Assessing cardiac liability of compounds using new approach methodologies (NAMs)

Abstract

Animal studies have been used extensively to gain information about the toxicity of new compounds. Although these studies have proved beneficial, they are limited by translational challenges at times. To overcome limitations associated with animal studies, there has been a growing interest to develop faster, less expensive, and more informative new approach methodologies (NAMs). Comprehensive in vitro Proarrhythmia assay (CiPA) initiative provides a potential NAMs for assessment of the proarrhythmic potential of new drugs that has improved specificity compared with the hERG assay plus Thorough QT study.

To assess cardiac liability of CiPA validated compounds in acute (30 min) and prolonged (24 h) exposure conditions, using human induced pluripotent stem cells (hiPSCs)-derived cardiomyocytes (CMs) and multi-electrode array (MEA) platform (NAMs).

Commercially available hiPSC-derived ventricular CMs were used for this study. hiPSC-derived CMs were cultured for up to 10 days using standard culture medium and sterile conditions. Cardiac activity was recorded every other day, starting at Days in vitro (DIV)- 3. Data were processed using the cardiac analysis tool (Axion BioSystems) and GeneData software.

We evaluated cardiac liability, upon acute and prolonged exposure of multiple CiPA validated compounds (Bepridil, Quinidine, Ondansetron & Verapamil) linked to low, intermediate, and high torsades de pointes (TdP) risk categories. Data suggests, acute and prolonged exposure of both Quinidine (≥3 μM) & Ondansetron (≥3 μM) results in arrhythmias. Furthermore, acute exposure of certain CiPA validated compounds (Bepridil, 1 μM) can inhibit spontaneous hiPSCs-derived CMs contractions, that recovers upon prolonged exposure, enabling cardiac liability assessment.

We successfully demonstrate that New Approach Methodologies (NAMs) incorporating hiPSCs-derived CMs, and MEA assay provides a valuable platform to determine cardiac liability of small molecules both in acute and prolonged exposure conditions. This in-vitro platform serves as a translational and accessible resource for determining safety pharmacology of novel compounds during drug discovery efforts.