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- Title
Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model.
- Authors
Yao, X.; Anderson, D. L.; Ross, S. A.; Lang, D. G.; Desai, B. Z.; Cooper, D. C.; Wheelan, P.; McIntyre, M. S.; Bergquist, M. L.; MacKenzie, K. I.; Becherer, J. D.; Hashim, M. A.
- Abstract
<bold>Background and Purpose: </bold>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.<bold>Experimental Approach: </bold>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.<bold>Key Results: </bold>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.<bold>Conclusions and Implications: </bold>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.
- Subjects
DRUG discrimination (Pharmacology); ARRHYTHMIA; PATCH-clamp techniques (Electrophysiology); POTASSIUM channels; GUINEA pigs as laboratory animals; DRUG development
- Publication
British Journal of Pharmacology, 2008, Vol 154, Issue 7, p1446
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1038/bjp.2008.267