Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk
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Open Access
- 7 February 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 91 (1), 53-61
- https://doi.org/10.1093/cvr/cvr044
Abstract
The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC50) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk. We collected multiple ion channel data (hERG, Na, l-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC50 values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers. The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.Keywords
This publication has 35 references indexed in Scilit:
- Chaste: A test-driven approach to software development for biological modellingComputer Physics Communications, 2009
- A novel computational model of the human ventricular action potential and Ca transientJournal of Molecular and Cellular Cardiology, 2009
- CellML and associated tools and techniquesPhilosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 2008
- A Rabbit Ventricular Action Potential Model Replicating Cardiac Dynamics at Rapid Heart RatesBiophysical Journal, 2008
- A Rabbit Langendorff Heart Proarrhythmia Model: Predictive Value for Clinical Identification of Torsades de PointesBritish Journal of Pharmacology, 2006
- Cumulative Experience of Azimilide-Associated Torsades de Pointes Ventricular Tachycardia in the 19 Clinical Studies Comprising the Azimilide DatabaseJournal of the American College of Cardiology, 2006
- Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic DrugsJournal of Pharmacology and Experimental Therapeutics, 2005
- Refining detection of drug-induced proarrhythmia: QT interval and TRIaDHeart Rhythm, 2005
- Torsade de pointes induced by psychotropic drugs and the prevalence of its risk factorsActa Psychiatrica Scandinavica, 2005
- Spectrum of drugs prolonging QT interval and the incidence of torsades de pointesEuropean Heart Journal Supplements, 2001