The 'overly-sensitive' heart: sodium channel block and QRS interval prolongation

Cardiac safety remains of paramount importance in the development of successful clinical drug candidates. Great progress has been made recently in understanding liabilities associated with delayed ventricular repolarization (manifest as QT prolongation) and in predicting (thus avoiding) drugs that delay repolarization based on application of strategic preclinical assays. Following the advances made in clinical electrophysiological monitoring and conduct of thorough QT studies, focus is now shifting towards monitoring of additional drug-induced effects, particularly on ventricular conduction (measured as changes in the QRS interval on the ECG) as part of evolving clinical thorough ECG studies. In this issue of the British Journal of Pharmacology, a study by Harmer et al. proposes provisional safety margins for QRS prolongation in man based on retrospective clinical data and a single in vitro approach to assess potency of block of cardiac sodium current (hNav1.5), the ionic current responsible for ventricular conduction (observed as QRS prolongation). The present commentary places their study in context with evolving preclinical cardiac electrophysiological safety assessments, along with discussions focused on ensuring the proper 'translation' of preclinical findings with potential clinical concerns. Given the extant limitations and uncertainties of presently available data, as well as our limited understanding of the pro-arrhythmic potential associated with these changes, due caution should be applied when considering the proposed in vitro-based margins for drug-induced QRS prolongation measured clinically. Additional validation with multiple preclinical models and more rigorous clinical safety studies will be necessary to substantiate these recommended margins.