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

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 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.