PT  - JOURNAL ARTICLE
AU  - Mao, Jialin
AU  - Johnson, Theodore R
AU  - Shen, Zhongzhou
AU  - Yamazaki, Shinji
TI  - Prediction of Crizotinib-Midazolam Interaction Using the Simcyp Population-Based Simulator: Comparison of CYP3A Time-Dependent Inhibition Between Human Liver Microsomes Versus Hepatocytes
AID  - 10.1124/dmd.112.049114
DP  - 2012 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.112.049114
4099  - http://dmd.aspetjournals.org/content/early/2012/11/05/dmd.112.049114.short
4100  - http://dmd.aspetjournals.org/content/early/2012/11/05/dmd.112.049114.full
AB  - 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 to: 1) characterize crizotinib time-dependent inhibition (TDI) potency for CYP3A in human liver microsomes (HLM) and cryopreserved human hepatocytes suspended in plasma (HSP), 2) characterize crizotinib enzyme induction potency on CYP3A4 in cryopreserved human hepatocytes (HEP), 3) predict crizotinib steady-state plasma concentrations in patients (e.g., autoinhibition and autoinduction) using the mechanistic dynamic model, Simcyp population-based simulator, and 4) predict a clinical crizotinib-midazolam interaction using the dynamic model as well as the static mathematical model. Crizotinib inactivation constant (KI) and maximum inactivation rate constant (kinact) 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 (kinact / KI) was approximately 20-fold lower in HSP relative to HLM. Crizotinib Emax and EC50 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 co-administration of crizotinib (21-fold) was significantly over-predicted 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.