Systemic Corticosteroid Pharmacokinetics and Pharmacodynamic Biomarker Identification in Children with Asthma and Obesity

Project Summary The overall goal of this 5-year K23 proposal is to support Dr. Kathryn Kyler to become an independent investigator in the field of pharmacokinetic (PK) modeling and pharmacodynamic (PD) biomarker development for children with asthma and obesity. This proposal aligns with the NHLBI’s Precision Medicine Initiative, as well as prioritization of obesity related research in relevant diseases like asthma. The proposal also aligns with the NIH Better Pharmaceuticals for Children Act which has named PK/PD studies focused on children with obesity as a priority. Children with asthma and obesity have a distinct asthma phenotype and endotype, characterized by more severe asthma than those without obesity (e.g., more exacerbations, hospitalizations), and different baseline inflammatory patterns (i.e., elevated IL-6 and TNF-) than asthmatic children without obesity (i.e., allergic-type inflammation). It is currently unknown how these differences modulate drug exposure and response for medications like systemic corticosteroids (SCS) used to treat asthma exacerbations. This career development proposal will leverage Dr. Kyler’s expertise as a pediatric hospitalist and clinical pharmacologist-in-training to expand her skills in clinical and translational PK/PD study methods, enabling her to define obesity’s effect on SCS dose-exposure-response relationships. The comprehensive career development plan contains three training objectives to improve Dr. Kyler’s skills in: 1) advanced PK modeling, 2) PD biomarker development, and 3) pediatric clinical trial best practices. This plan includes structured mentoring, didactic training, and experiential learning which will be applied to the following scientific aims: 1) determine differences in SCS-mediated immune cell response in vitro across weight groups, 2) determine differences in SCS exposure among asthmatic children with and without obesity, 3) evaluate the relationship between SCS exposure and PD biomarkers. Dr. Kyler’s career development and research plans will take place in an excellent environment which includes a tertiary academic children’s medical center, a pediatric research institute, a multi-institutional Clinical and Translational Science Institute (CTSI), as well as access to experts in fields directly related to both her training and scientific aims. After completing this project, Dr. Kyler will have advanced the field of drug pharmacokinetics and dynamics in children with asthma and obesity and generated data to support an R01 application to validate and test PK and PD model-informed SCS dosing strategies in children with asthma and obesity. This work will position her to become a leader in the field of precision therapeutics for children with asthma and obesity, able to link pharmacologic translational science to the bedside for performance of pediatric clinical trials.