Development and Evaluation of a Virtual Population of Children with Obesity for Physiologically Based Pharmacokinetic Modeling.
Development and Evaluation of a Virtual Population of Children with Obesity for Physiologically Based Pharmacokinetic Modeling.
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DOI：
10.1007/s40262-021-01072-4
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发表时间：
2022-03
影响因子：
4.5
通讯作者：
Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee
中科院分区：
文献类型：
--
作者：
Gerhart JG;Carreño FO;Edginton AN;Sinha J;Perrin EM;Kumar KR;Rikhi A;Hornik CP;Harris V;Ganguly S;Cohen-Wolkowiez M;Gonzalez D;Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee
虽然现在美国有五分之一的儿童肥胖，超过四分之三的儿童在儿童时期接受至少一种药物，但对这一脆弱患者群体的剂量指导有限。基于生理学的药代动力学建模可以通过纳入儿童中已知的肥胖相关生理变化来弥合理解药代动力学（包括药物分布和清除率）如何随肥胖而变化的差距。本研究的目的是开发一个肥胖儿童的虚拟人群，以实现基于生理学的药代动力学建模，然后将新的虚拟人群与先前开发的克林霉素和甲氧苄啶/磺胺甲恶唑模型结合使用，以更好地了解这些药物在肥胖儿童中的剂量。为了实现基于生理学的药代动力学建模，使用全国调查、电子健康记录和临床试验数据以及从文献中提取的数据开发了肥胖儿童的虚拟人群。虚拟人群解释了与药代动力学相关的生理学中与肥胖相关的关键变化，包括体型、身体组成、器官大小和血流量、血浆蛋白浓度和肾小球滤过率增加。然后，虚拟人群用于预测克林霉素和甲氧苄啶/磺胺甲恶唑在肥胖儿童中的药代动力学，使用以前开发的基于生理学的药代动力学模型。模型模拟预测观察到的浓度，克林霉素，甲氧苄啶，磺胺甲恶唑，分别与1.09，1.24和1.53的总体平均误差倍。与非肥胖儿童相比，肥胖儿童的克林霉素和甲氧苄啶/磺胺甲恶唑体重标准化清除率和分布容积降低，推荐的儿科体重给药方案的绝对剂量更高。模型模拟支持目前推荐的肥胖儿童克林霉素和甲氧苄啶/磺胺甲恶唑基于体重的剂量，因为尽管清除率和分布容积发生了这些变化，但它们仍达到了目标暴露量。在线版本包含补充材料，可通过10.1007/s40262-021-01072-4获得。
While one in five children in the USA are now obese, and more than three-quarters receive at least one drug during childhood, there is limited dosing guidance for this vulnerable patient population. Physiologically based pharmacokinetic modeling can bridge the gap in the understanding of how pharmacokinetics, including drug distribution and clearance, changes with obesity by incorporating known obesity-related physiological changes in children. The objective of this study was to develop a virtual population of children with obesity to enable physiologically based pharmacokinetic modeling, then use the novel virtual population in conjunction with previously developed models of clindamycin and trimethoprim/sulfamethoxazole to better understand dosing of these drugs in children with obesity. To enable physiologically based pharmacokinetic modeling, a virtual population of children with obesity was developed using national survey, electronic health record, and clinical trial data, as well as data extracted from the literature. The virtual population accounts for key obesity-related changes in physiology relevant to pharmacokinetics, including increased body size, body composition, organ size and blood flow, plasma protein concentrations, and glomerular filtration rate. The virtual population was then used to predict the pharmacokinetics of clindamycin and trimethoprim/sulfamethoxazole in children with obesity using previously developed physiologically based pharmacokinetic models. Model simulations predicted observed concentrations well, with an overall average fold error of 1.09, 1.24, and 1.53 for clindamycin, trimethoprim, and sulfamethoxazole, respectively. Relative to children without obesity, children with obesity experienced decreased clindamycin and trimethoprim/sulfamethoxazole weight-normalized clearance and volume of distribution, and higher absolute doses under recommended pediatric weight-based dosing regimens. Model simulations support current recommended weight-based dosing in children with obesity for clindamycin and trimethoprim/sulfamethoxazole, as they met target exposure despite these changes in clearance and volume of distribution. The online version contains supplementary material available at 10.1007/s40262-021-01072-4.
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影响因子：
3.5
作者：
Kuepfer, L;Niederalt, C;Wendl, T;Schlender, J-F;Willmann, S;Lippert, J;Block, M;Eissing, T;Teutonico, D
通讯作者：
Teutonico, D
DOI：
10.1111/cts.12896
发表时间：
2021-03
期刊：
Clinical and translational science
影响因子：
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作者：
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影响因子：
3.4
作者：
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通讯作者：
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影响因子：
3
作者：
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通讯作者：
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影响因子：
6.9
作者：
Hwaung, Phoenix;Bosy-Westphal, Anja;Heymsfield, Steven B.
通讯作者：
Heymsfield, Steven B.