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

 描述（由申请人提供）：该指导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，以及旨在促进丹尼尔冈萨雷斯博士作为独立临床研究人员发展的实践和教学培训。冈萨雷斯博士的首要职业目标是通过整合机械建模和生理学概念来促进公共卫生，以促进儿童安全有效地使用药物。由于抗生素耐药性细菌引起的侵入性感染是常见和致命的。不幸的是，在过去的10年里，只有3种新的抗生素被FDA批准用于成人，没有一种用于儿童。此外，一旦获得成人批准，在抗生素被指示用于儿童之前，通常会有很大的延迟。 需要设计创新的工具来加快儿科对新型抗生素的批准。基于生理学的药代动力学/药效学（PBPK/PD）模型是一种数学结构，它包含了从儿童到成年的生理变化。通过结合这些生理变化，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模型并没有在药物开发中得到一致的应用，主要是由于缺乏前瞻性的模型验证。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地验证成人和儿童的PBPK/PD模型，以开发一种新型抗生素。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性理解，有助于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。该候选人最近毕业于剑桥/杜克T32合作临床药理学培训项目，通过该项目，他获得了儿科临床药理学培训。候选人的K23计划的短期目标是：1）获得PBPK/PD建模和模拟的知识和技能; 2）发展成功领导临床试验研究团队的专业技能;和3）生成初步数据和出版物的临界质量，以支持R 01拨款申请重要的博士冈萨雷斯的发展作为一个独立的临床研究人员。这项提案利用了杜克大学和查佩尔山的北卡罗来纳州大学之间长期合作的历史，以及已经可以完成拟议研究的数据。导师团队拥有成功指导初级教师的良好记录，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。在成功完成这项提案后，冈萨雷斯博士将获得必要的技能，以追求终身职业，促进儿童安全有效地使用药物。

 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.