An impedance-based approach using human iPSC-derived cardiomyocytes significantly improves in vitro prediction of in vivo cardiotox liabilities

• Published in: Toxicology and applied pharmacology Vol. 329; pp. 121 - 127
• Main Authors: Koci, Bryan, Luerman, Gregory, Duenbostell, Anika, Kettenhofen, Ralf, Bohlen, Heribert, Coyle, Luke, Knight, Brian, Ku, Warren, Volberg, Walter, Woska, Joseph R., Brown, Martha P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.08.2017
• Subjects: Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - pathology; Arrhythmias, Cardiac - physiopathology; Biological Assay; Cardiomyocytes; Cardiotoxicity; Cell Differentiation; Cell Lineage; Cells, Cultured; Dose-Response Relationship, Drug; Drug discovery; Drug Discovery - methods; Electric Impedance; Heart Rate - drug effects; High-Throughput Screening Assays; Humans; Impedance; In vitro; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; iPSC; Molecular Structure; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Phenotype; Reproducibility of Results; Risk Assessment; Structure-Activity Relationship; Time Factors; Toxicity Tests - methods; hIPSC-CMs; iPSC; CiPA; Cardiomyocytes; Cardiotoxicity; Drug discovery; Impedance; In vitro; HDAC
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2017.05.023

Current in vitro approaches to cardiac safety testing typically focus on mechanistic ion channel testing to predict in vivo proarrhythmic potential. Outside of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, structural and functional cardiotoxicity related to chronic dosing effects are of great concern as these effects can impact compound attrition. Development and implementation of an in vitro cardiotoxicity screening platform that effectively identifies these liabilities early in the discovery process should reduce costly attrition and decrease preclinical development time. Impedence platforms have the potential to accurately identify structural and functional cardiotoxicity and have sufficient throughput to be included in a multi-parametric optimization approach. Human induced pluripotent stem cell cardiomyocytes (hIPSC-CMs) have demonstrated utility in cardiac safety and toxicity screening. The work described here leverages these advantages to assess the predictive value of data generated by two impedance platforms. The response of hIPSC-CMs to compounds with known or predicted cardiac functional or structural toxicity was determined. The compounds elicited cardiac activities and/or effects on “macro” impedance often associated with overt structural or cellular toxicity, detachment, or hypertrophy. These assays correctly predicted in vivo cardiotox findings for 81% of the compounds tested and did not identify false positives. In addition, internal or literature Cmax values from in vivo studies correlated within 4 fold of the in vitro observations. The work presented here demonstrates the predictive power of impedance platforms with hIPSC-CMs and provides a means toward accelerating lead candidate selection by assessing preclinical cardiac safety earlier in the drug discovery process. •Assessment of the impedance platform to predict both chronic and acute in vivo cardiotoxicity.•Cardiac functional and structural cardiotoxicity was evaluated.•The impedance assay predicted >80% of known in vivo cardiotoxicity.•Data supports utilization of this assay for early drug discovery cardiac safety profiling.