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Cardiovascular Safety Assessment in Early‐Phase Clinical Studies: A Meta‐Analytical Comparison of Exposure‐Response Models
Exposure‐response analysis of QT interval in clinical studies has been proposed as a thorough QT study alternative. Many exposure‐response model structures have been proposed for cardiovascular (CV) safety markers, but few studies have compared models across multiple drugs. To recommend preferred dr...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131889/ https://www.ncbi.nlm.nih.gov/pubmed/27318037 http://dx.doi.org/10.1002/psp4.12086 |
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author | Conrado, DJ Chen, D Denney, WS |
author_facet | Conrado, DJ Chen, D Denney, WS |
author_sort | Conrado, DJ |
collection | PubMed |
description | Exposure‐response analysis of QT interval in clinical studies has been proposed as a thorough QT study alternative. Many exposure‐response model structures have been proposed for cardiovascular (CV) safety markers, but few studies have compared models across multiple drugs. To recommend preferred drug‐effect exposure‐response models on vital signs and electrocardiogram (ECG) intervals, an individual‐level model‐based meta‐analysis (39 studies and 1,291 subjects) compared 90 model structures. Models were selected to describe the data and cross‐validate studies on the same drug. The most commonly selected baseline model was an unstructured model (estimation of a value at each study nominal time) for all measures but blood pressure. The unstructured model estimated a better cross‐validated drug‐effect when considering all markers. A linear model was the most commonly selected to characterize drug‐effect on all markers. We propose these models as a starting point assisting with CV safety exposure‐response assessment in nondedicated small studies with healthy subjects. |
format | Online Article Text |
id | pubmed-5131889 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-51318892016-12-15 Cardiovascular Safety Assessment in Early‐Phase Clinical Studies: A Meta‐Analytical Comparison of Exposure‐Response Models Conrado, DJ Chen, D Denney, WS CPT Pharmacometrics Syst Pharmacol Original Articles Exposure‐response analysis of QT interval in clinical studies has been proposed as a thorough QT study alternative. Many exposure‐response model structures have been proposed for cardiovascular (CV) safety markers, but few studies have compared models across multiple drugs. To recommend preferred drug‐effect exposure‐response models on vital signs and electrocardiogram (ECG) intervals, an individual‐level model‐based meta‐analysis (39 studies and 1,291 subjects) compared 90 model structures. Models were selected to describe the data and cross‐validate studies on the same drug. The most commonly selected baseline model was an unstructured model (estimation of a value at each study nominal time) for all measures but blood pressure. The unstructured model estimated a better cross‐validated drug‐effect when considering all markers. A linear model was the most commonly selected to characterize drug‐effect on all markers. We propose these models as a starting point assisting with CV safety exposure‐response assessment in nondedicated small studies with healthy subjects. John Wiley and Sons Inc. 2016-06-18 2016-06 /pmc/articles/PMC5131889/ /pubmed/27318037 http://dx.doi.org/10.1002/psp4.12086 Text en © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics. 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 | Original Articles Conrado, DJ Chen, D Denney, WS Cardiovascular Safety Assessment in Early‐Phase Clinical Studies: A Meta‐Analytical Comparison of Exposure‐Response Models |
title | Cardiovascular Safety Assessment in Early‐Phase Clinical Studies: A Meta‐Analytical Comparison of Exposure‐Response Models |
title_full | Cardiovascular Safety Assessment in Early‐Phase Clinical Studies: A Meta‐Analytical Comparison of Exposure‐Response Models |
title_fullStr | Cardiovascular Safety Assessment in Early‐Phase Clinical Studies: A Meta‐Analytical Comparison of Exposure‐Response Models |
title_full_unstemmed | Cardiovascular Safety Assessment in Early‐Phase Clinical Studies: A Meta‐Analytical Comparison of Exposure‐Response Models |
title_short | Cardiovascular Safety Assessment in Early‐Phase Clinical Studies: A Meta‐Analytical Comparison of Exposure‐Response Models |
title_sort | cardiovascular safety assessment in early‐phase clinical studies: a meta‐analytical comparison of exposure‐response models |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131889/ https://www.ncbi.nlm.nih.gov/pubmed/27318037 http://dx.doi.org/10.1002/psp4.12086 |
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