Utility of the 13C-pantoprazole breath test as a CYP2C19 phenotyping probe for childrenShow full item record
Title | Utility of the 13C-pantoprazole breath test as a CYP2C19 phenotyping probe for children |
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Author | Feldman K.; Kearns G.L.; Pearce R.E.; Abdel-Rahman S.M.; Steven Leeder J.; Friesen A.; Staggs V.S.; Gaedigk A.; Weigel J.; Shakhnovich V. |
Date | 2022 |
Abstract | The 13C-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 13C-pantoprazole. Plasma concentrations of pantoprazole and its metabolites, and changes in exhaled 13CO2 (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. © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. |
Link | https://doi.org/10.1111/cts.13232
https://repository.tcu.edu/handle/116099117/55749 |
Department | Burnett School of Medicine |
Subject | cytochrome P450 2C19
drug metabolite pantoprazole pantoprazole c 13 radiopharmaceutical agent unclassified drug 2 [[(2 pyridyl)methyl]sulfinyl]benzimidazole derivative CYP2C19 protein, human cytochrome P450 2C19 pantoprazole proton pump inhibitor adolescent age distribution area under the curve Article bootstrapping breath analysis child cohort analysis controlled study drug blood level drug clearance drug dose escalation drug dose reduction female gastroesophageal reflux genetic variability genotype high performance liquid chromatography human major clinical study male obesity pantoprazole c 13 breath test patient selection phenotype practice guideline prevalence prospective study random forest sex difference single drug dose spectrophotometry ultraviolet spectroscopy adult genetics metabolism procedures 2-Pyridinylmethylsulfinylbenzimidazoles Adult Breath Tests Child Cytochrome P-450 CYP2C19 Genotype Humans Pantoprazole Proton Pump Inhibitors |
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