A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents.

Published

Journal Article

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. METHODS: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. RESULTS: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. CONCLUSIONS: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.

Full Text

Duke Authors

Cited Authors

  • Shakhnovich, V; Brian Smith, P; Guptill, JT; James, LP; Collier, DN; Wu, H; Livingston, CE; Zhao, J; Kearns, GL; Cohen-Wolkowiez, M; Best Pharmaceuticals for Children Act–Pediatric Trials Network,

Published Date

  • October 2018

Published In

Volume / Issue

  • 20 / 5

Start / End Page

  • 483 - 495

PubMed ID

  • 30097906

Pubmed Central ID

  • 30097906

Electronic International Standard Serial Number (EISSN)

  • 1179-2019

International Standard Serial Number (ISSN)

  • 1174-5878

Digital Object Identifier (DOI)

  • 10.1007/s40272-018-0305-1

Language

  • eng