Quantifying intraindividual variations in plasma clozapine levels: A population pharmacokinetic approach

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.