title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Clinical Pharmacology Research Center , Beijing , China +86 10 69158366 ; +86 10 69158365 ; -hubei@pumch.cn.
authors: Jia
authors: J
authors: Chen
authors: Dongyang
authors: D
authors: Liu
authors: Xin
authors: X
authors: Zheng
authors: Qian
authors: Q
authors: Zhao
authors: Ji
authors: J
authors: Jiang
authors: Pei
authors: P
authors: Hu
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003198:Computer Simulation; D043844:Crown Ethers / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D011799:Quinazolines / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D043844:Crown Ethers; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D011799:Quinazolines; D003577:Cytochrome P-450 Enzyme System; C531470:icotinib; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D012293:Rifampin
keywords: contribution of CYP450s; drug–drug interaction; human liver microsome; icotinib; physiologically based pharmacokinetic; supersome