Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults

BACKGROUND: The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults. METHODS: Data from 19 obese adolescents [102.7 kg (62–149.5 kg)] and 20 morbidly obese adults [144 kg (112–186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WT(for age and length)) and excess body weight (WT(excess) = TBW − WT(for age and length)) was evaluated. RESULTS: The population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WT(excess), and for which a so-called ‘excess weight’ model scaling WT(for age and length) to the power of 0.75 and a separate function for WT(excess) was proposed. DISCUSSION: We hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WT(excess) is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40262-017-0579-4) contains supplementary material, which is available to authorized users.