Ontogeny and Genetics of NSAID Dose-Exposure Relationship in Preterm Infants

点击翻译按钮获取中文摘要

Project Summary/Abstract Dr Tamorah Lewis, an Assistant Professor at the University of Missouri Kansas City SOM, is re- applying for a K23 award. After completing fellowships in Neonatology and Clinical Pharmacology (Clin Pharm) and a PhD in Clinical Investigation, she is a tenure-track clinician researcher at Children’s Mercy Hospital. She is awarded a start-up package and 70% protected time and is working to establish herself as a translational investigator in neonatal pharmacology. Her career aspirations include bringing Precision Therapeutics to neonates via the incorporation of pharmacogenetics, pharmacometabolomics and an improved understanding of ontogeny and genetics in variability in drug efficacy and toxicity. The K23 grant will provide: (1) expertise quantifying developmental changes in drug metabolism pathways with in vitro methods (2) learning complex physiologically-based pharmacokinetic (PBPK) modeling techniques to analyze pharmacogenetic and pharmacokinetic results in newborns (3) microsampling methodologies for drug quantification assays and pharmacometabolomic studies, and (4) the skills needed to become an independent NIH-funded investigator. To achieve these goals, (1) J Steven Leeder (Clin Pharm), primary mentor, (2) William Truog (Clinical Trialist), (3) John Jeffrey Reese (Ductus Arteriosus Expert) and (4) Rima Kaddurah-Daouk (Pharmacometabolomics) will serve as the mentorship team. These faculty have a strong track record of mentorship, know Dr Lewis well and have already established collaborative research, and will assist in career development through didactic meetings, frequent formal and informal conferences, and career guidance. The proposed combined approach of in vivo and in vitro experiments addresses an important problem in neonatology and developmental pharmacology, specifically that current indomethacin dosing results in erratic clinical efficacy and toxicity in preterm infants. We propose to study a dose→exposure→response paradigm, focusing on individualizing drug dose to achieve a common target exposure in all infants, thus allowing for the study of variability in drug response at the level of the drug target. Using both in vivo and in vitro data obtained during this K23, we will build an indomethacin dose-exposure model, accounting for gestational age, postnatal age and pharmacogenetics. We hypothesize that developmental variation in metabolic pathways (gestational /postnatal age) and individual genetics will substantially influence indomethacin exposure. The final dose-exposure model will be used prospectively in future drug exposure- response studies. This K23 provides training and enables establishment of a research paradigm for other neonatal drugs where the dose→exposure→response profile is unclear, creating a natural career path for Dr Lewis’ future. The expertise gained and the research results afforded will form the basis for an R01 proposal investigating the variability in indomethacin treatment response given a standard exposure, paving the way for personalized drug use in preterm neonates and improved clinical outcomes.