Najah Abi Gerges
AnaBios Corporation, USA
Title: Integrating adult human primary cardiomyocytes into early cardiac safety assessment
Biography
Biography: Najah Abi Gerges
Abstract
Drug-induced pro-arrhythmia and/or changes in contractility can limit the utility of potential novel therapeutics. Since abnormal ventricular repolarization can cause not only electrical disorders, but also affect the heart’s contractile function, we developed a new model based on adult human primary cardiomyocytes to provide a preclinical tool for the simultaneous prediction of drug-induced inotropic and pro-arrhythmia risks. We recorded fractional sarcomere shortening (SS) using a digital, cell geometry measurement system (IonOptix™) and then record changes in the contractility transients to infer both inotropic (SS) as well as pro-arrhythmia risk (aftercontraction). Validation data were generated with 38 clinically well characterized controls: 23 torsadogenic and 10 non-torsadogenic drugs, and 5 positive inotropes. When the assessment of pro-arrhythmia risk was based on effects observed at 10x of the free effective therapeutic plasma concentration, human cardiomyocyte-based model had excellent assay 96% sensitivity and 100% specificity. Human cardiomyocytes also identified drugs associated with negative and positive inotropic effects. Moreover, positive inotrope-induced changes in contractility parameters illustrated the potential for finger-printing different mechanisms of action. Thus, human cardiomyocytes can simultaneously predict risks associated with pro-arrhythmia and inotropic activity. This approach enables the generation of predictive preclinical human-based cardiotoxicity data and appears to be more predictive than the stem cell-derived cardiomyocyte models.