Many of the in vitro assays for evaluating cardiac liability are based on the prediction of proarrhythmias from acute short term dosing. Indeed, this has been a focus of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative. The risk of this approach is that other cardiotoxic mechanisms which rely on chronic longer term dosing may be not be picked up by these in vitro assays, and typically, chronic dosing studies have to be performed in telemerized dogs at great expense in order to detect these liabilities.
Our research at Cyprotex has highlighted the real power of iPSC-derived cardiomyocytes used in conjunction with microelectrode array (MEA). The benefit of this in vitro system is that cells can be maintained and monitored over long periods of time allowing assessment of acute and chronic dosing with relatively low compound requirements.
Four compounds with known chronic cardiac liability were assessed using the MEA platform. These included:
- Pentamidine – Inhibitor of hERG trafficking
- BMS-986094 – Hepatitis C drug that caused death in clinical trial after multiple weeks
- Compound X – Loss of Na amplitude and slope after 24 hr
- Compound Y – Delayed arrhythmias after 6 days (delay in repolarisation but no hERG effect)
It is important to note that all of these compounds only display cardiotoxic effects after longer term dosing. Furthermore, we demonstrate that the iPSC-derived cardiomyocyte MEA platform is capable of detecting these liabilities through chronic dosing over 14 days. As electrical activity is measured without addition of any reagents, continual monitoring of activity over multiple time points is possible in order to capture any acute or chronic effects.
This research was presented at the Safety Pharmacology Society Annual Meeting in Washington DC from Sept 30-Oct 3, 2018.