Physiologically-Based Pharmacokinetic Modeling to Guide Drug Dosing in Children with Obesity

摘要 肥胖症儿童经常在没有足够的剂量信息来解释体型和体重的情况下被开药 年龄。由于生理和身体成分的变化，肥胖儿童可能需要调整剂量，因为 以及药物清除器官功能的改变，这两者都会影响药物处置。 基于生理的药代动力学(PBPK)模型是结合了生理学的数学构造 儿童时期的身体成分也会发生变化。通过结合生理和身体成分的变化 有了药物的物理化学性质的信息，PBPK模型可以用来预测药物 肥胖儿童的倾向性和药物剂量的优化。这项提案将使用系统的方法来 开发和评估肥胖儿童的PBPK模型，这将为在这方面提供知情的药物剂量 弱势群体。我们挑选了12种处方给肥胖儿童的药物 生物制药药物处置分类系统(BDDCS)分类，这将使我们能够表征 肥胖对表现出不同物理化学和代谢特性的药物的影响。对于这12种药物， 从肥胖儿童收集的可用药代动力学(PK)数据将用于开发PBPK模型 其中包含了已知的肥胖引起的生理变化。然后我们将开发PBPK模型来预测 4种额外药物对肥胖的影响(每个BDDCS类别一种)，并前瞻性收集药物浓度 用于评估这些模型的数据。开发的模型将用于指导肥胖儿童的剂量。一次 建立后，这一方法将应用于其他常用药物，这将通知所有药物的剂量 在美国用于肥胖儿童或1270万儿童和青少年。

ABSTRACT Children with obesity are often prescribed drugs without adequate dosing information to account for size and age. Dose adjustments in obese children may be required due to physiologic and body composition changes, as well as alterations in the function of drug eliminating organs, both of which can affect drug disposition. Physiologically-based pharmacokinetic (PBPK) models are mathematical constructs that incorporate physiologic and body composition changes during childhood. By incorporating physiologic and body composition changes with information about the drug's physicochemical properties, PBPK models can be used to predict drug disposition and optimize drug dosing in children with obesity. This proposal will use a systematic approach to developing and evaluating PBPK models in children with obesity, which will provide informed drug dosing in this vulnerable population. We have selected 12 drugs prescribed to children with obesity across the 4 Biopharmaceutical Drug Disposition Classification System (BDDCS) classes, which will allow us to characterize the effect of obesity for drugs that exhibit varying physicochemical and metabolic properties. For these 12 drugs, available pharmacokinetic (PK) data collected from children with obesity will be used to develop PBPK models that incorporate known obesity-induced physiological changes. Then we will develop PBPK models to predict the effect of obesity for 4 additional drugs (one per BDDCS class), and prospectively collect drug concentration data to evaluate these models. The developed models will be used to guide dosing in children with obesity. Once established, this approach will be applied to other commonly used drugs, which will inform dosing of all drugs used in children with obesity or 12.7 million children and adolescents in the U.S.