title: Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia.
abstract: OBJECTIVE
  To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters.
  
  
  METHODS
  Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors.
  
  
  RESULTS
  A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients.
  
  
  CONCLUSIONS
  Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.
authors: Laboratory of Clinical Psychopharmacology, Beijing An Ding Hospital, Capital Medical University, China.
authors: Li-jun
authors: LJ
authors: Li
authors: De-wei
authors: DW
authors: Shang
authors: Wen-biao
authors: WB
authors: Li
authors: Wei
authors: W
authors: Guo
authors: Xi-pei
authors: XP
authors: Wang
authors: Yu-peng
authors: YP
authors: Ren
authors: An-ning
authors: AN
authors: Li
authors: Pei-xin
authors: PX
authors: Fu
authors: Shuang-min
authors: SM
authors: Ji
authors: Wei
authors: W
authors: Lu
authors: Chuan-yue
authors: CY
authors: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People; D002681:China; D003024:Clozapine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011446:Prospective Studies; D012559:Schizophrenia / Q000188:drug therapy*; D012737:Sex Factors; D012907:Smoking / Q000378:metabolism; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; C058272:norclozapine; D003024:Clozapine