Pediatric obesity has reached epidemic proportions, with >30% children meeting criteria for overweight/obese. The alarming obesity epidemic brings with it increasing need for pediatricians to treat chronic obesity-related comorbidities (e.g., GERD) that frequently require long-term medical management. Yet, guidelines are lacking for optimal dosing of medications in this population. The proposed investigation builds on my recently published findings, from two independent prospective investigations that demonstrate increased systemic exposure to the proton pump inhibitor (PPI) pantoprazole in obese vs. non-obese children, suggesting slower PPI drug clearance in obesity. Using intravenous pantoprazole as a model drug probe for the hepatic drug metabolizing pathway CYP2C19, I will test the hypothesis that hepatic adiposity underlies the observed reduction in pantoprazole clearance, and that weight-reduction reverses alterations in liver adiposity, hepatic drug clearance and drug effect. Understanding of the biologic and physiologic mechanisms underlying altered drug metabolism and clearance is the first step toward developing accurate predictive models for optimizing the dose selection of PPIs, and other drugs commonly prescribed to obese patients. Postdoctoral training in an NIH-funded pediatric clinical pharmacology program at Children's Mercy Kansas City (CMKC; T32HD069038) prepared me well for a research-focused career in pediatric therapeutics by providing didactic training in curve fitting and compartmental/noncompartmental pharmacokinetic analysis; however, clinical pharmacology training has limited exposure to quantitative systems pharmacology, a biomedical discipline that uses mathematical computer models to characterize interactions of biological systems, disease processes and pharmacology, to individualize drug therapeutics in a variety of circumstances. The K23 mechanism will enable me to build on my basic pharmacology skill-set and pursue this advanced training, essential for developing physiololgically-based pharmacokinetic and pharmacodynamic (PBPK/PD) models for simulating and predicting the drug doseconcentrationresponse relationship for children with gastrointestinal disorders, starting with PPI dosing for obese children, who are disproportionately affected by GERD. To test the validity of the PBPK/PD models that I develop, I will need to design, conduct and effectively lead prospective longitudinal clinical trials, a mentored-research opportunity afforded to me by this K23. To expand my models to other drugs commonly prescribed to children, I will also need to update my knowledge base of drug metabolizing enzymes beyond CYP2C19, as proposed in my Education Plan. As a pediatric gastroenterologist and clinical pharmacologist at CMH, with 75% protected research time, a mentoring team comprised of expert NIH-funded faculty, lead by pharmacogenomics expert J. Steven Leeder, PharmD, PhD, I have the requisite institutional support, pedigree and academic environment to accomplish the research and training goals described in this K23 application. !
Currently, a critical information gap exists regarding optimal dosing of medications for obese children, who are at greater risk than non-obese peers for chronic medical conditions, including gastroesophageal reflux disease (GERD). My recently published data demonstrate higher systemic exposure and reduced drug clearance for the proton pump inhibitor (PPI) pantoprazole for obese vs. non-obese children with GERD. The proposed investigation is designed to test the hypothesis that liver adiposity underlies this decrease in hepatic drug clearance of PPIs in obesity, which is timely and highly relevant to public health in light of the pediatric obesity epidemic, the frequency of PPI use in children, and the applicability of the physiology and pharmacology knowledge generated to other drugs commonly prescribed to obese patients.