title: Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method.
abstract: OBJECTIVE
  To evaluate the distribution of population kinetic parameters for clozapine and their relationship to age and gender in patients on continuous treatment with the drug.
  
  
  METHODS
  Retrospective therapeutic drug monitoring data (391 samples from 241 patients) were evaluated using the nonparametric maximum likelihood method. Patients treated concomitantly with drugs known to interact with clozapine were not included. The distribution of clozapine clearance was compared with the distribution of the activity of the drug metabolic enzyme CYP1A2 found in other populations, as recent studies indicate that CYP1A2 is a major determinant for clozapine elimination. The kinetic linearity for clozapine was studied in 41 patients who each provided data from more than one dose level.
  
  
  RESULTS
  Clozapine clearance was highly variable in the population and skewed towards high values. Men had higher clearances CL/F (median with 25% and 75% quartiles 38.2 (22.0, 60.0) vs 28.3 (15.2, 48.6) l h(-1)) and a larger volume of distribution V/F (694 (224, 970) vs 401 (189, 932) l) than women. Clearance did not decrease with age in any gender. Clozapine clearance was similarly distributed as the indices of CYP1A2-activity found in other populations by other authors. Evidence of nonlinear kinetics was not found.
  
  
  CONCLUSIONS
  The large kinetic variability for clozapine found in this study implies that the dose of clozapine needs to be individualised over a wide dose range. The similarity of the distribution of clozapine clearance in this study and the CYP1A2-activity in other populations support the assumption that CYP1A2 is a major determinant for clozapine elimination.
authors.affiliation: Department of Clinical Pharmacology at the Karolinska Institute, Huddinge Hospital, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Jerling
authors.forename: Y
authors.initials: Y
authors.lastname: Merlé
authors.forename: F
authors.initials: F
authors.lastname: Mentré
authors.forename: A
authors.initials: A
authors.lastname: Mallet
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D003024:Clozapine / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012737:Sex Factors; D018709:Statistics, Nonparametric
chemical_list: D014150:Antipsychotic Agents; D019388:Cytochrome P-450 CYP1A2; D003024:Clozapine