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

Journal Article · · Clinical Pharmacology and Therapeutics
DOI:https://doi.org/10.1002/cpt.1303· OSTI ID:1491414
 [1];  [2];  [1];  [2];  [3];  [4];  [4];  [5];  [2];  [2];  [2];  [1];  [1];  [1];  [2]
  1. Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USA
  2. Office of Clinical Pharmacology Office of Translational Science Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USA
  3. Department of Medicine Division of Cardiology University of Utah Salt Lake City Utah USA, Spaulding Clinical Research West Bend Wisconsin USA
  4. Spaulding Clinical Research West Bend Wisconsin USA
  5. Stanford University Palo Alto California USA
+ Show Author Affiliations

Balanced multi‐ion channel‐blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (Ci PA ) 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 ΔΔJ‐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‐à‐go‐go related gene (hERG), prolonged ΔΔ QT c and ΔΔJ‐T peak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide‐induced Δ QT c prolongation, but shortened ΔJ‐T peak c and prolonged ΔT 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.

Research Organization:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
SC0014664
OSTI ID:
1491414
Alternate ID(s):
OSTI ID: 1491415; OSTI ID: 1623521
Journal Information:
Clinical Pharmacology and Therapeutics, Journal Name: Clinical Pharmacology and Therapeutics Vol. 105 Journal Issue: 4; ISSN 0009-9236
Publisher:
Wiley-BlackwellCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 50 works
Citation information provided by
Web of Science

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