Physiologically Based Pharmacokinetic Modeling of Metformin in Children and Adolescents With Obesity.
Physiologically Based Pharmacokinetic Modeling of Metformin in Children and Adolescents With Obesity.
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DOI：
10.1002/jcph.2034
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发表时间：
2022-08
影响因子：
2.9
通讯作者：
Gonzalez, Daniel
中科院分区：
文献类型：
--
作者：
Ford, Jennifer Lynn;Gerhart, Jacqueline G.;Edginton, Andrea N.;Yanovski, Jack A.;Hon, Yuen Yi;Gonzalez, Daniel
在美国，儿童肥胖率持续上升，二甲双胍的超说明书使用也随之而来。此前尚未使用机制框架研究年龄和肥胖对药物的处置和暴露的影响。在这里，二甲双胍的成人生理学药代动力学 (PBPK) 模型被扩展到不肥胖、超重/肥胖和严重肥胖的儿科人群；在模型评估过程中，利用了已发布的肥胖儿童和青少年的虚拟人群。当在 10 – 18 岁年龄组中模拟儿科模型时，肥胖和重度肥胖患者服用 1,000 毫克二甲双胍后的口腔清除率 (CL/F) 高于未超重和超重组 (约 1000 mL/min) (约 1200 mL/min)。此外，肥胖和重度肥胖的年龄较大儿童和青少年的模拟 AUC 与具有相似剂量暴露关系的成人相当。总体而言，使用儿科 PBPK 模型进行的模拟支持对年龄较大的肥胖儿童和青少年使用成人剂量的二甲双胍。此外，肥胖儿童和青少年的虚拟人群提供了一个宝贵的工具，可以促进儿科 PBPK 模型的开发，以研究肥胖人群，进而为这一特殊人群的药物标签提供信息。
Childhood obesity continues to rise in the United States, and with it the off-label use of metformin for weight loss. The influence of age and obesity on the drug’s disposition and exposure has not previously been studied using a mechanistic framework. Here, an adult physiologically based pharmacokinetic (PBPK) model of metformin was scaled to pediatric populations without obesity, with overweight / obesity, and with severe obesity; a published virtual population of children and adolescents with obesity was leveraged during model evaluation. When the pediatric model was simulated in groups 10 – 18 y of age, oral clearance (CL/F) following 1,000 mg of metformin was higher (~1200 mL/min) in those with obesity and severe obesity compared to the groups without and with overweight (~1000 mL/min). In addition, simulated AUC in older children and adolescents with obesity and severe obesity was comparable to that in adults with a similar dose-exposure relationship. Overall, simulations using the pediatric PBPK model support the use of adult doses of metformin in older children and adolescents with obesity. Moreover, the virtual population of children and adolescents with obesity offers a valuable tool to facilitate development of pediatric PBPK models for studying populations with obesity and, in turn, contribute information to inform drug labeling in this special population.
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影响因子：
5.4
作者：
Zisowsky J;Krause A;Dingemanse J
通讯作者：
Dingemanse J
影响因子：
26.1
作者：
Momper, Jeremiah D.;Mulugeta, Yeruk;Burckart, Gilbert J.
通讯作者：
Burckart, Gilbert J.
影响因子：
4.5
作者：
Sanchez-Infantes, David;Diaz, Marta;Ibanez, Lourdes
通讯作者：
Ibanez, Lourdes
影响因子：
37.8
作者：
Steinberger, J;Daniels, SR
通讯作者：
Daniels, SR
DOI：
10.2147/dmso.s95299
发表时间：
2017
期刊：
Diabetes, metabolic syndrome and obesity : targets and therapy
影响因子：
--
作者：
Hendricks EJ
通讯作者：
Hendricks EJ