title: Population pharmacokinetic-pharmacodynamic (PopPK/PD) modeling of risperidone and its active metabolite in Chinese schizophrenia patients.
abstract: OBJECTIVE
  Risperidone is a second-generation antipsychotic agent commonly used in the treatment of ~ 31.1% of schizophrenia patients in China, it is the most commonly-prescribed antipsychotic agent. Despite the abundant use of risperidone, population pharmacokinetic-pharmacodynamic models of risperidone have not been performed in Chinese schizophrenia patients. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PopPK/PD) model to describe the PK behavior and efficacy of risperidone and 9-hydroxy-risperidone (active metabolite) in Chinese patients.
  
  
  METHODS
  Plasma concentration data (702 measurements from 131 patients) and positive and negative syndrome scale (PANSS) scores (258 observations from 56 patients) were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach with first-order conditional estimation with interaction (FOCEI). The influence of potential covariates was evaluated. Model robustness was assessed using external validation, normalized prediction distribution error, nonparametric bootstrap, and visual predictive check approaches.
  
  
  RESULTS
  Risperidone concentration data were well described by a one-compartmental model incorporating an additional compartment that refers to the concentration profiles of 9-hydroxy-risperidone. A complex absorption procedure was incorporated into the model to describe the metabolism of risperidone to 9-hydroxy-risperidone in the gastrointestinal (GI) tract. A binomial distribution in the estimated clearance (CL) of risperidone has been identified in our model. Decrease in PANSS score along with total AUC (AUCtotal) of risperidone and 9-hydroxy-risperidone was best characterized by an Emax model with 3 transit compartments describing the delay of drug effect.
  
  
  CONCLUSIONS
  Considerable differences in PK behavior and drug effect of risperidone have been identified among Chinese extensive metabolizing (EM) and poor metabolizing (PM) patients. This PopPK/PD model may fulfill individualized treatment in clinical practice and may potentially be transferred to other antipsychotic therapies.
authors.forename: Shuangmin
authors.initials: S
authors.lastname: Ji
authors.forename: Dewei
authors.initials: D
authors.lastname: Shang
authors.forename: Kehua
authors.initials: K
authors.lastname: Wu
authors.forename: Anning
authors.initials: A
authors.lastname: Li
authors.forename: Xiwei
authors.initials: X
authors.lastname: Li
authors.forename: Chenhui
authors.initials: C
authors.lastname: Deng
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Tianyan
authors.initials: T
authors.lastname: Zhou
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D001711:Biotransformation; D002681:China / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D000068882:Paliperidone Palmitate / Q000493:pharmacokinetics*; D010641:Phenotype; D018967:Risperidone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012559:Schizophrenia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000208:ethnology; D012565:Schizophrenic Psychology
chemical_list: D014150:Antipsychotic Agents; D018967:Risperidone; D000068882:Paliperidone Palmitate