Electrocardiographic biomarkers to confirm drug's electrophysiological effects used for proarrhythmic risk prediction under CiPA.

The ECG plays a critical role in the thorough QT study. This clinical study is part of the assessment of proarrhythmic potential of drugs under the current regulatory paradigm. While the current paradigm has been successful in preventing drugs with unexpected QT prolongation or torsade risk from reaching the market, the focus on QT prolongation has likely resulted in potentially beneficial compounds with minimal torsade risk being dropped from development. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new mechanistic-based paradigm for cardiac safety evaluation of drugs. The fourth component of CiPA uses ECG data in phase 1 clinical studies to confirm there are no unanticipated ion channel effects compared to nonclinical data. The J-Tpeak interval was identified as the best biomarker for differentiating QTc prolonging drugs with predominant hERG block from drugs with multichannel (hERG plus late sodium and/or calcium block). This manuscript describes ECG methods for J-Tpeak assessment and their relationship with the features of new ECG biomarkers for detecting multichannel effects under CiPA.