The pre-clinical assessment of QT interval prolongation: a comparison of in vitro and in vivo methods.
The literature was searched for in vivo dog studies reporting QT prolongation and in vitro studies reporting increased myocardial action potential duration, which indicates the potential to prolong QT interval, for nine non-cardiac drugs that have been reported to produce QT prolongation in man. The drugs were: astemizole; terfenadine; erythromycin; sparfloxacin; cisapride; probucol; terodiline; risperidone and sertindole. 1. There were reports of the appropriate finding with in vitro methods for six of the drugs and with in vivo methods for seven of the drugs. No reports were found concerning the remaining drugs with each method. This indicates that both methods are effective and each method would have correctly identified the drugs in question as having the potential to prolong the QT interval in man in all cases for which studies were reported. 2. This suggests that, if properly conducted, either method alone is sufficient for the pre-clinical assessment of QT interval prolongation. This does not support the routine use of both methods before the administration of new drugs to man.
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Animal Welfare Group, Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004562:Electrocardiography / Q000187:drug effects*; D066298:In Vitro Techniques