Gerhart Jacqueline G, Balevic Stephen, Sinha Jaydeep, Perrin Eliana M, Wang Jian, Edginton Andrea N, Gonzalez Daniel
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
Front Pharmacol. 2022 Mar 10;13:818726. doi: 10.3389/fphar.2022.818726. eCollection 2022.
Childhood obesity is an alarming public health problem. The pediatric obesity rate has quadrupled in the past 30 years, and currently nearly 20% of United States children and 9% of children worldwide are classified as obese. Drug distribution and elimination processes, which determine drug exposure (and thus dosing), can vary significantly between patients with and without obesity. Obesity-related physiological changes, such as increased tissue volume and perfusion, altered blood protein concentrations, and tissue composition can greatly affect a drug's volume of distribution, which might necessitate adjustment in loading doses. Obesity-related changes in the drug eliminating organs, such as altered enzyme activity in the liver and glomerular filtration rate, can affect the rate of drug elimination, which may warrant an adjustment in the maintenance dosing rate. Although weight-based dosing (i.e., in mg/kg) is commonly practiced in pediatrics, choice of the right body size metric (e.g., total body weight, lean body weight, body surface area, etc.) for dosing children with obesity still remains a question. To address this gap, the interplay between obesity-related physiological changes (e.g., altered organ size, composition, and function), and drug-specific properties (e.g., lipophilicity and elimination pathway) needs to be characterized in a quantitative framework. Additionally, methodological considerations, such as adequate sample size and optimal sampling scheme, should also be considered to ensure accurate and precise top-down covariate selection, particularly when designing opportunistic studies in pediatric drug development. Further factors affecting dosing, including existing dosing recommendations, target therapeutic ranges, dose capping, and formulations constraints, are also important to consider when undergoing dose selection for children with obesity. Opportunities to bridge the dosing knowledge gap in children with obesity include modeling and simulating techniques (i.e., population pharmacokinetic and physiologically-based pharmacokinetic [PBPK] modeling), opportunistic clinical data, and real world data. In this review, key considerations related to physiology, drug parameters, patient factors, and methodology that need to be accounted for while studying the influence of obesity on pharmacokinetics in children are highlighted and discussed. Future studies will need to leverage these modeling opportunities to better describe drug exposure in children with obesity as the childhood obesity epidemic continues.
儿童肥胖是一个令人担忧的公共卫生问题。在过去30年里，儿科肥胖率增长了两倍，目前美国近20%的儿童以及全球9%的儿童被归类为肥胖。决定药物暴露量（进而决定给药剂量）的药物分布和消除过程，在肥胖和非肥胖患者之间可能存在显著差异。与肥胖相关的生理变化，如组织体积和灌注增加、血液蛋白浓度改变以及组织成分变化，会极大地影响药物的分布容积，这可能需要调整负荷剂量。与肥胖相关的药物消除器官的变化，如肝脏中酶活性改变和肾小球滤过率变化，会影响药物消除速率，这可能需要调整维持给药速率。尽管儿科通常采用基于体重的给药方式（即每千克体重多少毫克），但对于肥胖儿童给药时选择合适的身体尺寸指标（如总体重、瘦体重、体表面积等）仍然是一个问题。为了弥补这一差距，需要在一个定量框架中描述与肥胖相关的生理变化（如器官大小、组成和功能改变）与药物特定性质（如亲脂性和消除途径）之间的相互作用。此外，还应考虑方法学因素，如足够的样本量和最佳采样方案，以确保准确、精确地自上而下选择协变量，特别是在儿科药物开发中设计机会性研究时。在为肥胖儿童进行剂量选择时，还需要考虑影响给药的其他因素，包括现有的给药建议、目标治疗范围、剂量上限和制剂限制。弥合肥胖儿童给药知识差距的机会包括建模和模拟技术（即群体药代动力学和基于生理的药代动力学[PBPK]建模）、机会性临床数据和真实世界数据。在这篇综述中，强调并讨论了在研究肥胖对儿童药代动力学的影响时需要考虑的与生理学、药物参数、患者因素和方法学相关的关键因素。随着儿童肥胖流行的持续，未来的研究需要利用这些建模机会来更好地描述肥胖儿童的药物暴露情况。
