Project Summary/Abstract Critically ill infants, including those with heart disease, suffer significant morbidity and mortality due to low cardiac output (CO) states. Inotropes such as milrinone are used to improve CO, but current dosing strategies lead to frequent therapeutic failures and toxicities. Therapeutic failures occur because current dosing is based on drug disposition (pharmacokinetics; PK) assessed at a single time point, and fails to account for the substantial, time-varying physiologic alterations that affect drug PK in critical illness, variability in drug response (pharmacodynamics; PD) based on hemodynamic factors, and the reciprocal effects of PD on PK. Identifying systematic approaches to optimize drug dosing based on time-varying PK/PD relationships in critically ill infants are urgently needed. Dr. Thompson proposes to meet this need, using milrinone in critically ill infants with heart disease as a pilot population, by: 1) identifying the optimal milrinone population PK model using a systematic approach to external validation and prospectively collected real world data (RWD) in an independent cohort, 2) developing an advanced PK/PD model to evaluate the complex interplay between milrinone dose, exposure, and response, accounting for time-varying covariates characterized by high frequency RWD, and 3) prospectively validating the observed PK/PD relationships in a multicenter, observational cohort. This Mentored Patient-Oriented Research Career Development Award will provide structured training and expert mentorship to enable Dr. Thompson to develop into an independent investigator and future leader in the field of clinical pharmacology in children with critical illness, including those with heart disease. Her overarching career goal is to design and lead innovative, PK/PD- and RWD-enabled clinical trials to optimize drug dosing in critically ill children. To achieve this goal, Dr. Thompson created a career development plan that capitalizes on the longstanding collaboration between Duke University, where she will transition to faculty in the Department of Pediatrics/Duke Clinical Research Institute, and the University of North Carolina Eshelman School of Pharmacy, where she is pursuing a PhD in Pharmaceutical Sciences. In addition, she will enhance her training in the regulatory conduct of clinical trials through the Intergovernmental Personnel Act (IPA) Scholars program at the FDA Office of Pediatric Therapeutics. Her short-term goals for the K23 program are: 1) to acquire knowledge using RWD to develop advanced PK/PD models; 2) develop the professional skills and techniques to lead a research program; and 3) generate a critical mass of preliminary data and publications to support R01 grant applications. She has assembled a mentorship team with expertise in pediatric pharmacology in critically ill children, advanced PK/PD modeling, the use of high frequency RWD, and novel, regulatory-compliant, clinical trials who have history of successfully mentoring junior faculty. Upon completion of this proposal, Dr. Thompson will have acquired the necessary skillset to pursue a lifelong career developing safe and effective drugs for critically ill children.

PROJECT NARRATIVE Drug dosing in critically ill infants is typically based on drug disposition at a single time point, and does not account for substantial, time-varying physiologic alterations that affect drug disposition and drug response, or the reciprocal effects of drug response on disposition. This oversimplified approach to drug dosing results in therapeutic failures and toxicities, but traditional clinical pharmacology approaches do not generate the necessary data to efficiently address this problem. This proposal will use an innovative combination of high frequency real world data collected per routine ICU care and advanced pharmacokinetic/pharmacodynamic modeling techniques to develop a systematic approach to inform safe and effective drug dosing in critically ill children.