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Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults
St Antonius Hosp, Dept Clin Pharm, Koekoekslaan 1, NL-3435 CM Nieuwegein, Netherlands;Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands;Reinier de Graaf Hosp, Dept Clin Pharm, Delft, Netherlands.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. St Antonius Hosp, Dept Clin Pharm, Koekoekslaan 1, NL-3435 CM Nieuwegein, Netherlands;Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands.
Childrens Natl Hlth Syst, Div Anesthesiol & Pain Med, Washington, DC USA;Childrens Natl Hlth Syst, Div Clin Pharmacol, Washington, DC USA.
Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands.
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2018 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 57, no 5, p. 601-611Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2018. Vol. 57, no 5, p. 601-611
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-354103DOI: 10.1007/s40262-017-0579-4ISI: 000430321100006PubMedID: 28785981OAI: oai:DiVA.org:uu-354103DiVA, id: diva2:1220923
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-19Bibliographically approved

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