Body mass index as a determinant of clozapine plasma concentrations: A pharmacokinetic-based hypothesis.

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, 20-30 kg/m, =266), a group with high body mass index (CLZ, body mass index ⩾30 kg/m, =162) and with low body mass index values (CLZ, body mass index <20 kg/m, =27). Comparisons of plasma and dose-adjusted plasma concentrations (C/D) of clozapine were based on the Spearman's correlation (s), Kruskal Wallis and Mann-Whitney-U tests. For percentages we used the Pearson chi-square test (χ). 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 and CLZ compared to CLZ (=0.001 for χ test). Plasma and C/D values were positively associated with body mass index (s=0.108, =0.022 and s=0.156, =0.001 respectively). Intergroup differences were observed for plasma and dose-adjusted concentrations of clozapine (=0.031 and =0.029 for Kruskal Wallis respectively): post-hoc pairwise comparisons showed higher plasma concentrations and C/D of clozapine in CLZ compared to CLZ (=0.014 and =0.007 respectively for Mann-Whitney U-test), by mean 21 and 18%, respectively. Differences for C/D values remained after accounting for sex (=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.