Impact of Ethnicity-Specific Hepatic Microsomal Scaling Factor, Liver Weight, and Cytochrome P450 (CYP) 1A2 Content on Physiologically Based Prediction of CYP1A2-Mediated Pharmacokinetics in Young and Elderly Chinese Adults.

Abstract

The vast majority of physiological and biological data required for physiologically based predictions are primarily available in Caucasians rather than other ethnic populations, which leads to a lack of confidence in the application of physiologically based pharmacokinetic (PBPK) modeling for ethnicity-specific prediction of pharmacokinetics in the Chinese population. In this study we recalibrate the system parameters of Chinese-specific PBPK modeling and explore for the first time the relative importance of ethnicity-specific microsomal protein per gram of liver (MPPGL), liver weight, and cytochrome P450 (CYP) 1A2 abundance to the projection of drug disposition mediated by CYP1A2 in young and elderly Chinese adults. Chinese MPPGL levels and associated variability were parameterized and incorporated for the first time into ethnicity-specific PBPK models for the Chinese adults. Parameterization of Chinese liver weights was also recalibrated on the basis of autopsy data from Chinese individuals (n = 4081) across the entire adult age range. Uncertainty surrounding the Chinese-specific CYP1A2 content has also been explored and clarified by conducting ethnicity-related PBPK simulations under different scenarios. Various ethnicity-related or 'what-if' scenarios for PBPK modeling were implemented to assess the predictive performance and explore the relative importance of ethnicity-specific MPPGL and liver weight to the projection of drug disposition mediated by CYP1A2 in terms of two typical CYP1A2 substrates, caffeine and theophylline, in young and elderly Chinese adults by comparing the predicted concentration-time data and associated pharmacokinetic parameter estimates with observations. Compared with 0.85, the liver scalar of 0.9 generally produced more accurate liver weight levels in virtual Chinese peers. Additionally, simulated MPPGL levels on the basis of Caucasian data were not able to reflect the age-independent pattern observed in Chinese adults, dissimilar to that on the basis of Chinese-specific adult MPPGL data. The modeling Scenarios A and B provided similar predictions for theophylline pharmacokinetics in young Chinese adults across different age groups, while Scenario B provided the most accurate prediction for theophylline pharmacokinetics in elderly Chinese adults. However, the use of a stratified value of CYP1A2 content derived from a Han Chinese cohort with a small sample size instead of the pooled value of all Chinese cohorts involved regardless of Chinese sub-ethnicity resulted in inadequate prediction of CYP1A2-mediated pharmacokinetics in terms of caffeine and theophylline in either young or elderly Chinese subjects. Additionally, the impact of ethnic-specific MPPGL on predictive accuracy of theophylline pharmacokinetics in elderly Chinese subjects is more evident than that of liver weight. We provided quantitative information pertaining to Chinese-specific levels of liver weight and MPPGL, and recalibrated these system parameters for PBPK modeling for young and elderly Chinese subjects. Uncertainty surrounding the Chinese-specific CYP1A2 content has also been clarified. PBPK modeling based on the recalibrated system parameters can accurately simulate CYP1A2-mediated pharmacokinetics in both young and elderly Chinese adults, particularly in elderly individuals.