Body mass index as a determinant of clozapine plasma concentrations: A pharmacokinetic-based hypothesis
M. I. Kuzin, Ekkehard Haen, Christoph Hiemke, Benjamin Bochon, Karolina Bochon, Gerhard Gründer, Michael Paulzen, Georgios Schoretsanitis
Abstract
Background: Knowledge regarding the impact of body composition measures on pharmacokinetics of antipsychotics is limited. Aims: Our aim was to investigate the impact of body weight and body mass index on clozapine pharmacokinetics using a therapeutic drug monitoring database. Methods: A large therapeutic drug monitoring dataset of clozapine plasma concentrations considering three patient subgroups was analysed: a control group (CLZ 0 , 20–30 kg/m 2 , n=266), a group with high body mass index (CLZ high , body mass index ⩾30 kg/m 2 , n=162) and with low body mass index values (CLZ low , body mass index <20 kg/m 2 , n=27). Comparisons of plasma and dose-adjusted plasma concentrations (C/D) of clozapine were based on the Spearman’s correlation ( rs), Kruskal Wallis and Mann-Whitney-U tests. For percentages we used the Pearson chi-square test (χ 2 ). To assess effects of confounders we used bootstrapping analysis of covariates. Results/outcomes: Regarding demographic characteristics, groups differed only for sex percentage with more females than males in CLZ low and CLZ high compared to CLZ 0 ( p=0.001 for χ 2 test). Plasma and C/D values were positively associated with body mass index ( rs=0.108, p=0.022 and rs=0.156, p=0.001 respectively). Intergroup differences were observed for plasma and dose-adjusted concentrations of clozapine ( p=0.031 and p=0.029 for Kruskal Wallis respectively): post-hoc pairwise comparisons showed higher plasma concentrations and C/D of clozapine in CLZ high compared to CLZ 0 ( p=0.014 and p=0.007 respectively for Mann-Whitney U-test), by mean 21 and 18%, respectively. Differences for C/D values remained after accounting for sex ( p=0.02). Conclusions/interpretation: In obese patients, bioavailability, distribution or elimination of clozapine may be altered due to increased clozapine deposits in fat tissue and hepatic enzyme activity changes.