Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study
Jose Vicente, Robbert Zusterzeel, Lars Johannesen, Roberto Ochoa-Jimenez, Jay W Mason, Carlos Sanabria, Sarah Kemp, Philip T Sager, Vikram Patel, Murali K Matta, Jiang Liu, Jeffry Florian, Christine Garnett, Norman Stockbridge, David G Strauss, Jose Vicente, Robbert Zusterzeel, Lars Johannesen, Roberto Ochoa-Jimenez, Jay W Mason, Carlos Sanabria, Sarah Kemp, Philip T Sager, Vikram Patel, Murali K Matta, Jiang Liu, Jeffry Florian, Christine Garnett, Norman Stockbridge, David G Strauss
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-à-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.
Trial registration: ClinicalTrials.gov NCT03070470.
Conflict of interest statement
P.T.S. has consulting agreements with Biomedical Systems, Charles River, and iCardiac. The other authors report no conflicts of interest.
Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.
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