Quantifying intraindividual variations in plasma clozapine levels

A population pharmacokinetic approach

Jimmy Lee, Robert Bies, Hiroyoshi Takeuchi, Gagan Fervaha, Amaal Bhaloo, Valerie Powell, Gary Remington

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Objective: 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. Methods: 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. Results: 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). Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)681-687
Number of pages7
JournalJournal of Clinical Psychiatry
Volume77
Issue number5
DOIs
StatePublished - May 1 2016

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norclozapine
Clozapine
Pharmacokinetics
Population
Smoking
Drug Monitoring

ASJC Scopus subject areas

  • Psychiatry and Mental health

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Quantifying intraindividual variations in plasma clozapine levels : A population pharmacokinetic approach. / Lee, Jimmy; Bies, Robert; Takeuchi, Hiroyoshi; Fervaha, Gagan; Bhaloo, Amaal; Powell, Valerie; Remington, Gary.

In: Journal of Clinical Psychiatry, Vol. 77, No. 5, 01.05.2016, p. 681-687.

Research output: Contribution to journalArticle

Lee, Jimmy ; Bies, Robert ; Takeuchi, Hiroyoshi ; Fervaha, Gagan ; Bhaloo, Amaal ; Powell, Valerie ; Remington, Gary. / Quantifying intraindividual variations in plasma clozapine levels : A population pharmacokinetic approach. In: Journal of Clinical Psychiatry. 2016 ; Vol. 77, No. 5. pp. 681-687.
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abstract = "Objective: 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. Methods: 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. Results: 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). Conclusions: 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.",
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