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

基于生理学的药代动力学模型指导肥胖儿童的药物剂量

基本信息

批准号：
10456301
负责人：
Julie Brumer Dumond
金额：
$ 21.49万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456301
关键词：
Adolescent Adult Affect Age Biological Products Body Composition Child Childhood Classification Clinical Pharmacology Clinical Trials Collection Data Doctor of Pharmacy Doctor of Philosophy Dose Drug Evaluation Drug Exposure Drug Kinetics Drug Prescriptions Drug usage Enrollment Environment Evaluation Exhibits Goals Infrastructure Knowledge Metabolic Modeling National Institute of Child Health and Human Development Obesity Organ Overweight Patients Pharmaceutical Preparations Physiological Physiology Population Principal Investigator Property Public Health Recommendation Recording of previous events Reporting Research Research Personnel Sampling System Training Treatment Failure Vulnerable Populations appropriate dose base dose information drug disposition mathematical model member obesity in children patient population pediatric drug development pharmacokinetic model prospective skills tool virtual

项目摘要

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.

抽象的肥胖儿童经常在没有足够的剂量信息来考虑体型和体重的情况下开出药物。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，因为以及药物消除器官功能的改变，两者都会影响药物的处置。基于生理的药代动力学 (PBPK) 模型是结合了生理学的数学结构以及童年时期身体成分的变化。通过结合生理和身体成分的变化有了有关药物理化性质的信息，PBPK 模型可用于预测药物肥胖儿童的处置和优化药物剂量。该提案将采用系统方法开发和评估肥胖儿童的 PBPK 模型，这将为该领域提供明智的药物剂量弱势群体。我们在 4 个国家中选择了 12 种针对肥胖儿童的药物生物制药药物处置分类系统 (BDCS) 类别，这将使我们能够表征肥胖对表现出不同理化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 模型其中包括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 种其他药物（每个 BDDCS 类别一种）对肥胖的影响，并前瞻性收集药物浓度数据来评估这些模型。开发的模型将用于指导肥胖儿童的用药剂量。一次确定后，该方法将应用于其他常用药物，这将告知所有药物的剂量用于肥胖儿童或美国 1270 万儿童和青少年