Effect of Obesity on Pantoprazole Pharmacokinetics and Pharmacodynamics in Children - PROJECT SUMMARY
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 doseàconcentrationàresponse 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.
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