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Abstract: Introduction: Drug-induced QT interval prolongation has been one of the critical issues for developing new chemical entities and pharmaceutical companies need to evaluate the risk early in the development stage. At such stage, guinea pigs are appropriate due to their small size requiring only small amounts of test drugs. The purpose of this study was to determine the utility of guinea pig monophasic action potential (MAP) using 12 reference drugs in order to clarify prediction of the QT interval prolonging risk. Methods: Male guinea pigs were anaesthetized with pentobarbital (40 mg/kg, i.p.). Parameters analyzed were epicardial MAP duration (MAP90) at sinus rhythm (MAP90(sinus)) and MAP90 during atrial pacing (MAP90(pacing)). Test drugs were administered to animals intravenously and cumulatively. Results: Vehicle control did not affect the parameters tested. All 8 QT-prolonging drugs prolonged MAP90(sinus) and MAP90(pacing) dose-dependently, whereas all 4 non-QT-prolonging drugs showed no or very slight prolongations of these MAP90 parameters. Rank order potency of MAP90(pacing) prolongations by the QT-prolonging drugs tended to correspond to clinical plasma concentrations associated with QT interval prolongations or Torsades de Pointes but showed less of a link with hERG inhibition activities. Conclusion: The present study demonstrates that the MAP model using anaesthetized guinea pigs could predict the liability of drugs for QT interval prolongation with high accuracy. QT assessment using the combination of the hERG assay with high sensitivity and the current in vivo assay would be desirable for early risk assessment within drug development. [Copyright &y& Elsevier]

Abstract: Introduction: QT intervals are strongly influenced by preceeding heart rate history and are also characterized by rate-independent variability, leading to difficulty in precise rate-correction of the raw QT interval. The present study elucidates a novel analytical method that effectively addresses this problematic phenomenon in telemetered common marmosets. Methods: ECGs were collected from telemetered common marmosets (male and female) and analyzed by computerized algorithms. Descriptive statistics were calculated from the mean of QT intervals for 5-ms increments of RR. The QT interval was corrected for the RR interval by applying Bazett''s, Fridericia''s, and individual probabilistic QT rate-correction formulae. Results: The linear regression of log-transformed QT and RR intervals derived from a probabilistic approach yielded a well-correlated QT–RR fit. Assessed as the slope of the QTc–RR interval, application of individual probabilistic QT rate-corrections resulted in the most effective dissociation of the effects of rate from the raw QT interval, compared to generic rate-correction formulae. Using individual corrections, the QTc was stable while the interquartile range (IQR) of the QTc distribution was stable, spanning 5–10ms for each subject over all physiological RR intervals. Heart rate variability distributions were centered about unity during both photoperiods and sinus arrhythmia was far less pronounced compared with measurements in dogs. Discussion: Probabilistic QT rate-correction eliminated the confounding effects of heart rate and provided a stable QTc baseline. These results indicate that application of this method of analysis in telemetered common marmosets results in a high degree of sensitivity for the consistent detection of small (5–10ms) changes in the QTc interval. [Copyright &y& Elsevier]