Characterizing the Impact of Genetic Polymorphism on Fentanyl Efficacy and Tolerance in Pediatrics

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Project Summary - Kristin Grimsrud, DVM, PhD is a translational veterinary researcher and clinician whose overreaching career goal is to become an expert in pharmacogenetics and development of translational precision animal models. The research she proposes utilizes a unique pediatric burn patient human model to identify genetical polymorphisms impact on opioid metabolism and efficacy Additionally, she proposes to develop a novel rat model possessing the human variant CYP2D6*9, which is known to alter opioid metabolism. Dr. Grimsrud is an Assistant Clinical Professor and the Associate Director the Mouse Biology Program. She completed a combined DVM/PhD specializing in pharmacology and completed a residency in Laboratory Animal Medicine. The proposed career plan will build on her previous training by focusing on multidisciplinary prospective human clinical studies, advanced translational genetics, and mentorship in career development. Dr. Grimsrud has constructed a strong mentoring committee that are world experts in their disciplines. Dr. Tina Palmieri, a burn surgeon and clinical researcher, will be the primary mentor for the proposed mentoring plan. Dr. Palmieri has a Shriner’s Hospital for Children grant to evaluate genetic polymorphisms in pediatric burn patients and their associations to fentanyl efficacy. Dr. Grimsrud will lead the operations of this study for her proposed training. Together with additional secondary mentors and consultants, these experts will provide Dr. Grimsrud with the necessary guidance she needs to become an expert in human clinical research with a focus on opioids, genetics, translational animal models, as well as career development and grantsmanship. Currently little knowledge is known regarding the impact of genetic polymorphisms on fentanyl efficacy in special populations and their influence on opioid tolerance. The proposed research utilizes human and animal models to optimize fentanyl dosing in critical patients. Pediatric burn patients represent the human model due to their need for chronic opioid therapy. Repeated samples will be collected for fentanyl analysis and genotyping, along with evaluating vital parameters and pain scores for assessing efficacy. A novel translational humanized CYP2D6*9 rat model will be developed to use as a tool for pediatric pharmacology studies. Cohorts of CYP2D6*9 humanized pediatric rats will be used for chronic fentanyl administration studies to evaluate alterations in kinetics, efficacy and tolerance. Physiological based pharmacokinetic models will be developed and used for in silco analysis and extrapolation to humans to validate this model and develop an in silco simulation tool for optimizing fentanyl dosing in humans. These efforts will provide clinicians with evidence-based conclusions to guide precision dosing of opioids and provide researchers with a new animal model that can be utilized in a variety of different pharmacology studies. This award will provide Dr. Grimsrud with the necessary mentoring and research needed to start her path towards becoming a nationally-recognized independent investigator and leader in pharmacogenetics, translational and precision medicine and opioid research.