Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model.
OBJECTIVE
Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans.


METHODS
Sixteen marketed drugs from various pharmacological classes with a known incidence -- or lack thereof -- of QT prolongation in humans were examined in hERG (human ether a-go-go-related gene) patch-clamp assay and an anaesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea-pigs were determined using liquid chromatography-mass spectrometry.


RESULTS
Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model.


CONCLUSIONS
Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea-pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization.
Yao
X
X
Department of Biochemical & Analytical Pharmacology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. xiaozhou.x.yao@gsk.com
Anderson
D L
DL
Ross
S A
SA
Lang
D G
DG
Desai
B Z
BZ
Cooper
D C
DC
Wheelan
P
P
McIntyre
M S
MS
Bergquist
M L
ML
MacKenzie
K I
KI
Becherer
J D
JD
Hashim
M A
MA
D000818:Animals; D002853:Chromatography, Liquid; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D013058:Mass Spectrometry; D023421:Models, Animal; D018408:Patch-Clamp Techniques
D051638:Ether-A-Go-Go Potassium Channels