2023 FDA Science Forum
Cardiotoxicity Assessment of HESI Reference Compounds Using HiPSC-CMs
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Contributing OfficeNational Center for Toxicological Research
Abstract
Background
Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are increasingly used in preclinical in vitro cardiac toxicity testing. Combined with various high-throughput assay platforms, hiPSC-CMs have the potential to enhance drug-induced cardiotoxicity detection and prediction, particularly of those that cannot be easily identified with the current preclinical safety evaluation in animals due to species differences. Moreover, patients with prolonged exposure to numerous drugs, such as anthracyclines, tyrosine kinase inhibitors, and drugs that disrupt ion channel trafficking, often exhibit some late onset cardiotoxic effects.
Purpose
To evaluate the predictability of current hiPSC-CM in vitro assays for detection of chronic cardiac toxicity, the Health and Environmental Sciences Institute (HESI) Stem Cell Working Group organized a multi-site blinded study.
Methodology
Twelve well-characterized cardiotoxins with different mechanisms were selected, coded, and tested using different platforms following the same drug preparation protocol at multiple sites, including the National Center for Toxicological Research (NCTR). The compounds were uncoded after all the raw data were sent to HESI for statistical analysis. Specifically, at NCTR, the responses of iCell2 cardiomyocytes (FCDI, FujiFilm Cellular Dynamics) to the 12 compounds over 144 hours of exposure were evaluated using the xCELLigence RTCA Cardio instrument (Agilent). Dynamic changes in impedance parameters, including cell index (an indicator of cytotoxicity), beating amplitude, beating rate, and beating rhythm, were analyzed.
Results
Most of the HESI reference compounds exhibited some cardiotoxic effects at clinically relevant concentrations or at concentrations used in pharmacology and toxicology studies; only arsenic trioxide and milrinone showed little changes on impedance parameters. Arsenic trioxide was tested at relatively low concentrations, below maximum clinical plasma concentrations (< Cmax), due to a solubility issue. The positive inotropic effect of milrinone is challenging to detect and typically requires a 3D system or highly matured iPSC-CMs.
Conclusion
Drug screening for chronic cardiotoxicity using a hiPSC-CM impedance assay may provide some useful information for cardiotoxicity prediction; however, further characterizations are needed to identify the related electrophysiological, structural, energetic, and contractility changes of cardiomyocytes upon chronic drug exposure.
