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Background: The aim of this study was to characterize the time course of the Positive and Negative Syndrome Scale (PANSS) scores of clozapine in Chinese schizophrenia patients by pharmacokinetic/pharmacodynamic (PK/PD) modeling.Methods: Sparse clozapine pharmacokinetic data and PANSS scores from two clinical studies of Chinese inpatients with schizophrenia were pooled with another two rich PK datasets of clozapine.The relationships between clozapine concentration/eposure/accumulated exposure and PANSS score were investigated using linear, log-linear, Emax, and sigmoid models and each model was evaluated using visual predictive condition (VPC) and normalized prediction distribution error (NPDE)methods.Based on the final PK/PD model, the simulations of different dose regimens were preformed to predict the effect of clozapine on PANSS scores.Results:A total of 1391 blood clozapine concentrations from 198 subjects (180 patients and 18 healthy voluteers) and 576 PANSS scores from 137 patients were included for PK and PK/PD analysis.A first-order twocompartment pharmacokinetic model with covariates gender and smoking status influencing systemic clearance adequately described the PK profile of clozapine.The decrease in total PANSS score during treatment was best characterized using cumulated clozapine AUC data in the Emax model.The maximum decrease in PANSS during clozapine treatment (Emax) was 55.4% and the cumulated AUC50 (cAUC50) required to attain half of Emax was 296 mg/L·h·day.It was demonstrated in the simulations that a similar maximum drug response was achieved of either the accelerated dose titration or constant dose regimens but with a slower relief of symptoms in dose titration regimen.Conclusions: The PK/PD model can describe the clinical response as measured by decreasing PANSS scores during treatment and may be useful for optimizing the dose regimen for individual patients.