Drug-induced QT prolongation: Concordance of preclinical anesthetized canine model in relation to published clinical observations for ten CiPA drugs

• Published in: Journal of pharmacological and toxicological methods 2020-05, Vol.103, p.106871, Article 106871
• Main Authors: Koshman, Yevgeniya E., Wilsey, Amanda S., Bird, Brandan M., Endemann, Aimee L., Sadilek, Sabine, Treadway, Jessica, Martin, Ruth L., Polakowski, James S., Gintant, Gary A., Mittelstadt, Scott W.
• Format: Article
• Language: English
• Subjects: Anesthetized dog cardiovascular model; Animals; Anti-Arrhythmia Agents - pharmacology; CiPA; Dogs; Drug Evaluation, Preclinical; Electrocardiography; Heart Rate - drug effects; HEK293 Cells; Humans; IKr; In vivo preclinical model; Long QT Syndrome - chemically induced; Long QT Syndrome - drug therapy; Male; Models, Cardiovascular; Prospective Studies; QT prolongation; QTc; Repolarization; Risk Assessment; TdP; Torsades de pointes; Torsades de Pointes - chemically induced; Torsades de Pointes - drug therapy
• ISSN: 1056-8719; 1873-488X
• DOI: 10.1016/j.vascn.2020.106871

The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative differentiates torsadogenic risk of 28 drugs affecting ventricular repolarization based on multiple in vitro human derived ionic currents. However, a standardized prospective assessment of the electrophysiologic effects of these drugs in an integrated in vivo preclinical cardiovascular model is lacking. This study questioned whether QTc interval prolongation in a preclinical in vivo model could detect clinically reported QTc prolongation and assign torsadogenic risk for ten CiPA drugs. An acute intravenous administered ascending dose anesthetized dog cardiovascular model was used to assess QTc prolongation along with other electrocardiographic (PR, QRS intervals) and hemodynamic (heart rate, blood pressures, left ventricular contractility) parameters at plasma concentrations spanning and exceeding clinical exposures. hERG current block potency was characterized using IC50 values from automated patch clamp. All eight drugs eliciting clinical QTc prolongation also delayed repolarization in anesthetized dogs at plasma concentrations within four-fold clinical exposures. In vitro QTc safety margins (defined based on clinical Cmax values/plasma concentrations eliciting statistically significant QTc prolongation in dogs) were lower for high vs intermediate torsadogenic risk drugs. In comparison, hERG IC10 values represented as total drug concentrations were better predictors of preclinical QTc prolongation than hERG IC50 values. There was good concordance for QTc prolongation in the anesthetized dog model and clinical torsadogenic risk assignment. QTc assessment in the anesthetized dog remains a valuable part of a more comprehensive preclinical integrated risk assessment for delayed repolarization and torsadogenic risk as part of a global cardiovascular evaluation.