1. Assessment of Multi‐Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study
- Author
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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, and Strauss, David G.
- Subjects
Adult ,Male ,medicine.medical_specialty ,hERG ,Ranolazine ,030226 pharmacology & pharmacy ,Ion Channels ,03 medical and health sciences ,Electrocardiography ,0302 clinical medicine ,Heart Rate ,Torsades de Pointes ,Internal medicine ,Membrane Transport Modulators ,medicine ,Humans ,Pharmacology (medical) ,Myocytes, Cardiac ,Diltiazem ,Pharmacology ,Proarrhythmia ,Cross-Over Studies ,biology ,business.industry ,Research ,Drug-induced QT prolongation ,medicine.disease ,Crossover study ,Clinical Trial ,Potassium channel ,Long QT Syndrome ,Pharmaceutical Preparations ,030220 oncology & carcinogenesis ,Cardiology ,biology.protein ,Verapamil ,Female ,business ,Biomarkers ,medicine.drug - Abstract
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-Tpeak 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 ΔΔJ-Tpeak 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 ΔΔQTc and ΔΔJ-Tpeak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ΔQTc prolongation, but shortened ΔJ-Tpeak c and prolonged ΔTpeak -Tend . Absence of J-Tpeak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.
- Published
- 2019