QT shift method in guinea pig

QT interval prolongation constitutes a critical issue in the development of a new drug-candidate (Hanson et al, 2006). A recent methodological refinement in non-clinical safety pharmacology telemetry studies designed to detect drug-induced QT prolongation is the probabilistic method (Holzgrefe et al, 2007). This is the method that we use routinely in our laboratory in association with the QT shift method in large animals such as dogs and Cynomolgus monkeys (Champeroux et al, 2009). In the present study, we have developed this methodology in conscious Guinea pigs. The principle is based on the probabilistic determination of individual QT/RR relationships from a beat-tobeat ECG analysis over a 24-hour treatment-free period. The QT shift method consists of a direct reading of the drug-induced QT interval shift in relation to the normal individual QT/RR relationship. Accuracy and reliability of this method were tested by using several reference drugs such as sotalol, thioridazine, dofetilide, terfenadine, haloperidol, cisapride and moxifloxacin. n ro uc on