A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents
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Background and Aims
Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers. Subsequently, we developed a population-based pharmacokinetic (PopPK) model to characterize pantoprazole disposition and evaluated appropriate pantoprazole dosing strategies for obese pediatric patients, using simulation.
Pharmacokinetic data from the only prospective study of PPIs in obese children (aged 6–17 years; n = 40) included 273 pantoprazole and 256 pantoprazole-sulfone plasma concentrations, after single oral-dose administration, and were used for pantoprazole model development and covariate analysis (NONMEM®). Model evaluation was performed via bootstrapping and predictive checks, and the final model was applied to simulate systemic pantoprazole exposures for common dosing scenarios.
A two-compartment PopPK model, which included CYP2C19 genotype and total body weight, provided the best fit. Resultant, typical, weight-normalized pantoprazole parameter estimates were different than previously reported for children or adults, with significantly reduced pantoprazole CL/F for obese children. Of the dosing scenarios evaluated, the weight-tiered approach, approved by the US Food and Drug Administration, achieved pantoprazole exposures [area under the curve (AUC0–∞)] within ranges previously reported as therapeutic, without over- or under-prediction for obese children.
Our data argue against empiric dose escalation of PPIs for obese children and support current FDA-approved pediatric weight-tiered dosing for pantoprazole; however, 3- to 5-fold inter-individual variability in pantoprazole AUC0–∞ remained using this dosing approach.
Pediatric Trials Network (PTN) Members
The Best Pharmaceuticals for Children Act–PTN Steering Committee
Daniel K. Benjamin Jr., MD, PhD, Katherine Y. Berezny, BSMT, MPH, P., Michael Cohen-Wolkowiez, MD, PhD, Brian Smith, MD, MPH, MHS Duke Clinical Research Institute, Durham, NC; Gregory L. Kearns, PharmD, PhD, Arkansas Children’s Hospital, Little Rock, AR; Matthew M. Laughon, MD, MPH, University of North Carolina, Chapel Hill, NC; Ian M. Paul, MD, MSc, Penn State College of Medicine, Hershey, PA; Michael J. Smith, MD, MSCE, University of Louisville, Louisville, KY; John van den Anker, MD, PhD, George Washington University School of Medicine and Health, Washington, DC; Kelly Wade, MD, Children’s Hospital of Philadelphia, Philadelphia, PA.
The Eunice Kennedy Shriver National Institute of Child Health and Human Development
David Siegel, MD, Perdita Taylor-Zapata, MD, Anne Zajicek, PharmD, Zhaoxia Ren, MD, PhD, Ekaterini Tsilou, MD, Alice Pagan, BBA.
The EMMES Corporation (Data Coordinating Center)
Ravinder Anand, PhD, Traci Clemons, PhD, Gina Simone, BS.
PTN Study Team Investigators and Study Coordinators
Arkansas Children’s Hospital, Little Rock, AR (enrolled 13 subjects): Laura P. James, MD (Principal Investigator, PI), Lee Howard, RN, CCRC (Site Coordinator, SC); The Children’s Mercy Hospital, Kansas City, MO (enrolled 23 subjects): Valentina Shakhnovich, MD (PI), Jaylene Weigel, RN, MSN, MBA-HCM,CPN, CCRC (SC); East Carolina University, Greenville, NC (enrolled 5 subjects): David N. Collier, MD, PhD, FAAP (PI), Nancy Darden-Saad, BS, RN, CCRC (SC).
The study sponsor was consulted concerning study design; data collection, analysis, and interpretation; the writing of the report; and the decision to submit the manuscript for publication.
Compliance with ethical standards
All phases of this study were supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HHSN275201000003I), Pediatric Trials Network (NICHD-2012-PAN01).
Conflict of interest
VS. receives research support from the NASPGHAN Foundation for the investigation of PPIs in children. As an associate editor, V.S. receives honoraria from the journal Clinical and Translational Science. M.C.W. receives support for research from the National Institutes of Health (1R01-HD076676-01A1), the National Institute of Allergy and Infectious Disease (HHSN272201500006I and HHSN272201300017I), the National Institute of Child Health and Human Development (HHSN275201000003I), and the Biomedical Advanced Research and Development Authority (HHSO100201300009C). The remaining authors have nothing to disclose.
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