Ion Channel Toolbox for Cardiac Safety Evaluation

Abstract

The cardiac action potential is comprised of multiple ion channel currents acting in concert and these ion channels are important in cardiac safety liability assessment of potential drug candidates. Currently, hERG current screening is a critical part of the preclinical assessment of a drug candidate and is required before first in human (FIH) clinical studies. Through our ongoing efforts to provide efficient cardiac safety evaluation, while reducing animal usage, we have incorporated the use of several cellular ion channel whole-cell voltage clamp screens using heterologously expressed and native cardiac ion channels. With heterologously expressing cell lines, the use of planar patch technology (PatchXpress and QPatch) allows for moderate throughput by providing automated, simultaneous whole-cell voltage clamp recordings. In this study we highlight five cardiac ion channels; 3 heterologously expressed cardiac potassium channels (hERG [IKr], Kir2.1 [IK1], KvLQT1/minK [IKs]) that contribute to the repolarization phase of the action potential and two additional cardiac ion channels, whose primary contribution is to the upstroke and plateau of the action potential; Nav1.5 [INa] (heterologously expressed) and the native cardiac L-type Ca channel, Cav1.2 [ICaL] (cardiac myocytes). The biophysical properties of these two cardiac ion channels have been extensively characterized and each ion channel assay has been pharmacologically validated with reference compounds. In conclusion, this approach is part of our continuing effort to move to a cellular based in vitro safety approach to provide mechanistic SAR for solving cardiac safety issues. To date, our ion channel toolbox includes: hERG, Kir2.1, KvLQT1/minK, Nav1.5 and the native cardiac L-type Ca channel (Cav1.2); to be used on an as needed basis for cardiac safety evaluation.