Safety Pharmacology - Risk Assessment QT Interval Prolongation and Beyond

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Editorial

08 June 2018

Editorial: Safety Pharmacology – Risk Assessment QT Interval Prolongation and Beyond

Eleonora Grandi

,

Stefano Morotti

,

Esther Pueyo

and

Blanca Rodriguez

4,049 views

11 citations

Editors

4

Eleonora Grandi

University of California, Davis

Stefano Morotti

University of California, Davis

University of Zaragoza

Blanca Rodriguez

University of Oxford

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The main focus of safety pharmacology since its inception has been assessing drug-induced prolongation in the QT interval - a surrogate biomarker for torsades de pointes (TdP) liability. Because the vast majority of drugs that can cause QT prolongation inhibit hERG channels, current regulatory guidelines concerning cardiac safety recommend that all compounds are subject to an in vitro evaluation of hERG block together with assessment of in vivo QT interval prolongation in an appropriate animal model and in humans. However, it has now become apparent that QT prolongation and hERG block are an insufficient proxy for TdP risk, and that the current approach based on these markers might even lead to withdrawal from the drug development pipeline and clinical use of potentially safe drugs. Safety pharmacology has broadened its interests in recent years to the whole cardiovascular, respiratory, and central nervous systems, and is now extending to other body functions. The discipline has evolved to identify and incorporate new technologies for clinical and non-clinical applications, including refinement of in vitro assays and screens, in vivo models, non-invasive clinical modalities, and in silico approaches. Here we collect a series of review and original research articles that summarize the state of our knowledge and the latest advances in these technologies, and how these might contribute in shaping new and improved cardiac safety guidelines.

The main focus of safety pharmacology since its inception has been assessing drug-induced prolongation in the QT interval - a surrogate biomarker for torsades de pointes (TdP) liability. Because the vast majority of drugs that can cause QT prolongation inhibit hERG channels, current regulatory guidelines concerning cardiac safety recommend that all compounds are subject to an in vitro evaluation of hERG block together with assessment of in vivo QT interval prolongation in an appropriate animal model and in humans. However, it has now become apparent that QT prolongation and hERG block are an insufficient proxy for TdP risk, and that the current approach based on these markers might even lead to withdrawal from the drug development pipeline and clinical use of potentially safe drugs. Safety pharmacology has broadened its interests in recent years to the whole cardiovascular, respiratory, and central nervous systems, and is now extending to other body functions. The discipline has evolved to identify and incorporate new technologies for clinical and non-clinical applications, including refinement of in vitro assays and screens, in vivo models, non-invasive clinical modalities, and in silico approaches. Here we collect a series of review and original research articles that summarize the state of our knowledge and the latest advances in these technologies, and how these might contribute in shaping new and improved cardiac safety guidelines.

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Editors

Eleonora Grandi

University of California, Davis

Stefano Morotti

University of California, Davis

University of Zaragoza

Blanca Rodriguez

University of Oxford

Impact

209,995 Total views

165,052 Article views

37,353 Article downloads

7,590 Topic views

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Frontiers in Physiology

Cardiac Electrophysiology, Computational Physiology and Medicine, Integrative Physiology, Membrane Physiology and Membrane Biophysics, Clinical and Translational Physiology, Systems Biology Archive

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Frontiers in Pharmacology

Drugs Outcomes Research and Policies, Pharmacology of Ion Channels and Channelopathies, Predictive Toxicology

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Systems Biology Archive

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Frontiers in Genetics

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Frontiers in Neuroscience

Systems Biology Archive

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Frontiers in Bioengineering and Biotechnology

Systems Biology Archive, Computational Physiology and Medicine

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Frontiers in Cell and Developmental Biology

Systems Biology Archive, Membrane Physiology and Membrane Biophysics

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Frontiers in Applied Mathematics and Statistics

Systems Biology Archive

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Frontiers in Physics

Membrane Physiology and Membrane Biophysics

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