Safety Pharmacology - Risk Assessment QT Interval Prolongation and Beyond

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Frontiers Media SA, Aug 16, 2018
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Current regulatory guidelines for cardiac safety utilize hERG block and QT interval

prolongation as risk markers. This strategy has been successful at preventing harmful

drugs from being marketed, but criticized for leading to early withdrawal of potentially

safe drugs. Here we collected a series of articles presenting new technological and

conceptual advances, including refinement of ex vivo and in vitro assays, screens

and models, and in silico approaches reflecting the increasing effort that has been

put forward by regulatory agencies, industry, and academia to try and address the

need of a more accurate, mechanistically-based paradigm of proarrhythmic potential

of drugs.

This Research Topic is dedicated to the memory of Dr. J. Jeremy Rice, our wonderful

friend and colleague.
 

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Contents

Safety Pharmacology Risk Assessment QT Interval Prolongation and Beyond
6
Combined Experimental and Simulation Study
11
Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker dSotalol with AllAtom Simulations
31
The Devil Is in the Details
50
Role of Kinetics and StateDependence of Drug Binding
62
Global Optimization of Ventricular Myocyte Model to MultiVariable Objective Improves Predictions of DrugInduced Torsades de Pointes
76
Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment
86
Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment
101
Proton Pump Inhibitors and Serum Magnesium Levels in Patients With Torsades de Pointes
219
A Case Study for Combined Treatment of Coronary Heart Diseases with Atrial Fibrillation
229
Have the Findings from Clinical Risk Prediction and Trials Any Key Messages for Safety Pharmacology?
239
Humans Vary So Cardiac Models Should Account for That Too
250
Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical ProArrhythmic Cardiotoxicity
259
Quantitative Comparison of Effects of Dofetilide Sotalol Quinidine and Verapamil between Human Ex vivo Trabeculae and In silico Ventricular Mo...
274
Tailoring Mathematical Models to StemCell Derived Cardiomyocyte Lines Can Improve Predictions of DrugInduced Changes to Their Electrophysiol...
293
In Silico Investigation of Effects on Function and Disease Modeling
306

Uncertainty Quantification Reveals the Importance of Data Variability and Experimental Design Considerations for in Silico Proarrhythmia Risk Asse...
103
Composite Biomarkers Derived from MicroElectrode Array Measurements and Computer Simulations Improve the Classification of DrugInduced Ch...
120
Novel TwoStep Classifier for Torsades de Pointes Risk Stratification from Direct Features
137
Synergistic Antiarrhythmic Effects in Human Atria with Combined Use of Sodium Blockers and Acacetin
155
MultiDimensional Modulation of QTProlongation Associated Arrhythmic Dynamics by a hERG Channel Activator
176
Simultaneous Quantification of Spatially Discordant Alternans in Voltage and Intracellular Calcium in LangendorffPerfused Rabbit Hearts and Incons...
194
Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics
208
Role in Drug Target Discovery and Safety Pharmacology Testing
323
Using Dynamic Clamp to Join iPSCDerived Cardiomyocytes and Simulations of Ik1 Ion Channels in RealTime
331
Evaluation of Optogenetic Electrophysiology Tools in Human Stem CellDerived Cardiomyocytes
341
Adult Human Primary CardiomyocyteBased Model for the Simultaneous Prediction of DrugInduced Inotropic and Proarrhythmia Risk
355
Action Potential Recording and Proarrhythmia Risk Analysis in Human Ventricular Trabeculae
371
Back Cover
384
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