Functional evaluation of multiple cardiac ion channels during the drug discovery and development process provides a much clearer picture of a compound’s true cardiac risk compared to hERG block alone. These low-cost assays, typically performed on automated patch clamp platforms, ultimately provide better scientific insight and help guide subsequent development efforts.

The following table is a summary of cardiac ion channel screening data for a group of compounds that have been shown to exhibit varying degrees of cardiac risk.

Terfenadine, Cisapride and E-4031 are selective hERG blockers, increase QT and are dangerous. Laboratory testing is concordant with in vivo findings. Terfenadine does block Cav3.2 at supratherapeutic concentrations but the channels are unlikely to have an important effect on ventricular myocytes. Cav3.2 is thought to contribute to pacemaker depolarization.

Verapamil – a long-marketed drug for treatment of angina and hypertension. It blocks hERG in the therapeutic range but does not cause long QT. The Cardiac Channel Panel™ shows that verapamil blocks several ion channels including Na+ and Ca2+ to produce the opposite effect of hERG block. The multi-channel blockade results in normal repolarization.

Vanoxerine – under development as an antiarrhythmic. It blocks hERG at intended therapeutic concentrations but has been shown to be safe in clinical trials and does not affect cardiac repolarization in vitro. The Cardiac Channel Panel™ shows significant block of Na+ and Ca2+ channels that offsets hERG block.

Alfuzosin – a recently approved drug for treatment of benign prostatic hyperplasia causes a small QT prolongation. The Cardiac Channel Panel™ indicated that alfuzosin was a weak hERG blocker that also acted on Nav1.5 channels to prolong the action potential by increasing the sodium current. (Lacerda et al. 2008 JPET, 324:427-433)

Vardenafil – a recently approved drug for erectile dysfunction that causes a small QT prolongation. The Cardiac Channel Panel™ indicates that vardenafil is a weak hERG blocker. Stronger inhibition was observed in Kv1.5 (an atrial-specific potassium channel) and Kv4.3 (responsible for phase 1 early repolarization). Low level potentiation of the pacemaker channel HCN4, in addition to drug-induced hypotension, may contribute to heart rate elevation.

Ranolazine – a recently approved drug for treatment of angina that causes moderate QT prolongation but does not appear to be torsadogenic. Evidence from nonclinical studies indicates that it has antiarrhythmic characteristics. The Cardiac Channel Panel™ indicates that weak hERG block may be responsible for QT prolongation. The antiarrhythmic, non-torsadogenic mechanism is associated with inhibition of the late sodium current that, in the absence of drug, can cause non-uniform action potential repolarization. (Antzelevich et al. 2004 Circulation, 110:904-910).

Pentobarbital – a long-marketed drug used as a sedative. The drug prolongs the QT interval but is not torsadogenic. The Cardiac Channel Panel™ shows that pentobarbital’s effect on the QT interval may stem from block of non-hERG potassium channels (KvLQT1/minK and Kir2.1). Its lack of torsadogenicity may be related to Ca2+ channel block.