Drug Proarrhythmic Evaluation in a High Throughput Cardiac New Approach Methodology

Abstract Background and Purpose Cardiotoxicity is a major cause for drug failure throughout the drug development process, with particular concern for action potential prolongation and arrhythmia. Hence, such liabilities are heavily considered during the early phases of drug design to pre vent dangerous compounds from progressing. New approach methodologies ( NAMs ) that efficiently examine this risk early in the discovery pipeline should help streamline drug development programs. We developed a cardiac NAM, a 384-well open bath platform consisting of cardiac tissue derived from human induced pluripotent stem cell ( hiPSC )-derived cardiomyocytes, enabling high-throughput drug screening while maintaining the structural and functional complexity of 3D cardiac micromuscles. Methods We dramatically increased throughput without compromising physiological relevance provided by the 3D micromuscle …