Early prediction of proarrhythmic cardiotoxicity in the drug development process

Abstract

This editorial refers to ‘Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk’ by G.R. Mirams et al ., pp. 53–61, this issue. Drug-induced QT interval prolongation and the appearance of life-threatening Torsade de Pointes (TdP) arrhythmia are potential risks during treatment with a variety of drug compounds, including anti-arrhythmics and non-cardiovascular drugs.1–3 Because of this cardiotoxic side effect, a number of non-cardiovascular drugs have been withdrawn from the market, and the development of several compounds has been aborted in the late phases of the development programmes.2–6 The late detection of cardiotoxic side effects induced by compounds of pharmacological interest can significantly obstruct drug discovery and development projects and increase their cost. Consequently, it is desirable to identify the potential proarrhythmic cardiotoxicity of compounds at an early stage of drug development. In the majority of cases, drugs that prolong the QT interval preferentially inhibit the rapid component of the delayed rectifier potassium current I Kr (or hERG, the α-subunit of I Kr channels). It is the major repolarizing current of the cardiac action potential that is exceptionally susceptible to blockade by many different compounds. Drugs that block I Kr prolong the action potential duration and …