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

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.
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Wiley
Date
2022
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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.
Contents
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
Subject(s)
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Department
Burnett School of Medicine
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URI
https://doi.org/10.1111/cts.13232
 https://repository.tcu.edu/handle/116099117/55749