Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
CPT Pharmacometrics Syst Pharmacol. 2022 Jun;11(6):778-791. doi: 10.1002/psp4.12793. Epub 2022 May 2.
Obesity is an increasingly alarming public health threat, with nearly 20% of children classified as obese in the United States today. Children with obesity are commonly prescribed the opioids fentanyl and methadone, and accurate dosing is critical to reducing the risk of serious adverse events associated with overexposure. However, pharmacokinetic studies in children with obesity are challenging to conduct, so there is limited information to guide fentanyl and methadone dosing in these children. To address this clinical knowledge gap, physiologically-based pharmacokinetic models of fentanyl and methadone were developed in adults and scaled to children with and without obesity to explore the interplay of obesity, age, and pharmacogenomics. These models included key obesity-induced changes in physiology and pharmacogenomic effects. Model predictions captured observed concentrations in children with obesity well, with an overall average fold error of 0.72 and 1.08 for fentanyl and methadone, respectively. Model simulations support a reduced fentanyl dose (1 vs. 2 μg/kg/h) starting at an earlier age (6 years) in virtual children with obesity, highlighting the importance of considering both age and obesity status when selecting an infusion rate most likely to achieve steady-state concentrations within the target range. Methadone dosing simulations highlight the importance of considering genotype in addition to obesity status when possible, as cytochrome P450 (CYP)2B6*6/*6 virtual children with obesity required half the dose to match the exposure of wildtype children without obesity. This physiologically-based pharmacokinetic modeling approach can be applied to explore dosing of other critical drugs in children with obesity.
肥胖是一个日益严重的公共卫生威胁，如今美国近 20%的儿童被归类为肥胖。肥胖儿童通常会被开处芬太尼和美沙酮等阿片类药物，准确的剂量对于降低与过度暴露相关的严重不良事件的风险至关重要。然而，肥胖儿童的药代动力学研究很难进行，因此，关于这些儿童中芬太尼和美沙酮的剂量指导信息有限。为了解决这一临床知识空白，开发了芬太尼和美沙酮的成人生理药代动力学模型，并按比例缩小到肥胖和非肥胖儿童，以探讨肥胖、年龄和药物基因组学的相互作用。这些模型包括肥胖引起的生理学和药物基因组学效应的关键变化。模型预测很好地捕捉了肥胖儿童的观察到的浓度，芬太尼和美沙酮的总体平均折叠误差分别为 0.72 和 1.08。模型模拟支持在肥胖虚拟儿童中较早开始（6 岁）使用较低的芬太尼剂量（1 比 2μg/kg/h），这突出了在选择最有可能达到目标范围内稳态浓度的输注率时考虑年龄和肥胖状态的重要性。美沙酮剂量模拟强调了在可能的情况下除了肥胖状态外还要考虑基因型的重要性，因为 CYP2B6*6/*6 肥胖虚拟儿童需要一半的剂量才能与非肥胖野生型儿童的暴露量相匹配。这种基于生理学的药代动力学建模方法可用于探索肥胖儿童中其他关键药物的剂量。
