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Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21

Physiologically based pharmacokinetic (PBPK) modeling has a number of applications, including assessing drug–drug interactions (DDIs) in polymorphic populations, and should be iteratively refined as science progresses. The Simcyp Simulator is annually updated and version 21 included updates to hepat...

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Autores principales: Sychterz, Caroline, Gardner, Iain, Chiang, Manting, Rachumallu, Ramakrishna, Neuhoff, Sibylle, Perera, Vidya, Merali, Samira, Schmidt, Brian J., Gaohua, Lu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9607610/
https://www.ncbi.nlm.nih.gov/pubmed/36295903
http://dx.doi.org/10.3390/metabo12101001
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author Sychterz, Caroline
Gardner, Iain
Chiang, Manting
Rachumallu, Ramakrishna
Neuhoff, Sibylle
Perera, Vidya
Merali, Samira
Schmidt, Brian J.
Gaohua, Lu
author_facet Sychterz, Caroline
Gardner, Iain
Chiang, Manting
Rachumallu, Ramakrishna
Neuhoff, Sibylle
Perera, Vidya
Merali, Samira
Schmidt, Brian J.
Gaohua, Lu
author_sort Sychterz, Caroline
collection PubMed
description Physiologically based pharmacokinetic (PBPK) modeling has a number of applications, including assessing drug–drug interactions (DDIs) in polymorphic populations, and should be iteratively refined as science progresses. The Simcyp Simulator is annually updated and version 21 included updates to hepatic and intestinal CYP2C19 enzyme abundance, including addition of intermediate and rapid metabolizer phenotypes and changes to the ultra-rapid metabolizer enzyme abundance, with implications for population clearance and DDI predictions. This work details verification of the updates with sensitive CYP2C19 substrates, omeprazole and lansoprazole, using available clinical data from literature. Multiple assessments were performed, including recovery of areas under the concentration-time curve (AUC) and C(max) from compiled datasets for each drug, recovery of victim DDI ratios with CYP2C19 and/or CYP3A4 inhibition and recovery of relative exposure between phenotypes. Simulated data were within respective acceptance criteria for >80% of omeprazole AUC values, >70% of lansoprazole AUC and C(max), >60% of AUC and C(max) DDI ratios and >80% of exposure ratios between different phenotypes. Recovery of omeprazole C(max) was lower (>50–70% within 2-fold) and possibly attributed to the variety of formulations used in the clinical dataset. Overall, the results demonstrated that the updated data used to parameterize CYP2C19 phenotypes reasonably described the pharmacokinetics of omeprazole and lansoprazole in genotyped or phenotyped individuals.
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spelling pubmed-96076102022-10-28 Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21 Sychterz, Caroline Gardner, Iain Chiang, Manting Rachumallu, Ramakrishna Neuhoff, Sibylle Perera, Vidya Merali, Samira Schmidt, Brian J. Gaohua, Lu Metabolites Article Physiologically based pharmacokinetic (PBPK) modeling has a number of applications, including assessing drug–drug interactions (DDIs) in polymorphic populations, and should be iteratively refined as science progresses. The Simcyp Simulator is annually updated and version 21 included updates to hepatic and intestinal CYP2C19 enzyme abundance, including addition of intermediate and rapid metabolizer phenotypes and changes to the ultra-rapid metabolizer enzyme abundance, with implications for population clearance and DDI predictions. This work details verification of the updates with sensitive CYP2C19 substrates, omeprazole and lansoprazole, using available clinical data from literature. Multiple assessments were performed, including recovery of areas under the concentration-time curve (AUC) and C(max) from compiled datasets for each drug, recovery of victim DDI ratios with CYP2C19 and/or CYP3A4 inhibition and recovery of relative exposure between phenotypes. Simulated data were within respective acceptance criteria for >80% of omeprazole AUC values, >70% of lansoprazole AUC and C(max), >60% of AUC and C(max) DDI ratios and >80% of exposure ratios between different phenotypes. Recovery of omeprazole C(max) was lower (>50–70% within 2-fold) and possibly attributed to the variety of formulations used in the clinical dataset. Overall, the results demonstrated that the updated data used to parameterize CYP2C19 phenotypes reasonably described the pharmacokinetics of omeprazole and lansoprazole in genotyped or phenotyped individuals. MDPI 2022-10-20 /pmc/articles/PMC9607610/ /pubmed/36295903 http://dx.doi.org/10.3390/metabo12101001 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sychterz, Caroline
Gardner, Iain
Chiang, Manting
Rachumallu, Ramakrishna
Neuhoff, Sibylle
Perera, Vidya
Merali, Samira
Schmidt, Brian J.
Gaohua, Lu
Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21
title Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21
title_full Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21
title_fullStr Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21
title_full_unstemmed Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21
title_short Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21
title_sort performance verification of cyp2c19 enzyme abundance polymorphism settings within the simcyp simulator v21
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9607610/
https://www.ncbi.nlm.nih.gov/pubmed/36295903
http://dx.doi.org/10.3390/metabo12101001
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