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Meta‐Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure
Ertugliflozin, a sodium‐glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5′‐diphospho‐glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta‐analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exp...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453771/ https://www.ncbi.nlm.nih.gov/pubmed/33813736 http://dx.doi.org/10.1002/jcph.1866 |
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author | Marshall, Jean‐Claude Liang, Yali Sahasrabudhe, Vaishali Tensfeldt, Thomas Fediuk, Daryl J. Zhou, Susan Krishna, Rajesh Dawra, Vikas Kumar Wood, Linda S. Sweeney, Kevin |
author_facet | Marshall, Jean‐Claude Liang, Yali Sahasrabudhe, Vaishali Tensfeldt, Thomas Fediuk, Daryl J. Zhou, Susan Krishna, Rajesh Dawra, Vikas Kumar Wood, Linda S. Sweeney, Kevin |
author_sort | Marshall, Jean‐Claude |
collection | PubMed |
description | Ertugliflozin, a sodium‐glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5′‐diphospho‐glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta‐analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exposure and dose, and the effect of UGT1A9 genotype on ertugliflozin exposure. Pharmacokinetic data from 25 phase 1 studies were pooled. Structural models for dose proportionality described the relationship between ertugliflozin area under the plasma concentration‐time curve (AUC) or maximum observed plasma concentration (C(max)) and dose. A structural model for the UGT1A9 genotype described the relationship between ertugliflozin AUC and dose, with genotype information on 3 UGT1A9 polymorphisms (UGT1A9‐2152, UGT1A9*3, UGT1A9*1b) evaluated as covariates from the full model. Ertugliflozin AUC and C(max) increased in a dose‐proportional manner over the dose range of 0.5‐300 mg, and population‐predicted AUC and C(max) values for the 5‐ and 15‐mg ertugliflozin tablets administered in the fasted state demonstrated good agreement with the observed data. The largest change in ertugliflozin AUC was in subjects carrying the UGT1A9*3 heterozygous variant, with population‐predicted AUC (90% confidence interval) values of 485 ng·h/mL (458 to 510 ng·h/mL) and 1560 ng·h/mL (1480 to 1630 ng·h/mL) for ertugliflozin 5 and 15 mg, respectively, compared with 436 ng·h/mL (418 to 455 ng·h/mL) and 1410 ng·h/mL (1350 to 1480 ng·h/mL), respectively, in wild‐type subjects. Overall, the mean effects of the selected UGT1A9 variants on ertugliflozin AUC were within ±10% of the wild type. UGT1A9 genotype did not have any clinically meaningful effects on ertugliflozin exposure in healthy subjects. No ertugliflozin dose adjustment would be required in patients with the UGT1A9 variants assessed in this study. |
format | Online Article Text |
id | pubmed-8453771 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84537712021-09-27 Meta‐Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure Marshall, Jean‐Claude Liang, Yali Sahasrabudhe, Vaishali Tensfeldt, Thomas Fediuk, Daryl J. Zhou, Susan Krishna, Rajesh Dawra, Vikas Kumar Wood, Linda S. Sweeney, Kevin J Clin Pharmacol Pharmacogenomics Ertugliflozin, a sodium‐glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5′‐diphospho‐glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta‐analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exposure and dose, and the effect of UGT1A9 genotype on ertugliflozin exposure. Pharmacokinetic data from 25 phase 1 studies were pooled. Structural models for dose proportionality described the relationship between ertugliflozin area under the plasma concentration‐time curve (AUC) or maximum observed plasma concentration (C(max)) and dose. A structural model for the UGT1A9 genotype described the relationship between ertugliflozin AUC and dose, with genotype information on 3 UGT1A9 polymorphisms (UGT1A9‐2152, UGT1A9*3, UGT1A9*1b) evaluated as covariates from the full model. Ertugliflozin AUC and C(max) increased in a dose‐proportional manner over the dose range of 0.5‐300 mg, and population‐predicted AUC and C(max) values for the 5‐ and 15‐mg ertugliflozin tablets administered in the fasted state demonstrated good agreement with the observed data. The largest change in ertugliflozin AUC was in subjects carrying the UGT1A9*3 heterozygous variant, with population‐predicted AUC (90% confidence interval) values of 485 ng·h/mL (458 to 510 ng·h/mL) and 1560 ng·h/mL (1480 to 1630 ng·h/mL) for ertugliflozin 5 and 15 mg, respectively, compared with 436 ng·h/mL (418 to 455 ng·h/mL) and 1410 ng·h/mL (1350 to 1480 ng·h/mL), respectively, in wild‐type subjects. Overall, the mean effects of the selected UGT1A9 variants on ertugliflozin AUC were within ±10% of the wild type. UGT1A9 genotype did not have any clinically meaningful effects on ertugliflozin exposure in healthy subjects. No ertugliflozin dose adjustment would be required in patients with the UGT1A9 variants assessed in this study. John Wiley and Sons Inc. 2021-06-19 2021-09 /pmc/articles/PMC8453771/ /pubmed/33813736 http://dx.doi.org/10.1002/jcph.1866 Text en © 2021 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) 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. |
spellingShingle | Pharmacogenomics Marshall, Jean‐Claude Liang, Yali Sahasrabudhe, Vaishali Tensfeldt, Thomas Fediuk, Daryl J. Zhou, Susan Krishna, Rajesh Dawra, Vikas Kumar Wood, Linda S. Sweeney, Kevin Meta‐Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure |
title | Meta‐Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure |
title_full | Meta‐Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure |
title_fullStr | Meta‐Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure |
title_full_unstemmed | Meta‐Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure |
title_short | Meta‐Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure |
title_sort | meta‐analysis of noncompartmental pharmacokinetic parameters of ertugliflozin to evaluate dose proportionality and ugt1a9 polymorphism effect on exposure |
topic | Pharmacogenomics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453771/ https://www.ncbi.nlm.nih.gov/pubmed/33813736 http://dx.doi.org/10.1002/jcph.1866 |
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