Children supported with extracorporeal membrane oxygenation (ECMO) are at high risk for fungal infections. These infections are often deadly, but because the ECMO circuit can affect drug levels in the body, the appropriate dosing of antifungal drugs in this population is unknown. Dr. Watt will use an integrative approach to investigate the safest and most effective dose of antifungal drugs in children supported with ECMO. This approach will include: ex vivo studies evaluating antifungal disposition in isolated ECMO circuits;sophisticated physiologically based pharmacokinetic (PBPK) modeling;and model evaluation through clinical trials. The PBPK models developed in this proposal expand on traditional modeling techniques by incorporating the key physiological and physiochemical determinants of these processes, thereby providing a mechanistic understanding of drug disposition and allowing for modification of the model to account for derangements in the system (e.g., decreased renal function, addition of ECMO support). The candidate is a pediatric intensivist with a proven commitment to patient-oriented research, and a desire to develop sophisticated modeling skills. The modeling skills developed from this proposal will facilitate the candidate's long-term career goal to advance public health by integrating physiology and pharmacology into the design and conduct of early-phase trials in critically ill children. The candidate's short-term career goals for the K23 program are to: 1) acquire knowledge and skills in clinical pharmacology, modeling, and simulation;2) develop the professional skills to successfully lead a clinical trial research team;and 3) produce a critical mass of preliminary data and publications to support an R01 grant application and establish a program of independent research in clinical pharmacology. This proposal will capitalize on unique opportunities provided by the Duke ECMO program (4th largest in the world), Duke Clinical Research Institute (DCRI;Benjamin, mentor), and the Eshelman School of Pharmacy at UNC (Brouwer, co-mentor). Concomitant with this proposed research, the candidate will receive advanced training in pharmacokinetic modeling through a PhD program in pharmaceutical sciences and through work with his mentors. The mentorship team assembled is uniquely qualified, and strengths include extensive clinical research experience;internationally recognized thought leadership in trial design, research methods, pharmacology, and modeling;and a successful history of mentorship of junior faculty. At the conclusion of this program, Dr. Watt will be well positioned to be an independent physician-scientist leading a research team.
Fungal infections in children on extracorporeal life support (ECMO) are often fatal, and therapy relies on optimal dosing. Unfortunately, appropriate dosing of antifungal drugs in this population is unknown, because the ECMO machine can substantially alter drug levels in the body. To address this knowledge gap, this proposal will investigate the pharmacokinetics (PK) of antifungal agents frequently given to children on ECMO using novel, sophisticated PK modeling techniques.