DDMODEL00000250: Midazolam PK in obese adults and adolescents

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Short description:
in addition to the final model code, code is also provided for the "access weight model" in the publication
Original code
  • Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults.
  • van Rongen A, Brill MJE, Vaughns JD, Välitalo PAJ, van Dongen EPA, van Ramshorst B, Barrett JS, van den Anker JN, Knibbe CAJ
  • Clinical pharmacokinetics, 8/2017
  • Department of Clinical Pharmacy, Reinier de Graaf Hospital, Delft, The Netherlands.
  • 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.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.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.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.
Catherijne Knibbe
Context of model development: Dose & Schedule Selection and Label Recommendation;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: The clearance of cytochrome P450 (CYP) 3A substrates is believed to be reduced in children, in patients with inflammation and obese patients. This study investigates the influence of combinations of these variables by quantifying the clearance of midazolam in obese adolescents and morbidly obese adults.;
Modelling task in scope: estimation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: Metabolism;
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  • Model owner: Catherijne Knibbe
  • Submitted: Oct 9, 2017 1:16:52 PM
  • Last Modified: Oct 9, 2017 1:16:52 PM
  • Version: 10 public model Download this version
    • Submitted on: Oct 9, 2017 1:16:52 PM
    • Submitted by: Catherijne Knibbe
    • With comment: Edited model metadata online.