Use of Physiologically-Based PK/PD Models to Streamline Drug Approvals

使用基于生理学的 PK/PD 模型简化药物审批

基本信息

批准号：
8868524
负责人：
Daniel Gonzalez
金额：
$ 13.02万
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：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8868524
关键词：
Accounting Adult Affect Antibiotic Resistance Antibiotics Applications Grants Bacteria Bacterial Pneumonia Child Childhood Clinical Clinical Pharmacology Clinical Research Clinical Trials Clinical Trials Design Collaborations Communicable Diseases Communities Data Development Dose Drug Approval Drug Exposure Drug Kinetics Drug Transport Drug usage Environment FDA approved Faculty Fellowship Funding Future Goals Growth Infant Infection Knowledge Lead Liquid substance Liver Macrolide Antibiotics Macrolides Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Modeling National Institute of Child Health and Human Development North Carolina Pediatrics Pharmaceutical Preparations Pharmacodynamics Physiological Physiology Plasma Population Postdoctoral Fellow Premature Infant Public Health Publications Recording of previous events Research Research Infrastructure Research Personnel Resistance Sampling Secure Site Time Training Training Programs United States National Institutes of Health Universities Validation authority bacterial resistance base career career development design drug development experience innovation model development models and simulation novel novel strategies pharmacodynamic model phase 3 study professor programs prospective public health relevance research and development skills tool

项目摘要

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development Award proposal will provide the ideal environment, expert mentorship, and practical and didactic training designed to facilitate Dr. Daniel Gonzalez's development as an independent clinical researcher. Dr. Gonzalez's overarching career goal is to advance public health by integrating mechanistic modeling and physiology concepts to promote safe and effective use of medications in children. Invasive infections due to antibiotic resistant bacteria are common and deadly. Unfortunately, in the last 10 years only 3 new antibiotics have been approved by the FDA in adults and none in children. Furthermore, once adult approval is obtained, often there is a substantial delay before an antibiotic is indicated for use in children. Innovative tools designed to expedite pediatric approval of novel antibiotics are needed. Physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) models are mathematical constructs that incorporate physiologic changes from childhood to adulthood. By incorporating these physiologic changes, PBPK/PD models can be used to design pediatric clinical trials using adult data, and, thus, reduce the time to antibiotic approval in children. However, PBPK/PD models have not been applied consistently in drug development largely due to a lack of prospective model validation. In this proposal Dr. Gonzalez will evaluate a platform to systematically develop and prospectively validate PBPK/PD models in adults and children for a novel antibiotic in development. He hypothesizes that the developed PBPK/PD models will provide a mechanistic understanding of the factors affecting drug exposure at the site of infection for a new antibiotic, aid in selection of optimal dosing in adults and children, and serv as a model for future antibiotic drug approvals. The candidate is a recent graduate of the UNC/Duke T32 Collaborative Clinical Pharmacology training program, through which he acquired training in pediatric clinical pharmacology. The candidate's short term goals for the K23 program are: 1) to acquire knowledge and skills in PBPK/PD modeling and simulation; 2) to develop the professional skills to successfully lead a clinical trial research team; and 3) to generate a critical mass of preliminary data and publications to support an R01 grant application important for Dr. Gonzalez's development as an independent clinical researcher. This proposal capitalizes on a long history of collaboration between Duke University and University of North Carolina at Chapel Hill as well as data already available to complete the proposed research. The mentorship team has a track record of successful mentorship of junior faculty and has internationally recognized expertise in pediatric clinical trials, clinical pharmacology, PBPK/PD modeling, and infectious diseases. Upon successful completion of this proposal, Dr. Gonzalez will have acquired the necessary skillset to pursue a lifelong career in promoting safe and effective use of drugs in children.

描述（由申请人提供）：这项以患者为导向的研究职业发展奖提案将提供理想的环境、专家指导以及实践和教学培训，旨在促进 Daniel Gonzalez 博士作为独立临床研究员的发展。目标是通过整合机械模型和生理学概念来促进公共健康，以促进儿童安全有效地使用药物。由抗生素耐药细菌引起的侵袭性感染是常见且致命的。不幸的是，在过去 10 年中，FDA 只批准了 3 种新抗生素用于成人治疗，而没有批准用于儿童治疗。此外，一旦获得成人批准，抗生素在儿童中使用的时间通常会很长。需要旨在加快儿科批准新型抗生素的创新工具基于生理学的药代动力学/药效学 (PBPK/PD) 模型是结合了从儿童到成年的生理变化的数学结构。使用成人数据设计儿科临床试验，从而缩短儿童抗生素批准的时间。然而，PBPK/PD 模型并未在药物开发中得到一致应用，这主要是由于缺乏前瞻性模型验证。 Gonzalez 博士将评估一个平台，以系统地开发和前瞻性验证成人和儿童的 PBPK/PD 模型，以开发正在开发的新型抗生素。他相信所开发的 PBPK/PD 模型将提供对影响药物暴露的因素的机制理解。该候选人是北卡罗来纳大学/杜克大学 T32 合作临床项目的应届毕业生。药理学培训计划，通过该计划，候选人获得了儿科临床药理学培训，K23 计划的短期目标是：1) 获取 PBPK/PD 建模和模拟方面的知识；2) 培养成功领导技能的专业技能。临床试验研究团队；3) 生成大量的初步数据和出版物，以支持对 Gonzalez 博士作为独立临床研究员的发展至关重要的 R01 拨款申请。杜克大学和北卡罗来纳大学教堂山分校以及已提供的数据可用于完成拟议的研究。指导团队拥有成功指导初级教师的记录，并在儿科临床试验、临床药理学、PBPK/方面拥有国际公认的专业知识。成功完成该提案后，冈萨雷斯博士将获得必要的技能，以从事促进儿童安全有效使用药物的终身职业。