Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study

Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-T-peak (J-T(peak)c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of Delta Delta J-T(peak)c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether-a-go-go related gene (hERG), prolonged Delta Delta QTc and Delta Delta J-T(peak)c by >= 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced Delta QTc prolongation, but shortened Delta J-T(peak)c and prolonged Delta T-peak-T-end. Absence of J-T(peak)c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.