Blockade of the I(Ks) potassium channel: an overlooked cardiovascular liability in drug safety screening?
The problem of drug-induced hERG channel blockade, which can lead to acquired long QT syndrome and potentially fatal arrhythmias, has exercised drug developers and regulatory authorities for over 10 years, and exacting guidelines have been put into place to test for this liability both preclinically (ICH S7B) and clinically (ICH E14). However, the I(Ks) channel, which along with the transient outward current (I(to)) is the other main potassium channel affecting cardiac repolarisation and thus the length of the QT interval, has received little attention, and potent I(Ks) blocking drugs with serious side effects could potentially enter into human testing without being detected by the existing regulatory core battery and standard screening strategies. Here we review the pharmacology of cardiac I(Ks) channel blockade and describe the discovery of a potent I(Ks) blocker whose activity was not detected by standard hERG or invitro action potential screens, but subsequently evoked unprovoked torsades de pointes (TdP) invivo in our anaesthetised dog model. We have exploited this molecule to develop a ligand binding assay to detect I(Ks) blockade at an earlier stage in drug discovery, and note that several other laboratories developing new drugs have also developed higher throughput screens to detect I(Ks) blockade (e.g., [Trepakova, E. S., Malik, M. G., Imredy, J. P., Penniman, J. R., Dech, S. J., & Salata, J. J. (2007) Application of PatchXpress planar patch clamp technology to the screening of new drug candidates for cardiac KCNQ1/KCNE1 (I(Ks)) activity. Assay Drug Development Technology 5, 617-627]). Because of the presence of I(Ks) channels in other tissues, including blood vessels and in the epithelia of intestine, kidney, lung and the cochlea, I(Ks) blockade has the potential to cause extensive side effects in addition to QT prolongation and arrhythmias. We therefore suggest that compounds selected for development should also be examined for I(Ks) liability before testing in humans. The possibility of undetected I(Ks) blockade is therefore an additional gap to that identified earlier [Lu, H. R., Vlaminckx, E., Hermans, A. N., Rohrbacher, J., Van Ammel, K., Towart, R., et al. (2008) Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICH S7B Guidelines. British Journal of Pharmacology, 154, 1427-1438] in the ICH S7B regulatory guidelines.
Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. rtowart@its.jnj.com
Rob
R
Towart
Joannes T M
JT
Linders
An N
AN
Hermans
Jutta
J
Rohrbacher
Henk J
HJ
van der Linde
Martine
M
Ercken
Miroslav
M
Cik
Peter
P
Roevens
Ard
A
Teisman
David J
DJ
Gallacher
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors*; D018408:Patch-Clamp Techniques; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
D051638:Ether-A-Go-Go Potassium Channels; D051657:KCNQ1 Potassium Channel