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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：
9981482
负责人：
Daniel Gonzalez
金额：
$ 51.45万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981482
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.

摘要患有肥胖症的儿童经常被处方药物，而没有足够的剂量信息来说明尺寸和剂量。年龄由于生理和身体组成的变化，可能需要对肥胖儿童进行剂量调整，以及药物排泄器官功能的改变，这两者都可以影响药物处置。基于生理学的药代动力学（PBPK）模型是结合生理学特征的数学构造。和身体组成的变化。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药物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，这将为肥胖儿童提供知情的药物剂量。弱势群体。我们选择了12种药物，在4个肥胖儿童处方生物制药药物处置分类系统（BDDCS）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，从肥胖儿童中收集的可用药代动力学（PK）数据将用于开发PBPK模型包含已知的肥胖引起的生理变化。然后我们将开发PBPK模型来预测另外4种药物（每种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给药。一旦一旦确定，这种方法将适用于其他常用药物，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。