title: Quantifying intraindividual variations in plasma clozapine levels: a population pharmacokinetic approach.
abstract: Clozapine has strong recommendations for therapeutic drug monitoring. While factors that influence interindividual variation in plasma clozapine levels have been extensively reported, intraindividual variation remains poorly studied. We employed a population pharmacokinetic approach to assess intraindividual variations in plasma levels of both clozapine and N-desmethylclozapine, as well as the impact of smoking on this variability.
  
  
  
  Patients who were initiated on clozapine from January 2009 to December 2010 and who provided at least 2 plasma samples were included in this study. The observed concentrations of clozapine and N-desmethylclozapine were applied in a Bayesian pharmacokinetic modeling approach by using a previously published pharmacokinetic model from an independent sample to compute a predicted concentration. The predicted concentrations of clozapine and N-desmethylclozapine were then compared with the observed concentrations in the form of a ratio: predicted-to-observed concentration ratio (Cpred/Cobs). The coefficient of variation of the Cpred/Cobs ratios was taken as a measure of intraindividual variation.
  
  
  
  A total of 723 plasma levels from 61 patients were included in this analysis. The coefficient of variation of Cpred/Cobs ratios for clozapine and N-desmethylclozapine were 29.8% (SD = 17.2%) and 27.4% (SD = 16.4%), respectively. Though values were higher, smoking did not have a significant effect on coefficients of variation of clozapine (33.5% vs 26.3%, P = .184) or N-desmethylclozapine (30.7% vs 24.2%, P = .100).
  
  
  
  Clinicians need to be aware of intraindividual variability and not assume that plasma levels are static. If plasma levels are used to guide dosing of clozapine, serial measurements rather than a single level might be necessary to make an informed clinical decision. The clinical implications of intraindividual variability in plasma clozapine levels need further study.
authors.affiliation: Schizophrenia Division, Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario M5T 1R8, Canada jimmy_lee@imh.com.sg.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Bies
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Gagan
authors.initials: G
authors.lastname: Fervaha
authors.forename: Amaal
authors.initials: A
authors.lastname: Bhaloo
authors.forename: Valerie
authors.initials: V
authors.lastname: Powell
authors.forename: Gary
authors.initials: G
authors.lastname: Remington
mesh_terms: D001499:Bayes Theorem; D003024:Clozapine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D057285:Precision Medicine; D012907:Smoking / Q000097:blood
chemical_list: C058272:norclozapine; D003024:Clozapine