Appraise QT interval prolongation risk with collected telemetry ECG data

Although the QT /QTc interval is overall an imperfect biomarker,it is currently the best available clinical surrogate for the development of drug-induced torsades de pointes.The following results from cardiovascular telemetry studies should be considered for appraising QT interval prolongation risk:Dose-or concentration-dependent increases in mean QTca compared to mean time matched vehicle control QTca are considered to be a signal for a potential to delay the ventricular repolarization.The magnitude of the increase in QTca will be considered in relationship to the increase induced by the positive control substance,moxifloxacin,in the respective species(historical data).A relevant non-clinical effect of moxifloxacin is defined as an increase of 5-10 ms(sensitivity threshold = signal).Due to the species specific differences in the range of raw QT,it is not possible to predict the magnitude of QT prolongation in humans.However,validation data have shown that a concentration of moxifloxacin that induces a mean QT prolongation in humans of 5-10 ms also increases QT interval in dogs and monkeys.If a 5%-10% increase in QTca occurs at a mean maximum plasma concentration less than 30-fold the maximum plasma concentration envisaged for therapeutic efficacy,the compound is considered to possess risk for QT interval prolongation in humans.If no QT interval prolongation signal is observed at free plasma concentrations > 30-fold the mean maximal free Cmax necessary for efficacy in appropriate animal pharmacology models,the molecule would be considered of low risk /liability.If a QT interval prolongation signal is observed at free plasma concentrations < 10-fold the mean maximal free Cmax necessary for efficacy in appropriate animal pharmacology models,the molecule is not suitable for indications where no QT-interval prolongation risk is acceptable.If a QT-prolongation signal is observed at free plasma concentrations ≥10-fold but ≤30-fold the mean maximal free Cmax associated with efficacy in appropriate animal pharmacology models,further development should be subjected to a risk /benefit analysis.Special considerations for the estimation of the safety margin:the steady-state Cmax differs from Cmax before steady-state,external factors(eg drug-drug interactions) increase Cmax,pro-drugs and major metabolites are expected to reach relevant concentrations in humans,and certain dose-limiting side effects may occur at plasma concentrations lower than those necessary to ob-serve a QT interval prolongation.