Purpose: Physiologically based pharmacokinetic (PBPK) analyses have been frequently used in the clinical pharmacology section of regulatory applications. However, whether models developed and validated in healthy populations can be extrapolated to untested populations is not well known. This study aimed to determine whether a drug-specific PBPK model validated in a healthy population could be used to predict drug disposition in populations with different ethnicities, ages, genetic phenotypes, and pregnant population considering an example for risperidone and its active metabolite, paliperidone. Methods: PBPK modeling and simulation were performed using Simcyp Population-based ADME Simulator version 20. The risperidone and paliperidone compound models were developed based on physicochemical and pharmacokinetic parameters reported in the literature. The model was validated using observed values from 25 clinical studies including 15 in the adult population (8 Caucasian, 5 Chinese, and 2 Japanese), 8 in the pediatric population (5 Caucasian, 2 Chinese, and 1 Japanese), and 2 in the pregnant population. Visual predictive checks (VPC) for predicted and observed plasma concentrations, goodness-of-fit plots, prediction fold error, mean error (ME), and root-mean-square error (RMSE) were used for the graphical and statistical analyses. Results: Almost all (98.9%) of observed serum risperidone and paliperidone concentrations werewithin the 90% prediction intervals of each concentration by the PBPK simulation. All predicted values of serum risperidone concentration and AUC values in adult, pediatric, and pregnant populations met the 2fold acceptance criterion. A 91.8% of predicted values of paliperidone concentration and 97.4% of AUC values fall within the 2-fold criterion in all populations. The mean error (ME) and root-mean-square error (RMSE) for all predicted Cmax for risperidone were 0.61±0.4%, and 2.85%, respectively. Regarding paliperidone, the values were -0.038±0.45% and 3.16%, respectively. Conclusion: This study successfully shows an experimental application of PBPK modeling for the adaptation of ethnic variety and pediatric population.