Page, Guy, Ratchada, Phachareeya, Miron, Yannick, Steiner, Guido, Ghetti, Andre, Miller, Paul E, Reynolds, Jack A, Wang, Ken, Greiter-Wilke, Andrea, Polonchuk, Liudmila, Traebert, Martin, Gintant, Gary A and Abi-Gerges , Najah (2016) Human ex-vivo action potential model for pro-arrhythmia risk assessment. Journal of Pharmacological and Toxicological Methods, http:/ (http:/). pp. 12-25. ISSN PM-06368

Abstract

While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of potentially important, high quality drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to record APs. Effects of torsadogenic (Dofetilide, D,L-Sotalol, Quinidine) and non-torsadogenic (Paracetamol, Verapamil) drugs were assessed on AP parameters (AP duration at 30% (APD30), 50% (APD50) and 90% (APD90) of repolarization, short-term variability (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations (EADs) at 1 and 2 Hz) to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 ascending concentrations in triplicate trabeculae from 5 hearts, with one time-matched control per heart. Electrophysiological stability of the model was not affected by 3 sequential applications of vehicle (0.1% dimethyl sulfoxide). Dofetilide, D,L-Sotalol and Quinidne exhibited a concentration-dependent increase in the manifestation of pro-arrhythmia markers. Paracetamol and Verapamil did not significantly alter anyone of the parameters used in this study and were classified as devoid of pro-arrhythmic risk. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to detect drug-induced AP effects. In conclusion, the human ex-vivo AP-based model provides an integrative translational assay assisting in decision/guidance for clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

Item Type:	Article
Date Deposited:	12 Aug 2016 00:45
Last Modified:	12 Aug 2016 00:45
URI:	https://oak.novartis.com/id/eprint/28753