Document Type
Article
Publication Date
5-13-2025
Abstract
Children represent a highly complex and variable population for treatment, including interindividual differences in drug dose-exposure. Midazolam has been used as a sedative for hospitalized children on- and off-label; however, factors affecting interindividual variability (IIV) in observed clearance for this population are not fully understood and can result in extreme under- or overexposure. Obesity has been described as a significant influence on midazolam in adolescents, which could potentially alter drug exposure. The goal of this study was to use two modeling strategies to evaluate dose-exposure of midazolam in children with and without obesity. Population pharmacokinetic modeling assessed whether measures of obesity status would explain some of the observed IIV for midazolam clearance. In all, 164 plasma concentrations were collected from 93 participating children, many with obesity. Covariate modeling did not identify any factors influential to clearance beyond body weight. Model IIV was similar to that observed in previous models of critically ill children (coefficient of variation, 175%) along with considerable residual unexplained variability (50.4%). Then, a previously published virtual population of children with obesity was incorporated into an existing physiologically based pharmacokinetic model of midazolam in the open-source PK-Sim software. Dosing simulations for a subset of 46 participants demonstrated minor overpredictions in children with obesity compared to those without. Both models predicted a minor (< 20%) increase in exposure for children with obesity given the same weight-based dose. This research demonstrates the use of population pharmacokinetics combined with physiologically based pharmacokinetic modeling to compare simulated exposures in children with and without obesity.
Recommended Citation
McCann, Sean; Helfer, Victória E.; Balevic, Stephen J.; Muller, William J.; van den Anker, John N.; Al-Uzri, Amira; Meyer, Marisa L.; Anderson, Sarah G.; Turdalieva, Sitora; Edginton, Andrea N.; Gonzalez, Daniel; and Best Pharmaceuticals for Children Act Pediatric Trials Network Steering Committee, "Physiologically Based and Population Pharmacokinetic Modeling of Midazolam in Children With Obesity Using Real-World Data" (2025). Department of Pediatrics Faculty Papers. Paper 174.
https://jdc.jefferson.edu/pedsfp/174
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
40364501
Language
English
Included in
Chemicals and Drugs Commons, Nutritional and Metabolic Diseases Commons, Pediatrics Commons
Comments
This article is the author’s final published version in Clinical and Translational Science, Volume 18, Issue 5, May 2025, Article number e70247.
The published version is available at https://doi.org/10.1111/cts.70247. Copyright © 2025 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.