Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures

Valentina Shakhnovich, Children's Mercy Hospital
P. Brian Smith, Duke Clinical Research Institute
Jeffrey T, Guptill, Duke Clinical Research Institute
Laura P. James, University of Arkansas for Medical Sciences
David N. Collier, East Carolina University
Huali Wu, Duke Clinical Research Institute
Chad E. Livingston, Pediatric Trials Network
Jian Zhao, The Emmes Statistical Group
Gregory L. Kearns, University of Arkansas for Medical Sciences
Daniel K. Benjamin, Duke Clinical Research Institute
Katherine Y. Berezny, Duke Clinical Research Institute
P. Michael Cohen Wolkowiez, Duke Clinical Research Institute
Matthew M. Laughon, The University of North Carolina at Chapel Hill
Ian M. Paul, Penn State College of Medicine
Michael J. Smith, University of Louisville
John van den Anker, School of Medicine and Health Sciences
Kelly Wade, The Children's Hospital of Philadelphia
David Siegel, National Institute of Child Health and Human Development (NICHD)
Perdita Taylor-Zapata, National Institute of Child Health and Human Development (NICHD)
Anne Zajicek, National Institute of Child Health and Human Development (NICHD)
Zhaoxia Ren, National Institute of Child Health and Human Development (NICHD)
Ekaterini Tsilou, National Institute of Child Health and Human Development (NICHD)
Alice Pagan, National Institute of Child Health and Human Development (NICHD)
Ravinder Anand, The EMMES Corporation
Traci Clemons, The EMMES Corporation
Gina Simone, The EMMES Corporation
Lee Howard, Arkansas Children's Hospital
Jaylene Weigel, Children's Mercy Hospital
Nancy Darden Saad, East Carolina University


© 2017 Elsevier Inc. Objective: To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. Study design: A total of 41 obese children (6-17 years of age), genotyped for CYP2C19 variants *2, *3, *4, and *17, received a single oral dose of pantoprazole, ~1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula. Ten post-dose pantoprazole plasma concentrations were measured, and PK variables generated via noncompartmental methods (WinNonlin). Linear and nonlinear regression analyses and analyses of variance were used to explore obesity, age, and CYP2C19 genotype contribution to pantoprazole PK. PK variables of interest were compared with historic nonobese peers treated with pantoprazole. Results: Independent of genotype, when normalized to dose per kg total body weight, pantoprazole apparent clearance and apparent volume of distribution were significantly lower (P <. 05) and systemic exposure significantly higher (P < .01) in obese vs nonobese children. When normalized per kg LBW, these differences were not evident in children ≥ 12 years of age and markedly reduced in children < 12 years of age. Conclusions: LBW dosing of pantoprazole led to pantoprazole PK similar to nonobese peers. Additional factors, other than body size (eg, age-related changes in CYP2C19 activity), appear to affect pantoprazole PK in children <1 2 years of age. Trial registration: ClinicalTrials.gov: NCT02186652