Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-05

AUTHORS

Anne van Rongen, Margreke J. E. Brill, Janelle D. Vaughns, Pyry A. J. Välitalo, Eric P. A. van Dongen, Bert van Ramshorst, Jeffrey S. Barrett, Johannes N. van den Anker, Catherijne A. J. Knibbe

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. More... »

PAGES

601-611

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s40262-017-0579-4

    DOI

    http://dx.doi.org/10.1007/s40262-017-0579-4

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1091083894

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28785981


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