Perception of validity of clinical and preclinical methods for assessment of torsades de pointes liability

Abstract

In 2007 a meeting on drug-induced torsades de pointes (TdP) was held in London, UK, under the auspices of the British Society for Cardiovascular Research (BSCR). One of the objectives was to explore the validity of available biomarkers, risk factors and preclinical investigational methods for the detection of drug-induced TdP liability - preclinical methods and clinical 'thorough QT' testing. The first symposium was entitled "How validated are current models and biomarkers for testing drug-induced torsades de pointes liability?" Validation, as far as the symposium was concerned, meant that the endpoints measured in the method predict TdP liability specifically, selectively and quantitatively. Topics (and the publications derived from the presentations) were: human volunteer phase 1 studies [Vik, T., Pollard, C., & Sager, P. (2008-this issue), the anaesthetized rabbit TDP model [Carlsson, L. (2008-this issue), the AV blocked canine preparation [Oros, A., Beekman, J. D. M., & Vos, M. A. (2008-this issue), QT interval and its corrections in the in vivo conscious canine [Fossa, A. A. (2008-this issue), the rabbit heart failure model [Hamlin, R. L., & Kijtawornrat, A. (2008-this issue), the rabbit Langendorff preparation and the Screenit approach [Dumotier, B. M., Deurinck, M., Yang, Y., Traebert, M., & Suter, W. (2008-this issue), the wedge preparation [Yan G.-X. (2008-this issue)] and hERG screens [Hancox, J. C., McPate, M. J., El Harchi, A., & Zhang, Y. h. (2008-this issue). Unbeknownst to the speakers before the start of the sessions, the audience were invited, during the session, to rate each approach on a 0 to 10 scale in terms of the extent to which each approach appeared to be validated. The outcome of this exercise forms the basis of this article. We invite you to evaluate for yourselves the accompanying reviews in this edition of Pharmacology and Therapeutics.