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

Best Pharmaceuticals for Children Act – Pediatric Trials Network

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 *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 <12 years of age. Trial registration: ClinicalTrials.gov: NCT02186652

Original languageEnglish (US)
Pages (from-to)102-108.e1
JournalJournal of Pediatrics
Volume193
DOIs
StatePublished - Feb 2018

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Pharmaceutical Preparations
Pharmacokinetics
Body Weight
Genotype
pantoprazole
Body Size
Linear Models
Analysis of Variance
Obesity
Regression Analysis
Clinical Trials
Population
Cytochrome P-450 CYP2C19

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health

Cite this

Best Pharmaceuticals for Children Act – Pediatric Trials Network. / Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures. In: Journal of Pediatrics. 2018 ; Vol. 193. pp. 102-108.e1.
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title = "Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures",
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 *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 <12 years of age. Trial registration: ClinicalTrials.gov: NCT02186652",
author = "{Best Pharmaceuticals for Children Act – Pediatric Trials Network} and Valentina Shakhnovich and Smith, {P. Brian} and Guptill, {Jeffrey T.} and James, {Laura P.} and Collier, {David N.} and Huali Wu and Livingston, {Chad E.} and Jian Zhao and Kearns, {Gregory L.} and Benjamin, {Daniel K.} and Berezny, {Katherine Y.} and Wolkowiez, {P. Michael Cohen} and Laughon, {Matthew M.} and Paul, {Ian M.} and Smith, {Michael J.} and {van den Anker}, John and Kelly Wade and David Siegel and Perdita Taylor-Zapata and Anne Zajicek and Zhaoxia Ren and Ekaterini Tsilou and Alice Pagan and Ravinder Anand and Traci Clemons and Gina Simone and Lee Howard and Jaylene Weigel and {Darden Saad}, Nancy",
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Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures. / Best Pharmaceuticals for Children Act – Pediatric Trials Network.

In: Journal of Pediatrics, Vol. 193, 02.2018, p. 102-108.e1.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures

AU - Best Pharmaceuticals for Children Act – Pediatric Trials Network

AU - Shakhnovich, Valentina

AU - Smith, P. Brian

AU - Guptill, Jeffrey T.

AU - James, Laura P.

AU - Collier, David N.

AU - Wu, Huali

AU - Livingston, Chad E.

AU - Zhao, Jian

AU - Kearns, Gregory L.

AU - Benjamin, Daniel K.

AU - Berezny, Katherine Y.

AU - Wolkowiez, P. Michael Cohen

AU - Laughon, Matthew M.

AU - Paul, Ian M.

AU - Smith, Michael J.

AU - van den Anker, John

AU - Wade, Kelly

AU - Siegel, David

AU - Taylor-Zapata, Perdita

AU - Zajicek, Anne

AU - Ren, Zhaoxia

AU - Tsilou, Ekaterini

AU - Pagan, Alice

AU - Anand, Ravinder

AU - Clemons, Traci

AU - Simone, Gina

AU - Howard, Lee

AU - Weigel, Jaylene

AU - Darden Saad, Nancy

PY - 2018/2

Y1 - 2018/2

N2 - 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 <12 years of age. Trial registration: ClinicalTrials.gov: NCT02186652

AB - 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 <12 years of age. Trial registration: ClinicalTrials.gov: NCT02186652

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JO - Journal of Pediatrics

JF - Journal of Pediatrics

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