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Background: Risperidone, an anatypical antipsychotic agent, characterized as an antagonist of dopaminergic and serotonergic receptors, is now widely used in the treatment of patients with positive symptoms, negative symptoms and depressive mood of schizophrenia.According to a survey of antipsychotic usage in the treatment of schizophrenia in China in 2006, risperidone is the most frequently prescribed antipsychotic medication.However, risperidones therapeutic window is unclear for the present, while its use has been associated with relatively high risks for hyperprolactinemia.In conclusion, it makes sense for us to further explore the relationship between its dosage regimen and efficacy.Aim: Risperidone was used as the model drug, and sparse plasma concentrations were collected via conventional therapeutic drug monitoring of patients with refractory schizophrenia.A population pharmacokinetic model was established for risperidone and its active metabolite 9-hydroxyl risperidone.Population pharmacokinetic/pharmacodynamic model was used to explore the relationship between active moiety exposure and positive and negative symptom scale scores.The final model may provide reference for clinical individual administration of risperidone.Methods: PopPK analysis of risperidone and 9-OH risperidone was performed using nonlinear mixed effect model (NONMEM).Age, gender and smoking status were evaluated as main covariates.The model was externally validated using other 30 patients data.In the PK/PD analysis, sparse risperidone pharmacokinetic data and PANSS scores of 56 Chinese inpatients with schizophrenia were collected from Beijing Anding Hospital.The relationship between the active moiety exposure and PANSS score was explored using linear, log-linear, Emax, and sigmoid models.The final model was evaluated using visual predictive check (VPC) and normalized prediction distribution errors (NPDE) methods.Simulations based on the final PK/PD model were performed to investigate the effect of risperidone on PANSS scores under different dosage regimens.Results: A total of 300 risperidone concentration data set and 402 9-OH risperidone concentration data set from 131 inpatients (65 males, 66 females) were included for population pharmacokinetic (PopPK) analysis.A one-compartment pharmacokinetic model with flexible absorption process could best describe the concentration-time profiles of risperidone and 9-OH risperidone.The clearance of risperidone (Extensive metabolizer, Poor metabolizer subpopulation respectively) and 9-OH risperidone were 7.381, 4.037 and 4.483 L/h, respectively.The populationpredicted volumes of distribution for risperidone and 9-OH risperidone were 33.16 and 54.88L, respectively.The half-life of risperidone and 9-OH risperidone was similar with that of previously published paper.In PK/PD analysis, a total of 258 PANSS scores from 56 inpatients with schizophrenia were included.The decrease in total PANSS score during treatment was best characterized using AUC of total active moiety in the Sigmoid model.The maximum decrease in PANSS during risperidone treatment (Emax) was 56.2% and AUCTs0 (AUCRIs and AUCHRIS) required to attain half of Emax was 22.2 ng·hr/mL.Conclusion: The PK/PD model established for risperidone can well describe the characteristics of PANSS score.The results may further assist to optimize the dosage regimen, and provide guidance for the individualized treatment of risperidone