Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in the Comprehensive in vitro Proarrhythmia Assay (CiPA). The notable difference of the electrophysiological (EP) responses of hiPSC-CMs in serum and serum-free media (SFM) is puzzling and may impact regulatory decision-making on the cardiac safety of candidate drugs in inducing QT prolongation and torsade de pointes (TdP). In this study, we compared the EP responses of hiPSC-CMs to 10 CiPA compounds and moxifloxacin in serum and SFM; explained the potential reason behind the different EP responses-abiotic compound loss to plastic tubes/plates of hydrophobic compounds prepared in SFM; and investigated the impact of compound preparation methods on drug bioavailability in exposure media, which affects the TdP risk prediction of drugs tested in serum-containing and SFM. For assays to be conducted in SFM, awareness of abiotic compound loss of hydrophobic compounds in serum-free preparations is critical for delay repolarization evaluation and data extrapolation from in vitro to in vivo.
Keywords: Comprehensive in vitro Proarrhythmia Assay (CiPA); abiotic compound loss; human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM); microelectrode array (MEA); serum-free media (SFM).
Published by Oxford University Press on behalf of the Society of Toxicology 2022. This work is written by US Government employees and is in the public domain in the US.