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

• Published in: Clinical pharmacology and therapeutics Vol. 105; no. 4; pp. 943 - 953
• Main Authors: Vicente, Jose, Zusterzeel, Robbert, Johannesen, Lars, Ochoa‐Jimenez, Roberto, Mason, Jay W., Sanabria, Carlos, Kemp, Sarah, Sager, Philip T., Patel, Vikram, Matta, Murali K., Liu, Jiang, Florian, Jeffry, Garnett, Christine, Stockbridge, Norman, Strauss, David G.
• Format: Journal Article
• Language: English
• Published: United States 01.04.2019
• Subjects: Adult; Biomarkers - metabolism; Cross-Over Studies; Electrocardiography - drug effects; Female; Heart Rate - drug effects; Humans; Ion Channels - antagonists & inhibitors; Long QT Syndrome - drug therapy; Long QT Syndrome - metabolism; Male; Membrane Transport Modulators - therapeutic use; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Pharmaceutical Preparations - administration & dosage; Torsades de Pointes - drug therapy; Torsades de Pointes - metabolism
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1002/cpt.1303

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‐Tpeak (J‐Tpeakc) 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 ΔΔJ‐Tpeakc 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‐à‐go‐go related gene (hERG), prolonged ΔΔQTc and ΔΔJ‐Tpeakc by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide‐induced ΔQTc prolongation, but shortened ΔJ‐Tpeakc and prolonged ΔTpeak‐Tend. Absence of J‐Tpeakc prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration‐response in some cases.