Clinical Electrophysiology -> Ventricular Arrhythmias -> Physiology-Pharmacology D-PO06 - Poster Session VI (ID 26) Poster

D-PO06-055 - Automated Analysis Of Drug-induced Electrocardiogram Changes From Cardiac Safety Trials (ID 687)

 S.R. Jafarian Kerman: Nothing relevant to disclose.


Background: Drug-induced torsade de pointes (TdP) is associated with hERG channel (hERG) blockage and QT prolongation. However, drugs that block inward currents to a similar or larger extent than hERG can have low TdP risk (balanced blockers). The Comprehensive in-vitro Proarrhythmia Assay (CiPA) initiative proposes a mechanistic paradigm coupling in-vitro data with an in-silico model to predict TdP risk. In addition, surface ECG is used to confirm the ion channel effects in humans. Prior studies have shown that QT prolongers with balanced block do not prolong J-Tpeak.
Objective: Characterize ECG signature of a large number of drugs in the FDA ECG warehouse of QT studies and FDA-sponsored ECG biomarker studies.
Methods: Automated QT and J-Tpeak measures and concentration response analysis of 115 QT studies were performed. Each drug was classified based on its predominant ion channel blocking effects: hERG, late Na/Ca, balanced (hERG + late Na/Ca), none and unknown. Placebo-corrected changes from baseline (∆∆) for QTc and J-Tpeakc at Cmax were plotted for 147 different moieties and 39 moxifloxacins.
Results: The plot shows two key ECG signatures: 1) hERG blockers fall around a positive diagonal line; 2) balanced blockers fall in a horizontal region with QTc prolongation along with shortening or no significant J-Tpeakc prolongation (figure). Thirteen out of 32 drugs with unknown ion channel effects and ∆∆QTc > 10ms fall within the balanced region.
Conclusion: A considerable number of QTc prolongers do not prolong J-Tpeak, suggesting they may be balanced ion channel blockers with low TdP risk. Future work should involve a full CiPA assessment to predict TdP risk of these drugs.