Utility of the 13C‐pantoprazole breath test as a CYP2C19 phenotyping probe for children
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-05-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13232 |
| _version_ | 1818006013010247680 |
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| author | Keith Feldman Gregory L. Kearns Robin E. Pearce Susan M. Abdel‐Rahman James Steven Leeder Alec Friesen Vincent S. Staggs Andrea Gaedigk Jaylene Weigel Valentina Shakhnovich |
| author_facet | Keith Feldman Gregory L. Kearns Robin E. Pearce Susan M. Abdel‐Rahman James Steven Leeder Alec Friesen Vincent S. Staggs Andrea Gaedigk Jaylene Weigel Valentina Shakhnovich |
| author_sort | Keith Feldman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T04:54:43Z |
| format | Article |
| id | doaj.art-3c8aaa1f65f4464b98e131f129d96342 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-04-14T04:54:43Z |
| publishDate | 2022-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-3c8aaa1f65f4464b98e131f129d963422022-12-22T02:11:11ZengWileyClinical and Translational Science1752-80541752-80622022-05-011551155116610.1111/cts.13232Utility of the 13C‐pantoprazole breath test as a CYP2C19 phenotyping probe for childrenKeith Feldman0Gregory L. Kearns1Robin E. Pearce2Susan M. Abdel‐Rahman3James Steven Leeder4Alec Friesen5Vincent S. Staggs6Andrea Gaedigk7Jaylene Weigel8Valentina Shakhnovich9University of Missouri‐Kansas City School of Medicine Kansas City Missouri USATexas Christian University and UNTHSC School of Medicine Fort Worth Texas USAUniversity of Missouri‐Kansas City School of Medicine Kansas City Missouri USAUniversity of Missouri‐Kansas City School of Medicine Kansas City Missouri USAUniversity of Missouri‐Kansas City School of Medicine Kansas City Missouri USAOklahoma School of Community Medicine Tulsa Oklahoma USAUniversity of Missouri‐Kansas City School of Medicine Kansas City Missouri USAUniversity of Missouri‐Kansas City School of Medicine Kansas City Missouri USAUniversity of Missouri‐Kansas City School of Medicine Kansas City Missouri USAUniversity of Missouri‐Kansas City School of Medicine Kansas City Missouri USAAbstract 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.https://doi.org/10.1111/cts.13232 |
| spellingShingle | Keith Feldman Gregory L. Kearns Robin E. Pearce Susan M. Abdel‐Rahman James Steven Leeder Alec Friesen Vincent S. Staggs Andrea Gaedigk Jaylene Weigel Valentina Shakhnovich Utility of the 13C‐pantoprazole breath test as a CYP2C19 phenotyping probe for children Clinical and Translational Science |
| title | Utility of the 13C‐pantoprazole breath test as a CYP2C19 phenotyping probe for children |
| title_full | Utility of the 13C‐pantoprazole breath test as a CYP2C19 phenotyping probe for children |
| title_fullStr | Utility of the 13C‐pantoprazole breath test as a CYP2C19 phenotyping probe for children |
| title_full_unstemmed | Utility of the 13C‐pantoprazole breath test as a CYP2C19 phenotyping probe for children |
| title_short | Utility of the 13C‐pantoprazole breath test as a CYP2C19 phenotyping probe for children |
| title_sort | utility of the 13c pantoprazole breath test as a cyp2c19 phenotyping probe for children |
| url | https://doi.org/10.1111/cts.13232 |
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