Safety Pharmacology - Risk Assessment QT Interval Prolongation and Beyond

215.9K

views

165

authors

28

articles

Editorial

08 June 2018

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

Eleonora Grandi

,

Stefano Morotti

,

Esther Pueyo

and

Blanca Rodriguez

4,067 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

Impact

Fetching...

About

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.

Download ebook

Share

Editors

Eleonora Grandi

University of California, Davis

Stefano Morotti

University of California, Davis

University of Zaragoza

Blanca Rodriguez

University of Oxford

Impact

215,931 Total views

169,858 Article views

38,439 Article downloads

7,634 Topic views

Published In

Journal Thumbnail

Frontiers in Physiology

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

Journal Thumbnail

Frontiers in Pharmacology

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

Journal Thumbnail

Frontiers in Psychiatry

Systems Biology Archive

Journal Thumbnail

Frontiers in Genetics

Systems Biology Archive

Journal Thumbnail

Frontiers in Neuroscience

Systems Biology Archive

Journal Thumbnail

Frontiers in Bioengineering and Biotechnology

Systems Biology Archive, Computational Physiology and Medicine

Journal Thumbnail

Frontiers in Cell and Developmental Biology

Systems Biology Archive, Membrane Physiology and Membrane Biophysics

Journal Thumbnail

Frontiers in Applied Mathematics and Statistics

Systems Biology Archive

Journal Thumbnail

Frontiers in Physics

Membrane Physiology and Membrane Biophysics

About Frontiers Research Topics

With their unique mixes of varied contributions from Original Research to Review Articles, Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author.

Suggest a topic