克里唑蒂尼
CYP3A型
咪唑安定
CYP3A4型
化学
人口
药理学
药代动力学
效力
微粒体
体外
细胞色素P450
生物
新陈代谢
生物化学
医学
内科学
环境卫生
胸腔积液
镇静
恶性胸腔积液
作者
Jialin Mao,Theodore M. Johnson,Zhongzhou Shen,Shinji Yamazaki
标识
DOI:10.1124/dmd.112.049114
摘要
Crizotinib (Xalkori) is an orally available potent inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase and mesenchymal-epithelial transition factor. Objectives of the present study were as follows: 1) to characterize crizotinib time-dependent inhibition (TDI) potency for CYP3A in human liver microsomes (HLM) and cryopreserved human hepatocytes suspended in human plasma (HSP); 2) to characterize crizotinib enzyme induction potency on CYP3A4 in cryopreserved human hepatocytes; 3) to predict crizotinib steady-state plasma concentrations in patients (e.g., autoinhibition and autoinduction) using the mechanistic dynamic model, Simcyp population-based simulator; and 4) to predict a clinical crizotinib-midazolam interaction using the dynamic model as well as the static mathematical model. Crizotinib inactivation constant (K(I)) and maximum inactivation rate constant (k(inact)) for TDI were estimated as, respectively, 0.37 µM and 6.9 h(-1) in HLM and 0.89 µM and 0.78 h(-1) in HSP. Thus, crizotinib inactivation efficiency (k(inact)/K(I)) was ∼20-fold lower in HSP relative to HLM. Crizotinib E(max) and EC(50) for CYP3A4 induction (measured as mRNA expression) were estimated as 6.4- to 29-fold and 0.47 to 3.1 µM, respectively. Based on these in vitro parameters, the predicted crizotinib steady-state area under plasma concentration-time curve (AUC) with HLM-TDI was 2.1-fold higher than the observed AUC, whereas that with HSP-TDI was consistent with the observed result (≤1.1-fold). The increase in midazolam AUC with coadministration of crizotinib (21-fold) was significantly overpredicted using HLM-TDI, whereas the prediction using HSP-TDI (3.6-fold) was consistent with the observed result (3.7-fold). Collectively, the present study demonstrated the value of HSP to predict in vivo CYP3A-mediated drug-drug interaction.
科研通智能强力驱动
Strongly Powered by AbleSci AI