Document Type
Journal Article
Publication Date
8-7-2017
Journal
Clinical Pharmacokinetics
Volume
57
Issue
5
Inclusive Pages
601-611
DOI
10.1007/s40262-017-0579-4
Abstract
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 (WTfor age and length) and excess body weight (WTexcess = TBW − WTfor 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 WTexcess, and for which a so-called ‘excess weight’ model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess 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 WTexcess 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.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
APA Citation
van Rongen, A., Brill, M., Vaughns, J., Välitalo, P., van Dongen, E., van Ramshorst, B., Barrett, J., van den Anker, J., & Knibbe, C. (2017). Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults.. Clinical Pharmacokinetics, 57 (5). http://dx.doi.org/10.1007/s40262-017-0579-4
Peer Reviewed
1
Open Access
1
Included in
Anesthesia and Analgesia Commons, Anesthesiology Commons, Critical Care Commons, Pharmacy and Pharmaceutical Sciences Commons
Comments
Reproduced with permission of Springer International Publishing. Clinical Pharmacokinetics