Key result
New Approach Methodologies using human iPSC-derived cardiomyocytes successfully captured compound-induced arrhythmogenic and cardiotoxic effects, supporting an alternative to animal testing.
Why the study?
The FDA's phase-out of animal testing requirements for drug development creates an urgent need for validated New Approach Methodologies in safety pharmacology using human-relevant platforms.
Automated human iPSC-derived cardiomyocyte platforms offer robust and reliable data for cardiac safety assessment, supporting the transition away from animal models in drug development.
The April 2025 FDA announcement to phase out animal testing requirements for drug development underscores the urgent need for validated New Approach Methodologies (NAMs) in safety pharmacology. NAMs—including automated patch clamp, impedance-based contractility, and high-throughput cell-based assays—offer human-relevant data, increased throughput, and improved mechanistic insight compared to traditional animal studies. Here, we utilized state-of-the-art NAMs to address regulatory and scientific challenges in cardiac safety assessment using human iPSC-derived cardiomyocytes in line with CiPA recommendations. We present data generated using multiple automated patch clamp systems and impedance-based assay platforms as well as a system for in vivo–like contractility measurements. Investigations utilizing a 384-well automated patch clamp system demonstrate robust and reproducible hERG, Nav1.5, and Cav1.2 voltage clamp recordings from single human iPSC-derived cardiomyocytes. We utilized dynamic clamp for action potential recordings to simulate IK 1 and perform a seal compensation. Reference compounds were applied and ion channel effects were recorded. For instance, the Ca 2+ -channel activator S-BayK 8644 (10 μM) significantly prolonged the action potential duration at 90% repolarization (APD90) while the selective blocker Nifedipine (10 μM) reversed this effect. Next, chronic and acute evaluation of contractility and electrophysiological parameters in hiPSC-cardiomyocyte networks were investigated. Notably, compound-induced arrhythmogenic effects (for example using dofetilide), correlated well with clinical observations. Next to automated patch clamp platforms, impedance-based cell monitoring was used to conduct multi-parametric readouts, capturing compound effects on cell viability, morphology, and barrier integrity. Here, we used a subset of chronic cardiotoxicity reference compounds known to act via different mechanisms of actions (MoAs) in cardiomyocytes, affecting cardiac energetics (for example doxorubicin), contractility (Nilotinib), electrophysiology (pentamidine), and myofilament organization. Our results collectively demonstrate that NAMs not only meet but often exceed the predictive value of traditional animal assays, supporting their integration into regulatory safety pharmacology workflows. Our findings support the global transition toward animal-free safety testing, offering practical examples of how automated human-based platforms can deliver reliable, regulatory-relevant data for drug development.
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Stoelzle‐Feix et al. (2026) studied Cardiac safety assessment (Cardiotoxicity). New Approach Methodologies (NAMs) using human iPSC-derived cardiomyocytes vs. Traditional animal assays was evaluated on Electrophysiological parameters (e.g., APD90), contractility, and cell viability. New Approach Methodologies using human iPSC-derived cardiomyocytes successfully captured compound-induced arrhythmogenic and cardiotoxic effects, supporting an alternative to animal testing.
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