title: Human ex-vivo action potential model for pro-arrhythmia risk assessment.
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 valuable 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 evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. 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 identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.
authors.affiliation: AnaBios Corporation, San Diego, CA 92109, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Page
authors.affiliation: AnaBios Corporation, San Diego, CA 92109, USA.
authors.forename: Phachareeya
authors.initials: P
authors.lastname: Ratchada
authors.affiliation: AnaBios Corporation, San Diego, CA 92109, USA.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Miron
authors.affiliation: Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland.
authors.forename: Guido
authors.initials: G
authors.lastname: Steiner
authors.affiliation: AnaBios Corporation, San Diego, CA 92109, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Ghetti
authors.affiliation: AnaBios Corporation, San Diego, CA 92109, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Miller
authors.affiliation: AnaBios Corporation, San Diego, CA 92109, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Reynolds
authors.affiliation: Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland.
authors.forename: Ken
authors.initials: K
authors.lastname: Wang
authors.affiliation: Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Greiter-Wilke
authors.affiliation: Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Polonchuk
authors.affiliation: Novartis Institutes of Biomedical Research, Safety Pharmacology, CH-4057 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Traebert
authors.affiliation: Department of Integrative Pharmacology Integrated Sciences & Technology, AbbVie, North Chicago, IL, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Gintant
authors.affiliation: AnaBios Corporation, San Diego, CA 92109, USA. Electronic address: Najah.abigerges@anabios.com.
authors.forename: Najah
authors.initials: N
authors.lastname: Abi-Gerges
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology*; D002317:Cardiovascular Agents / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D055808:Drug Discovery; D004562:Electrocardiography / Q000187:drug effects; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011237:Predictive Value of Tests; D018570:Risk Assessment; D059629:Signal-To-Noise Ratio; D055815:Young Adult
chemical_list: D002317:Cardiovascular Agents
keywords: Action potential; Drug discovery and development; Human heart; Pro-arrhythmia assessment; Ventricular trabeculae