Abstract 245: Assessing Proarrhythmic Potential of Drugs Using Human Induced Pluripotent Stem Cell Derived Cardiomyocytes and Optical Recordings With Voltage-sensitive Dyes

Abstract

Background: Drug-induced arrhythmias have been a leading reason for withdrawing drugs from the market and abandoning the development of new drugs. For the past decade FDA has required new drugs to be tested for block of the hERG potassium channel and QT interval prolongation. While these requirements have prevented arrhythmia-related drug recalls, some new drugs affecting multiple ion channels are being dropped from development inappropriately. Human induced pluripotent stem cell derived cardiomyocytes (iPS-CMs) are a new technology for preclinical risk assessment; however they have not been fully characterized or validated. Methods: We studied 26 drugs and 3 drug combinations that block multiple cardiac ion channels with two commercially available iPS-CM lines from Axiogenesis and Cellular Dynamics using optical recordings of action potentials with voltage-sensitive dyes. Drug-induced action potential duration (APD) prolongation was compared to clinical QT prolongation from two FDA-sponsored clinical trials. The effects of the drugs on multiple individual cardiac ion channels were assessed using manual patch clamp of overexpressed cell lines. Cardiac ion channel gene expression in the iPS-CMs was quantified and compared to primary human heart cell controls. Results: Of 19 drugs with an FDA label of clinical QT prolongation, 15 exhibited iPS-CM APD prolongation after acute drug exposure. None of the 6 drugs without clinical QT prolongation caused iPS-CM APD prolongation. Of 14 drugs with arrhythmia risk on the FDA label, nine caused arrhythmias in iPS-CMs. iPS-CM response had good correlation with clinical QT data for drugs that block hERG and calcium channels, while drugs blocking the late sodium current had variable response. This was in line with gene expression data, which showed most robust expression of hERG and calcium channels. Conclusion: Optical recordings from iPS-CMs with voltage sensitive dyes is a promising technology for high-throughput toxicity assessment for drug-induced arrhythmias. This study provides a comprehensive characterization of the cardiac ion channel properties of multiple commercially available iPS-CMs to support a potential new paradigm for assessing the arrhythmia risk of all new drugs.