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Published on: February 2, 2017
Physiologically Based and Population Pharmacokinetic Modeling of Midazolam in Children With Obesity Using Real-World
Sean McCann1, Victória E Helfer1, Stephen J Balevic2
1Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
Insights
This study examined midazolam (a sedative) dosing in children, finding obesity slightly increases drug exposure. Pharmacokinetic modeling showed weight-based dosing is key, with minimal differences between obese and non-obese children.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Computational Biology
Background:
- Interindividual variability in drug clearance complicates pediatric dosing.
- Midazolam is a common sedative in children, but its dose-exposure relationship is not fully understood.
- Obesity may significantly impact midazolam pharmacokinetics in children.
Purpose of the Study:
- To evaluate midazolam dose-exposure in children with and without obesity using two modeling strategies.
- To assess if obesity status explains interindividual variability in midazolam clearance.
- To compare simulated midazolam exposures in pediatric populations with and without obesity.
Main Methods:
- Population pharmacokinetic modeling using 164 plasma concentrations from 93 children.
- Covariate analysis to identify factors influencing midazolam clearance.
- Physiologically based pharmacokinetic (PBPK) modeling integrated with a virtual pediatric population with obesity using PK-Sim software.
Main Results:
- Covariate modeling identified body weight as the primary factor influencing midazolam clearance.
- Population pharmacokinetic model showed high interindividual variability (CV 175%) and residual variability (50.4%).
- Physiologically based pharmacokinetic modeling simulations predicted a minor (<20%) increase in midazolam exposure for children with obesity on weight-based doses.
Conclusions:
- Body weight is the main determinant of midazolam clearance in children.
- Obesity is associated with a minor increase in midazolam exposure when using weight-based dosing.
- Combined pharmacokinetic and PBPK modeling effectively compares simulated drug exposures in diverse pediatric populations.
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.
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