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Literature‐based evaluation of four ‘hard endpoint’ models for assessing drug‐induced torsades de pointes liability
Author(s) -
Vos M A
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.277
Subject(s) - torsades de pointes , terfenadine , proarrhythmia , medicine , safety pharmacology , methoxamine , qt interval , dofetilide , repolarization , pharmacology , drug , cardiology , electrophysiology , receptor , agonist
In safety pharmacology, a number of preclinical models for detecting drug‐induced proarrhythmia liability have been recently introduced that utilize hard endpoints: early after depolarziations (EADs), torsades de pointes (TdP) or both as the principal biomarker. To explore the validity of four of the most common of these models, (the isolated canine/rabbit left ventricular wedge preparation, the isolated rabbit heart, the methoxamine‐pretreated anaesthetized rabbit and the complete, chronic AV‐blocked (CAVB) dog (conscious and anaesthetized), the present article reviews published data sets for three drugs with recognized and different human TdP liabilities (cisparide, terfenadine and moxifloxacinin). Finally, this review considers the value of inclusion of analysis of beat‐to‐beat variability of repolarization (BVR) in TdP liability testing to improve sensitivity and specificity. British Journal of Pharmacology (2008) 154 , 1523–1527; doi: fn1 ; published online 7 July 2008