Project Summary/Abstract This Mentored Patient-Oriented Research Career Development Award will provide a structured environment with expert mentorship to enable Dr. Wesley M. Jackson to develop as an independent investigator and future leader in the field of neonatology. Hypoxic-ischemic encephalopathy (HIE) is a common and often fatal disease in infants. Mortality or severe neurodevelopmental impairment in infants with HIE remain high, despite the widespread use of therapeutic hypothermia. As a result, there is an urgent, unmet public health need to develop adjuvant therapies to improve neurodevelopmental outcomes in this population. Caffeine has been shown to reduce brain injury in animal models of HIE and may offer neuroprotection in infants with HIE. However, caffeine has not been studied in the setting of HIE and therapeutic hypothermia in humans. Dr. Jackson proposes to develop a population pharmacokinetics (PK) model of caffeine in the setting of therapeutic hypothermia to characterize the effects of hypothermia on caffeine disposition (AIM 1). He will utilize dosing simulations to optimize the caffeine treatment regimen to achieve therapeutic levels (AIM 2). Finally, he will validate the optimal dosing regimen in an open-label trial of caffeine in 24 infants receiving therapeutic hypothermia for HIE (AIM 3). Dr. Jackson developed a multidisciplinary career development plan to develop skills in clinical pharmacology, population PK modeling, and trials operations. The combination of structured and rigorous coursework with practical training provided by the aims of this proposal will allow Dr. Jackson to develop the skills necessary to become an independent researcher and leader in the field of neonatology. To guide him through this academic development, Dr. Jackson has assembled an experienced mentorship team with expertise in clinical pharmacology, trials operations, and drug development. Upon successful completion of the proposed Mentored Patient-Oriented Research Career Development Award, Dr. Jackson will have acquired the necessary advanced PK and clinical trial skills to pursue a lifelong career in developing safe and effective drugs for critically ill infants. Further, he will establish a platform to systematically evaluate therapies for critically ill infants in the setting of procedures or disease states which are likely to alter drug PK, thereby advancing drug development in this vulnerable population.