midazolam, obesity, pediatrics, pharmacokinetics, physiologically based model, population model, Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270

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 (