Scientific Publications by FDA Staff

Toxicol Sci 2017 Jan;155(1):234-7

Comprehensive translational assessment of human induced pluripotent stem cell derived cardiomyocytes for evaluating drug-induced arrhythmias.

Blinova K, Stohlman J, Vicente J, Chan D, Johannesen L, Hortigon-Vinagre MP, Zamora V, Smith G, Crumb WJ, Pang L, Lyn-Cook B, Ross J, Brock M, Chvatal S, Millard D, Galeotti L, Stockbridge N, Strauss DG

BACKGROUND: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the Comprehensive in Vitro Proarrhythmia Assay (CiPA). METHODS AND RESULTS: We studied the effects of 26 drugs and 3 drug combinations on two commercially available iPSC-CM types using high-throughput voltage-sensitive dye (VSD) and microelectrode-array (MEA) assays being studied for the Comprehensive in Vitro Proarrhythmia Assessment (CiPA) initiative and compared the results to clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced APDc and FPDc prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the 4 remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to hERG potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. CONCLUSION: Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted.