Detection of proarrythmic cardiotoxicity using microelectrode array (MEA) technology and human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) is one method currently being investigated as part of the CiPA initiative as a way to define a more complete means to assess preclinical cardiotoxicity. Under the current risk assessment paradigm, the hERG ion channel, and inhibition thereof, is one of the determining factor of a compound’s cardiotoxic risk. In other words, preclinical results of positive hERG inhibition can be all it takes to derail an otherwise promising compound. However, recent research shows that there are many more contributing factors to drug-induced proarrhythmia than hERG alone, and electrophysiology studies using hiPSC-CMs on an MEA platform can provide valuable insight into mechanistic causes.
Adverse cardiotoxic effects have recently been reported with the hepatitis C drug, sofosbuvir, with severe bradycardia observed when co-administered with amiodarone. While this concomitant pharmacodynamic interaction was previously found in the general population (both drugs are currently marketed), a collaborative study, with contributors from a variety of institutions, was undertaken to evaluate the ability of a number of techniques including MEA to detect such a reaction and understand its mechanism.
Common electrophysiological mechanisms for arrhythmia such as direct ion channel block were not observed. Furthermore, evidence from the study suggested neither P-glycoprotein (P-gp) inhibition, nor metabolite production were important factors in the cardiotoxic event. However, shortened field potential duration, most often associated with ICaL blockage was noted, but patch clamp assessment showed no obvious blocking of ICaL. Clinically relevant concentrations of co-administered sofosbuvir andamiodarone cause electrophysiological effects consistent with altered intracellular calcium handling, which can directly impact ICaL behaviour. At high, supra-physiological concentrations, total cessation of contractile beating of the hiPSC-CMs was observed. Together, these results provide evidence for a pharmacodynamics drug-drug interaction with a cardiac mechanism of action. Confirmation of affected intracellular calcium handling was conducted using calcium imaging, which showed dose-dependent decreases in intracellular calcium transients.
The data gathered demonstrate the utility of hiPSC-CMs in assessing electrophysiological impacts of xenobiotics in a variety of assays, and may be especially useful for detection of pharmacodynamic DDIs with cardiac mechanisms of actions. It also shows the ability of MEA technology to accurately detect a variety of electrophysiological endpoints to guide further mechanistic investigation.