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

• 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
• 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

 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。 Gonzalez 博士的首要职业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。抗生素耐药细菌引起的侵袭性感染很常见且致命。不幸的是，在过去 10 年里，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之前通常会出现相当长的延迟。 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) 模型是数学结构，融合了从儿童到成年的生理变化。通过纳入这些生理变化，PBPK/PD 模型可用于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模型在药物开发中并未得到一致应用，很大程度上是由于缺乏前瞻性模型验证。在这项提案中，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，以开发一种正在开发的新型抗生素。他假设开发的 PBPK/PD 模型将提供对影响新抗生素感染部位药物暴露的因素的机制理解，帮助选择成人和儿童的最佳剂量，并作为未来抗生素药物批准的模型。该候选人是北卡罗来纳大学/杜克大学 T32 合作临床药理学培训项目的应届毕业生，通过该项目他获得了儿科临床药理学培训。 K23项目候选人的短期目标是： 1）获得PBPK/PD建模和仿真方面的知识和技能； 2) 培养成功领导临床试验研究团队的专业技能； 3) 生成大量的初步数据和出版物，以支持 R01 拨款申请，这对于 Gonzalez 博士作为独立临床研究员的发展至关重要。该提案利用了杜克大学和北卡罗来纳大学教堂山分校之间悠久的合作历史，以及完成拟议研究的现有数据。导师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/PD 建模和传染病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。