Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures - 31/01/18

Doi : 10.1016/j.jpeds.2017.10.011

Valentina Shakhnovich, MD ^1,^* , P. Brian Smith, MD, MHS, MPH ², Jeffrey T. Guptill, MD, MA, MHS ³, Laura P. James, MD ⁴, David N. Collier, MD, PhD, FAAP ⁵, Huali Wu, PhD ², Chad E. Livingston, MBA ⁶, Jian Zhao, PhD ⁷, Gregory L. Kearns, PharmD, PhD ⁴
on behalf of the
Best Pharmaceuticals for Children Act – Pediatric Trials Network^*
List of additional members of the Best Pharmaceuticals for Children Act–Pediatric Trials Network is available at www.jpeds.com (Appendix).
Daniel K. Benjamin, MD, PhD ⁶, Katherine Y. Berezny, BSMT, MPH ⁶, P. Michael Cohen Wolkowiez, MD, PhD ⁶, Matthew M. Laughon, MD, MPH ⁷, Ian M. Paul, MD, MSc ⁸, Michael J. Smith, MD, MSCE ⁹, John van den Anker, MD, PhD ¹⁰, Kelly Wade, MD ¹¹, David Siegel, MD ¹², Perdita Taylor-Zapata, MD ¹², Anne Zajicek, PharmD ¹², Zhaoxia Ren, MD, PhD ¹², Ekaterini Tsilou, MD ¹², Alice Pagan, BBA ¹², Ravinder Anand, PhD ¹³, Traci Clemons, PhD ¹³, Gina Simone, BS ¹³, Lee Howard, RN, CCRC ¹⁴, Jaylene Weigel, RN, MSN, MBA-HCM,CPN, CCRC (SC) ¹⁵, Nancy Darden Saad, BS, RN, CCRC (SC) ¹⁶
⁶ Duke Clinical Research Institute, Durham, NC
⁷ University of North Carolina, Chapel Hill, NC
⁸ Penn State College of Medicine, Hershey, PA
⁹ University of Louisville, Louisville, KY
¹⁰ George Washington University School of Medicine and Health, Washington, DC
¹¹ Children's Hospital of Philadelphia, Philadelphia, PA
¹² The Eunice Kennedy Shriver National Institute of Child Health and Human Development
¹³ The EMMES Corporation (Data Coordinating Center)
¹⁴ Arkansas Children's Hospital, Little Rock, AR
¹⁵ The Children's Mercy Hospital, Kansas City, MO
¹⁶ East Carolina University, Greenville, NC

¹ Divisions of Gastroenterology & Clinical Pharmacology, Toxicology and Therapeutic Innovation, The Children's Mercy Hospital, Kansas City, MO
² Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Duke Clinical Research Institute, Durham, NC
³ Department of Neurology, Division of Neuromuscular Medicine, Duke Clinical Research Institute, Durham, NC
⁴ Department of Pediatrics, University of Arkansas for Medical Sciences Section of Clinical Pharmacology and Toxicology, Arkansas Children's Hospital, Little Rock, AR
⁵ Department of Pediatrics and Center for Health Disparities, Division of General Pediatrics, East Carolina University, Greenville, NC
⁶ Clinical Operations, Pediatric Trials Network
⁷ The Emmes Statistical Group, Rockville, MD

^*Reprint requests: Valentina Shakhnovich, MD, Division of Gastroenterology, Hepatology and Nutrition, The Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108.Division of GastroenterologyHepatology and NutritionThe Children's Mercy Hospital2401 Gillham RdKansas CityMO64108

Abstract

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 ^*

List of additional members of the Best Pharmaceuticals for Children Act–Pediatric Trials Network is available at www.jpeds.com (Appendix).

2, ^{*
List of additional members of the Best Pharmaceuticals for Children Act–Pediatric Trials Network is available at www.jpeds.com (Appendix).} 3, ^{*
List of additional members of the Best Pharmaceuticals for Children Act–Pediatric Trials Network is available at www.jpeds.com (Appendix).} 4, and ^{*
List of additional members of the Best Pharmaceuticals for Children Act–Pediatric Trials Network is available at www.jpeds.com (Appendix).} 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 <12 years of age.

Trial registration

ClinicalTrials.gov: NCT02186652

Le texte complet de cet article est disponible en PDF.

Keywords : pharmacokinetics, obesity, pediatrics, proton pump inhibitors

Abbreviations : AE, AUC, AUC_inf, AUC_last, BMI, CL/F, C_max, CYP, CYP2C19, CYP2C19, EMs, FDA, GERD, IMs, LBW, PK, PM, PPIs, t_1/2, TBW, T_max, Vd/F

Plan

Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Pediatric Trials Network (NICHD-2012-PAN01). P.S. receives research support from the National Institutes of Health (NIH-1R21HD080606-01A1) and the National Institute of Child Health and Human Development (HHSN275201000003I). The other authors declare no conflicts of interest.

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Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures - 31/01/18

Abstract

Objective

Study design

Results

Conclusions

Trial registration

Plan

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