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Influence of Meals and Glycemic Changes on QT Interval Dynamics
Thorough QT/QTc studies have become an integral part of early drug development programs, with major clinical and regulatory implications. This analysis expands on existing pharmacodynamic models of QT interval analysis by incorporating the influence of glycemic changes on the QT interval in a semime...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518218/ https://www.ncbi.nlm.nih.gov/pubmed/28543601 http://dx.doi.org/10.1002/jcph.933 |
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author | Cirincione, Brenda Sager, Philip T. Mager, Donald E. |
author_facet | Cirincione, Brenda Sager, Philip T. Mager, Donald E. |
author_sort | Cirincione, Brenda |
collection | PubMed |
description | Thorough QT/QTc studies have become an integral part of early drug development programs, with major clinical and regulatory implications. This analysis expands on existing pharmacodynamic models of QT interval analysis by incorporating the influence of glycemic changes on the QT interval in a semimechanistic manner. A total of 21 healthy subjects enrolled in an open‐label phase 1 pilot study and provided continuous electrocardiogram monitoring and plasma glucose and insulin concentrations associated with a 24‐hour baseline assessment. The data revealed a transient decrease in QTc, with peak suppression occurring approximately 3 hours after the meal. A semimechanistic modeling approach was applied to evaluate temporal delays between meals and subsequent changes that might influence QT measurements. The food effect was incorporated into a model of heart rate dynamics, and additional delayed effects of the meal on QT were incorporated using a glucose‐dependent hypothetical transit compartment. The final model helps to provide a foundation for the future design and analysis of QT studies that may be confounded by meals. This study has significant implications for QT study assessment following a meal or when a cohort is receiving a medication that influences postprandial glucose concentrations. |
format | Online Article Text |
id | pubmed-5518218 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55182182017-08-03 Influence of Meals and Glycemic Changes on QT Interval Dynamics Cirincione, Brenda Sager, Philip T. Mager, Donald E. J Clin Pharmacol Drug Development Thorough QT/QTc studies have become an integral part of early drug development programs, with major clinical and regulatory implications. This analysis expands on existing pharmacodynamic models of QT interval analysis by incorporating the influence of glycemic changes on the QT interval in a semimechanistic manner. A total of 21 healthy subjects enrolled in an open‐label phase 1 pilot study and provided continuous electrocardiogram monitoring and plasma glucose and insulin concentrations associated with a 24‐hour baseline assessment. The data revealed a transient decrease in QTc, with peak suppression occurring approximately 3 hours after the meal. A semimechanistic modeling approach was applied to evaluate temporal delays between meals and subsequent changes that might influence QT measurements. The food effect was incorporated into a model of heart rate dynamics, and additional delayed effects of the meal on QT were incorporated using a glucose‐dependent hypothetical transit compartment. The final model helps to provide a foundation for the future design and analysis of QT studies that may be confounded by meals. This study has significant implications for QT study assessment following a meal or when a cohort is receiving a medication that influences postprandial glucose concentrations. John Wiley and Sons Inc. 2017-05-22 2017-08 /pmc/articles/PMC5518218/ /pubmed/28543601 http://dx.doi.org/10.1002/jcph.933 Text en © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://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 | Drug Development Cirincione, Brenda Sager, Philip T. Mager, Donald E. Influence of Meals and Glycemic Changes on QT Interval Dynamics |
title | Influence of Meals and Glycemic Changes on QT Interval Dynamics |
title_full | Influence of Meals and Glycemic Changes on QT Interval Dynamics |
title_fullStr | Influence of Meals and Glycemic Changes on QT Interval Dynamics |
title_full_unstemmed | Influence of Meals and Glycemic Changes on QT Interval Dynamics |
title_short | Influence of Meals and Glycemic Changes on QT Interval Dynamics |
title_sort | influence of meals and glycemic changes on qt interval dynamics |
topic | Drug Development |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518218/ https://www.ncbi.nlm.nih.gov/pubmed/28543601 http://dx.doi.org/10.1002/jcph.933 |
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