dongyang
Zheng, Xin
Zhao, Qian
Jiang, Ji
Hu, Pei [1 ]
机构
[1] Peking Union Med Coll Hosp, Peking Union Med Coll, Beijing, Peoples R China
关键词
contribution of CYP450s; drug-drug interaction; human liver microsome; icotinib; physiologically based pharmacokinetic; supersome; TYROSINE KINASE INHIBITOR; HUMAN LIVER-MICROSOMES; EXPRESSED CYTOCHROMES P450; SENSITIVITY; GROWTH; POTENT;
D O I
10.1517/17425255.2015.1034688
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Objective: Icotinib is an anticancer drug, but relative contributions of CYP450 have not been identified. This study was carried out to identify the contribution percentage of CYP450 to icotinib and use the results to develop a physiologically based pharmacokinetic (PBPK) model, which can help to predict drug-drug interaction (DDI). Methods: Human liver microsome (HLM) and supersome using relative activity factor (RAF) were employed to determine the relative contributions of the major human P450 to the net hepatic metabolism of icotinib. These values were introduced to develop a PBPK model using SimCYP. The model was validated by the observed data in a Phase I clinical trial in Chinese healthy subjects. Finally, the model was used to simulate the DDI with ketoconazole or rifampin. Results: Final contribution of CYP450 isoforms determined by HLM showed that CYP3A4 provided major contributions to the metabolism of icotinib. The percentage contributions of the P450 to the net hepatic metabolism of icotinib were determined by HLM inhibition assay and RAF. The AUC ratio under concomitant use of ketoconazole and rifampin was 3.22 and 0.55, respectively. Conclusion: Percentage of contribution of CYP450 to icotinib metabolism was calculated by RAF. The model has been proven to fit the observed data and is used in predicting icotinib-ketoconazole/rifampin interaction.
引用
收藏
页码:857 / 868
页数:12
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