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
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
Duke Clinical Research Institute, Durham, North Carolina, USA.
Clin Transl Sci. 2025 May;18(5):e70247. doi: 10.1111/cts.70247.
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.
儿童是一个治疗起来极为复杂且具有多样性的群体，包括药物剂量暴露方面的个体差异。咪达唑仑已被用于住院儿童的镇静治疗，无论是有适应证还是超适应证使用；然而，影响该群体中观察到的清除率个体间变异性（IIV）的因素尚未完全明确，可能导致药物暴露严重不足或过量。肥胖被认为是对青少年咪达唑仑有显著影响的因素，这可能会改变药物暴露情况。本研究的目的是使用两种建模策略来评估肥胖和非肥胖儿童中咪达唑仑的剂量暴露情况。群体药代动力学建模评估肥胖状态指标是否能解释部分观察到的咪达唑仑清除率的个体间变异性。总共从93名参与研究的儿童（其中许多患有肥胖症）中收集了164份血浆浓度数据。协变量建模未发现除体重之外对清除率有影响的任何因素。模型的个体间变异性与先前在危重症儿童模型中观察到的情况相似（变异系数为175%），同时存在相当大的无法解释的残余变异性（50.4%）。然后，将先前发表的肥胖儿童虚拟群体纳入开源PK - Sim软件中现有的咪达唑仑生理药代动力学模型。对46名参与者的一个子集进行的给药模拟显示，与非肥胖儿童相比，肥胖儿童的预测结果略有高估。两个模型均预测，给予相同基于体重的剂量时，肥胖儿童的暴露量会有轻微（<20%）增加。本研究证明了使用群体药代动力学结合生理药代动力学建模来比较肥胖和非肥胖儿童的模拟暴露情况。
