Evaluating a physiologically based pharmacokinetic model for predicting the pharmacokinetics of midazolam in Chinese after oral administration

Aim: To evaluate the SimCYP simulator ethnicity-specific population model for predicting the pharmacokinetics of midazolam, a typical CYP3A4/5 substrate, in Chinese after oral administration. Methods: The physiologically based pharmacokinetic (PBPK) model for midazolam was developed using a SimCYP population-based simulator incorporating Chinese population demographic, physiological and enzyme data. A clinical trial was conducted in 40 Chinese subjects (the half was females) receiving a single oral dose of 15 mg midazolam. The subjects were separated into 4 groups based on age (20-50, 51-65, 66-75, and above 76 years), and the pharmacokinetics profiles of each age- and gender-group were determined, and the results were used to verify the PBPK model. Results: Following oral administration, the simulated profiles of midazolam plasma concentrations over time in virtual Chinese were in good agreement with the observed profiles, as were AUC and C-max. Moreover, for subjects of varying ages (20-80 years), the ratios of predicted to observed clearances were between 0.86 and 1.12. Conclusion: The SimCYP PBPK model accurately predicted the pharmacokinetics of midazolam in Chinese from youth to old age. This study may provide novel insight into the prediction of CYP3A4/5-mediated pharmacokinetics in the Chinese population relative to Caucasians and other ethnic groups, which can support the rational design of bridging clinical trials.