Development of a Physiologically Based Pharmacokinetic (PBPK) Population Model for Chinese Elderly Subjects.

AIMS To develop and verify a physiologically based pharmacokinetic (PBPK) population model for the Chinese geriatric population in Simcyp. METHODS Firstly, physiological information for the Chinese geriatric population was collected and later employed to develop the Chinese geriatric population model by recalibration of corresponding physiological parameters in the Chinese adult population model available in Simcyp (i.e., Chinese healthy volunteer model). Secondly, drug-dependent parameters were collected for six drugs with different elimination pathways (i.e., metabolized by CYP1A2, CYP3A4, or renal excretion). The drug models were then developed and verified by clinical data from Chinese adults, Caucasian adults, and Caucasian elderly subjects to ensure that drug-dependent parameters are correctly inputted. Finally, the tested drug models in combination with the newly developed Chinese geriatric population model were applied to simulate drug concentration in Chinese elderly subjects. The predicted results were then compared with the observed to evaluate model prediction performance. RESULTS 98% of predicted AUC, 95% of predicted Cmax , and 100% of predicted CL values were within 2-fold of the observed, indicating all drug models were properly developed. The drug models, combined with the newly developed population model, were then used to predict pharmacokinetics in Chinese elderly subjects aged 60-93. The predicted AUC, Cmax , and CL values were all within two folds of the observed. CONCLUSION The population model for the Chinese elderly subjects appears to adequately predict the concentration of the drug that was metabolized by CYP1A2, or CYP3A4 or eliminated by renal clearance.