Comprehensive In Vitro Proarrhythmia Assay (CiPA) Update from a Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA Meeting
Restricted accessResearch articleFirst published online July, 2019
Comprehensive In Vitro Proarrhythmia Assay (CiPA) Update from a Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA Meeting
A Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA-sponsored Think Tank Meeting was convened in Washington, DC, on May 21, 2018, to bring together scientists, clinicians, and regulators from multiple geographic regions to evaluate progress to date in the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative, a new paradigm to evaluate proarrhythmic risk. Study reports from the 4 different components of the CiPA paradigm (ionic current studies, in silico modeling to generate a Torsade Metric Score, human induced pluripotent stem cell–derived ventricular cardiomyocytes, and clinical ECG assessments including J-Tpeakc) were presented and discussed. This paper provides a high-level summary of the CiPA data presented at the meeting.
SagerPTGintantGTurnerJRPettitSStockbridgeN. Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium. Am Heart J. 2014;167:292–300.
de PontiF. Pharmacological and regulatory aspects of QT prolongation. In: VazJRKlabundeT, eds. Antitargets: Prediction and Prevention of Drug Side Effects. Weinheim, Germany: Wiley-VCH, 2008:55–88.
7.
FerminiBHancoxJCAbi-GergesN. A new perspective in the field of cardiac safety testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm. J Biomol Screen. 2016;21:1-11.
8.
VicenteJZusterzeelRJohannesenL. Mechanistic model-informed proarrhythmic risk assessment of drugs: review of the “CiPA” Initiative and design of a prospective clinical validation study. Clin Pharmacol Ther. 2018;103:54–66.
9.
O’HaraTViragLVarroARudyY. Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput Biol. 2011;7: e1002061.
10.
LiZDuttaSShengJ. Improving the in silico assessment of proarrhythmia risk by combining hERG (human ether-à-go-go-related gene) channel-drug binding kinetics and multichannel pharmacology. Circ Arrhythm Electrophysiol. 2017;10:e004628.
11.
DuttaSChangKCBeattieKA. Optimization of an in silico cardiac cell model for proarrhythmia risk assessment. Front Physiol. 2017;8:616.
12.
ChangKCDuttaSMiramsGR. Uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico proarrhythmia risk assessment. Front Physiol. 2017;8:917.
13.
BlinovaKStohlmanJVicenteJ. Comprehensive translational assessment of human-induced pluripotent stem cell derived cardiomyocytes for evaluating drug-induced arrhythmias. Toxicol Sci. 2017;155:234–247.
14.
AndoHYoshinagaTYamamotoW. A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes. J Pharmacol Toxicol Methods. 2017;84:111–127.
15.
MillardDDangQShiH. Cross-site reliability of human induced pluripotent stem-cell derived cardiomyocyte based safety assays using microelectrode arrays: results from a blinded CiPA pilot study. Toxicol Sci. 2018;164(2):550–562.
16.
JohannesenLVicenteJGrayRA. Improving the assessment of heart toxicity for all new drugs through translational regulatory science. Clin Pharmacol Ther. 2014;95:501–508.
17.
JohannesenLVicenteJMasonJW. Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil. Clin Pharmacol Ther. 2014;96:549–558.
18.
JohannesenLVicenteJMasonJW. Late sodium current block for drug-induced long QT syndrome: results from a prospective clinical trial. Clin Pharmacol Ther. 2016;99:214–223.
