Characterizing Pharmacokinetics in Children With Obesity-Physiological, Drug, Patient, and Methodological Considerations.
Characterizing Pharmacokinetics in Children With Obesity-Physiological, Drug, Patient, and Methodological Considerations.
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DOI：
10.3389/fphar.2022.818726
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发表时间：
2022
影响因子：
5.6
通讯作者：
Gonzalez D
中科院分区：
文献类型：
--
作者：
Gerhart JG;Balevic S;Sinha J;Perrin EM;Wang J;Edginton AN;Gonzalez D
儿童肥胖是一个令人担忧的公共卫生问题。在过去的30年里，儿童肥胖率翻了两番，目前近20%的美国儿童和全球9%的儿童被归类为肥胖。决定药物暴露（从而决定剂量）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。肥胖相关的生理变化，如组织体积和灌注增加、血蛋白浓度和组织组成的改变，可以极大地影响药物的分布体积，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，如肝脏酶活性和肾小球滤过率的改变，可以影响药物消除的速度，这可能需要调整维持给药率。虽然以体重为基础给药（即mg/kg）在儿科中普遍采用，但为肥胖儿童选择正确的体型度量（如总体重、瘦体重、体表面积等）给药仍然是一个问题。为了解决这一差距，肥胖相关的生理变化（如器官大小、组成和功能的改变）和药物特异性（如亲脂性和消除途径）之间的相互作用需要在定量框架中进行表征。此外，还应考虑方法学方面的考虑，如足够的样本量和最佳抽样方案，以确保准确和精确的自上而下的协变量选择，特别是在设计儿科药物开发的机会性研究时。影响剂量的其他因素，包括现有的剂量建议、目标治疗范围、剂量上限和配方限制，在为肥胖儿童进行剂量选择时也需要考虑。弥补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）、机会性临床数据和现实世界数据。在这篇综述中，强调和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生理学、药物参数、患者因素和方法等关键因素。未来的研究将需要利用这些建模机会来更好地描述随着儿童肥胖流行病的继续，肥胖儿童的药物暴露。
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.
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影响因子：
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作者：
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DOI：
10.1186/s13223-017-0220-y
发表时间：
2017
期刊：
Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology
影响因子：
--
作者：
Ameratunga R
通讯作者：
Ameratunga R