A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium

  • Publication Date :
  • Publication Type : Journal Article
  • Author(s) : Emmanuel Boulay, Matthew M. Abernathy, Ray Chu, Gregory S. Friedrichs, Nicolas Gendron-Parra, Andrea Greiter-Wilke, Jean-Michel Guillon, John E. Koerner, Ariane Menard, Jill Steidl-Nichols, Jennifer Pierson, Michael K. Pugsley, Eric I. Rossman, David Strauss, Eric Troncy, Jean-Pierre Valentin, Todd Wisialowski, Simon Authier
  • Journal Name : International Journal of Toxicology

Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers.

Full text online: https://journals.sagepub.com/doi/full/10.1177/1091581818813601

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