Prediction of Cardiotoxicity Potential Using Targeted Metabolomics and Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes [SPS 2018]
Presented at the Safety Pharmacology Society (SPS) Annual Meeting in Washington, DC, September / October 2018
- Cardiac safety is one of the leading causes of late-stage compound attrition in the pharmaceutical industry and accounts for 28% of the safety related withdrawals of FDA-approved drugs from the market.
- Current cardiac safety preclinical evaluations are heavily focused on electrophysiological assessment and fail to evaluate cardiomyopathy and other forms of structural cardiotoxicity.
- Metabolic perturbations are one of the primary mechanisms underlying the cardiotoxicity elicited by pharmaceuticals.
- We have developed a biomarker-based assay for evaluating the cardiotoxicity potential of compounds based on changes in the metabolism and viability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM).
- Assay development and testing was conducted in two phases: (1) biomarker identification and (2) targeted assay development / biomarker confirmation.
– In the first phase, hiPSC-CM were exposed to 57 compounds (37 cardiotoxic, 20 Non) and the spent media was analyzed using untargeted UPLC-HRMS-based metabolomics. The cardiotoxic compounds were broken into three categories, structural, functional, and compounds that cause both types of cardiotoxicity. Analysis of metabolomics data identified a set of biomarkers that represent different metabolic pathways.
– In phase two, a rapid, targeted UPLC-HRMS method was developed for the five most predictive biomarkers. A composite model was developed that discriminates cardiotoxic from non-cardiotoxic compounds based on changes in hiPSC-CM metabolism of five metabolites and cell viability. - The predictive model classified 78 compounds with known cardiotoxicity outcomes (49 cardiotoxic, 29 non-cardiotoxic) with 86% accuracy, 92% sensitivity, and 79% specificity based on the response observed at 10-times the therapeutic Cmax. The model correctly classified 100% of the functional cardiotoxicants, 79% of the structural cardiotoxicants, and 95% of the compounds known to cause both functional and structural cardiotoxicity.
- This new hiPSC-CM-based assay provides a paradigm that can identify both structural and functional cardiotoxic compounds that could be used in conjunction with CiPA and other endpoints to provide a more comprehensive evaluation of a compound’s cardiotoxicity potential.
