Patterns of clozapine pharmacokinetics in patient subgroups with different body mass index

 

Introduction Obesity is associated with changes in pharmacokinetics such as alterations in cytochrome P450 activity or regional blood flow, which may affect the disposition of several medications. However, the impact of obesity on the pharmacokinetics of antipsychotics are poorly understood. The objective of this study was to investigate the impact of body mass index (BMI) on clozapine pharmacokinetics using therapeutic drug monitoring (TDM).

Methods A large TDM dataset with clozapine plasma concentrations was analyzed. Three patient subgroups were compared: a control group (CLZ0, 30 kg/m² BMI 20 kg/m², n = 266), a group with high- (CLZOB, BMI ≥ 30 kg/m², n = 162) and a group with low-BMI (CLZLOW, < 20 kg/m², n = 29). Comparisons were performed with the non-parametric Kruskal Wallis and the Mann-Whitney-U test (M – W-U) with a significance level of 0.05. Percentages were compared using the Pearson chi-square test (χ²) and effects of confounders were assessed using analysis of covariance (ANCOVA).

Results Group differences regarding demographic parameters were significant only for sex distribution with more females in CLZLOW and CLZOB compared to CLZ0 (p = 0.002 for χ²). The pairwise comparisons showed significant differences for clozapine plasma concentrations and plasma concentrations corrected for the daily dose (C/D) of CLZ in CLZOB compared to CLZ0 (p = 0.014 and p = 0.007 respectively, M – W-U). After applying ANCOVA to control for the effects of sex, only differences for C/D values remained significant (p = 0.02), being higher in the CLZOB.

Conclusion Complex pathways including lower clearance, increased deposits of CLZ in fat tissue as well as changes in hepatic enzyme activity could lead to increased bioavailability of CLZ in obese patients.