title: Population pharmacokinetic/pharmacodynamic model of clozapine for characterizing the relationship between accumulated exposure and PANSS scores in patients with schizophrenia.
abstract: BACKGROUND
  The aim of this study was to characterize the relationship between accumulated exposure of clozapine and changes in Positive and Negative Syndrome Scale (PANSS) score in Chinese patients with schizophrenia by pharmacokinetic/pharmacodynamic (PK/PD) modeling.
  
  
  METHODS
  Sparse clozapine PK data and PANSS scores were collected from 2 clinical studies of Chinese inpatients with schizophrenia. Two other rich PK data sets were included for more accurate assessment of clozapine PK characteristics. The relationship between clozapine-accumulated exposure and PANSS score was investigated using linear, log-linear, E(max), and sigmoid models, and each model was evaluated using visual predictive condition and normalized prediction distribution error methods. Simulations based on the final PK/PD model were preformed to investigate the effect of clozapine on PANSS scores under different dose regimens.
  
  
  RESULTS
  A total of 1391 blood clozapine concentrations from 198 subjects (180 patients and 18 healthy volunteers) and 576 PANSS scores from 137 patients were included for PK and PK/PD analysis. A first-order 2-compartment PK 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 area under the curve (AUC) data in the E(max) model. The maximum decrease in PANSS during clozapine treatment (Emax) was 55.4%, and the cumulated AUC(50) (cAUC(50)) required to attain half of E(max) was 296 mg·L(-1)·h(-1)·d(-1). The simulations demonstrated that the accelerated dose titration and constant dose regimens achieved a similar maximum drug response 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 score during treatment and may be useful for optimizing the dose regimen for individual patients.
authors.affiliation: *Beijing Key Laboratory for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China; †Department of Pharmacy, Guangzhou Brain Hospital, Guangzhou Medical University; ‡Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; §Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University; and ¶Beijing Key Lab of Brain Major Disorders-State Key Lab Incubation Base, Beijing Neuroscience Disciplines, Capital Medical University, Beijing, China.
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Shang
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Li
authors.forename: Xi-Pei
authors.initials: XP
authors.lastname: Wang
authors.forename: Yu-Guan
authors.initials: YG
authors.lastname: Wen
authors.forename: Yu-Peng
authors.initials: YP
authors.lastname: Ren
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Wen-Biao
authors.initials: WB
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Tian-Yan
authors.initials: TY
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Chuan-Yue
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D002681:China; D003024:Clozapine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D012559:Schizophrenia / Q000188:drug therapy* / Q000453:epidemiology; D012737:Sex Factors; D012907:Smoking / Q000453:epidemiology / Q000378:metabolism; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine