Utility of the 13C-pantoprazole breath test as a CYP2C19 phenotyping probe for children

Creator(s)

Keith Feldman, Children's Mercy HospitalFollow
Gregory L. Kearns
Robin E. Pearce, Children's Mercy HospitalFollow
Susan M. Abdel-Rahman, Children's Mercy Kansas City
J Steven Leeder, Children's Mercy HospitalFollow
Alec Friesen
Vincent S. Staggs, Children's Mercy HospitalFollow
Andrea Gaedigk, Children's Mercy Kansas CityFollow
Jaylene Weigel, Children's Mercy HospitalFollow
Valentina Shakhnovich, Children's Mercy HospitalFollow

Document Type

Article

Publication Date

5-2022

Identifier

DOI: 10.1111/cts.13232; PMCID: PMC9099127

Abstract

The 13 C-pantoprazole breath test (PAN-BT) is a safe, noninvasive, in vivo CYP2C19 phenotyping probe for adults. Our objective was to evaluate PAN-BT performance in children, with a focus on discriminating individuals who, according to guidelines from the Clinical Pharmacology Implementation Consortium (CPIC), would benefit from starting dose escalation versus reduction for proton pump inhibitors (PPIs). Children (n = 65, 6-17 years) genotyped for CYP2C19 variants *2, *3, *4, and *17 received a single oral dose of 13 C-pantoprazole. Plasma concentrations of pantoprazole and its metabolites, and changes in exhaled 13 CO2 (termed delta-over-baseline or DOB), were measured 10 times over 8 h using high performance liquid chromatography with ultraviolet detection and spectrophotometry, respectively. Pharmacokinetic parameters of interest were generated and DOB features derived using feature engineering for the first 180 min postadministration. DOB features, age, sex, and obesity status were used to run bootstrap analysis at each timepoint (Ti ) independently. For each iteration, stratified samples were drawn based on genotype prevalence in the original cohort. A random forest was trained, and predictive performance of PAN-BT was evaluated. Strong discriminating ability for CYP2C19 intermediate versus normal/rapid metabolizer phenotype was noted at DOBT30 min (mean sensitivity: 0.522, specificity: 0.784), with consistent model outperformance over a random or a stratified classifier approach at each timepoint (p < 0.001). With additional refinement and investigation, the test could become a useful and convenient dosing tool in clinic to help identify children who would benefit most from PPI dose escalation versus dose reduction, in accordance with CPIC guidelines

Journal Title

Clin Transl Sci

Volume

15

Issue

5

First Page

1155

Last Page

1166

MeSH Keywords

2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Breath Tests; Child; Cytochrome P-450 CYP2C19; Genotype; Humans; Pantoprazole; Proton Pump Inhibitors

Keywords

2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Breath Tests; Child; Cytochrome P-450 CYP2C19; Genotype; Humans; Pantoprazole; Proton Pump Inhibitors

Comments

Grant support

• 1T32HD069038/NICHD-NIGMS T32 Training Program in Developmental/Pediatric Clinical Pharmacology
• 5K23DK115827/DK/NIDDK NIH HHS/United States

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Publisher's Link: https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.13232

Recommended Citation

Feldman K, Kearns GL, Pearce RE, et al. Utility of the 13 C-pantoprazole breath test as a CYP2C19 phenotyping probe for children. Clin Transl Sci. 2022;15(5):1155-1166. doi:10.1111/cts.13232