Toward a New Gold Standard for Early Safety: Automated Temperature-Controlled hERG Test on the PatchLiner®

Abstract

The Patchliner® temperature-controlled automated patch clamp system was evaluated for testing drug effects on potassium currents through human ether-à-go-go related gene (hERG) channels expressed in Chinese hamster ovary cells at 35–37°C. IC50 values for a set of reference drugs were compared with those obtained using the conventional voltage clamp technique. The results showed good correlation between the data obtained using automated and conventional electrophysiology. Based on these results, the Patchliner® represents an innovative automated electrophysiology platform for conducting the hERG assay that substantially increases throughput and has the advantage of operating at physiological temperature. It allows fast, accurate, and direct assessment of channel function to identify potential proarrhythmic side effects and sets a new standard in ion channel research for drug safety testing.

Assessment of temperature‐induced hERG channel blockade variation by drugs

“…In addition, the patch clamp technique is considered as a gold standard for evaluating the functional performance of ion channels (Polonchuk, 2012). Indeed, there have also been earlier efforts to understand the effect of temperature on hERG inhibition of certain therapeutics at those varying between 20°C and 42°C (Guo et al, 2005;Hu et al, 2010;Yao et al, 2005).…”

“…Indeed, there have also been earlier efforts to understand the effect of temperature on hERG inhibition of certain therapeutics at those varying between 20°C and 42°C (Guo et al, 2005;Hu et al, 2010;Yao et al, 2005). Furthermore, the temperature-dependent electrophysiological properties of the hERG channel have also been examined in the stably transfected Chinese Hamster Ovary (CHO) cell line using patch clamp electrophysiology (Golden et al, 2011) especially at 35-37°C (Polonchuk, 2012). It has also been accepted that use of different experimental conditions in various in vitro systems can lead to different hERG IC 50 values (Wisniowska and Polak, 2009).…”

New strategies in ion channel screening for drug discovery: are there ways to improve its productivity?

“…Another important area of use for APC-based screening is cardiac safety testing [11,12]. Increased throughput means that safety liability issues can be addressed early in the drug discovery process, preventing costly late-phase withdrawal of drug candidates.…”

Early identification of hERG liability in drug discovery programs by automated patch clamp

“…Automated patch clamp assays have been successfully used in a number of drug discovery programs, both for identifying compound effects on ion channel targets as well as for identifying undesired off-target effects. Technical advances in the automated patch clamp technique and in cell preparations have facilitated employing automated patch clamp assays with increasing success rates (Finkel et al, 2006; Zeng et al, 2008), high parallelization (and, consequently, increased throughput), at (or near) physiological temperature (Polonchuk, 2012), at increased ligand application rates, and also using more challenging cell preparations such as primary cells on these instruments (Farre et al, 2009; Jones et al, 2009; Milligan et al, 2009; Golden et al, 2011; Stoelzle et al, 2011a,b; Haythornthwaite et al, 2012; Becker et al, 2013; Gillie et al, 2013; Milligan and Möller, 2013). The development of higher throughput automated patch clamp instruments has allowed moving electrophysiological ion channel assays earlier into the drug discovery process and has made electrophysiology measurements compatible with medicinal chemistry iteration cycles.…”