Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines.
OBJECTIVE
The regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K(+) current (I(Kr)), carried by human ether-a-go-go-related gene (hERG) channels in cardiac cells (the hERG test), as a 'first line' test for identifying compounds inducing QT prolongation, have limitations, some of which are outlined here.


METHODS
hERG current was measured in HEK293 cells, stably transfected with hERG channels; action potential duration (APD) and arrhythmogenic effects were measured in isolated Purkinje fibres and perfused hearts from rabbits.


RESULTS
576 compounds were screened in the hERG test: 58% were identified as hERG inhibitors, 39% had no effect and 3% were classified as stimulators. Of the hERG inhibitors, 92 were tested in the APD assay: 55.4% of these prolonged APD, 28.3% had no effect and 16.3% shortened APD. Of the 70 compounds without effect on hERG channels, 54.3% did not affect APD, 25.7% prolonged, while 20% significantly shortened APD. Dofetilide (hERG inhibitor; IC(50), 29 nM) prolonged QT and elicited early after-depolarizations and/or torsade de pointes (TdP) in isolated hearts. Mallotoxin and NS1643 (hERG current stimulators at 3 microM), levcromakalim and nicorandil (no effect on hERG current), all significantly shortened APD and QT, and elicited ventricular fibrillation (VF) in isolated hearts.


CONCLUSIONS
The hERG assay alone did not adequately identify drugs inducing QT prolongation. It is also important to detect drug-induced QT shortening, as this effect is associated with a potential risk for ventricular tachycardia and VF, the latter being invariably fatal, whereas TdP has an approximately 15-25% incidence of death.
Lu
H R
HR
Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica NV, Beerse, Belgium. hlu@prdbe.jnj.com
Vlaminckx
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E
Hermans
A N
AN
Rohrbacher
J
J
Van Ammel
K
K
Towart
R
R
Pugsley
M
M
Gallacher
D J
DJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D064420:Drug-Related Side Effects and Adverse Reactions; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D017408:Guidelines as Topic; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008954:Models, Biological; D011690:Purkinje Fibers / Q000187:drug effects; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000139:chemically induced; D016171:Torsades de Pointes / Q000139:chemically induced; D014693:Ventricular Fibrillation / Q000139:chemically induced
D051638:Ether-A-Go-Go Potassium Channels