Abstract: Objective To establish a population pharmacokinetic (PPK) model of olanzapine in patients with schizophrenia so as to identify key covariates influencing its pharmacokinetic characteristics and to provide evidence for individualized dosing. Methods A total of 221 measurements of olanzapine plasma concentrations from 31 patients were included in the final analysis. A nonlinear mixed-effects model was developed in Phoenix NLME (version 8.7; Certara USA, Princeton, NJ) using first-order conditional estimation with extended least squares. A one-compartment model with first-order absorption and elimination without an absorption lag time was selected as the structural model. Covariates were screened through a stepwise forward inclusion followed by backward elimination approach. Internal validation was performed using goodness-of-fit plots, prediction-corrected visual predictive checks (pcVPC), and nonparametric bootstrapping. Results The typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) of the population were estimated by the final model at 28.95 L·h^-1 and 248.76 L, respectively. Covariate analysis identified total bilirubin as a statistically significant positive factor influencing the absorption rate constant (K_a). Gender, age, body weight, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine did not make much difference, which might be attributed to the limited sample size. Internal validation confirmed satisfactory predictive performance and stability of the final model. Conclusion Total bilirubin levels may influence the absorption of olanzapine and should be taken into consideration when individualized dosing regimens are formulated for patients with schizophrenia.

Key words: Olanzapine, Schizophrenia, Total Bilirubin, Nonlinear Mixed-Effects Model, Therapeutic Drug Monitoring, Population Pharmacokinetics (PPK)