QT PRODACT: in vivo QT assay with a conscious monkey for assessment of the potential for drug-induced QT interval prolongation.

In safety pharmacology studies, the effects on the QT interval of electrocardiograms are routinely assessed using a telemetry system in cynomolgus monkeys. However, there is a lack of integrated databases concerning in vivo QT assays in conscious monkeys. As part of QT Interval Prolongation: Project for Database Construction (QT PRODACT), the present study examined 10 positive compounds with the potential to prolong the QT interval and 6 negative compounds considered to have no such effect on humans. The experiments were conducted at 7 facilities in accordance with a standard protocol established by QT PRODACT. The vehicle or 3 doses of each test compound were administered orally to male cynomolgus monkeys (n=3-4), and telemetry signals were recorded for 24 h. None of the negative compounds prolonged the corrected QT using Bazett's formula (QTcB) interval. On the other hand, almost all of the positive compounds prolonged the QTcB interval, but haloperidol, terfenadine, and thioridazine did not. The failure to detect the QTcB interval prolongation appeared to be attributable for the differences in metabolism between species and/or disagreement with Bazett's formula for tachycardia. In the cynomolgus monkeys, astemizole induced Torsade de Pointes and cisapride caused tachyarrhythmia at lower plasma concentrations than those observed in humans and dogs. These results suggest that in vivo QT assays in conscious monkeys represent a useful model for assessing the risks of drug-induced QT interval prolongation.

QT PRODACT: inter-facility variability in electrocardiographic and hemodynamic parameters in conscious dogs and monkeys.

In safety pharmacology studies, the effect of a test compound on the electrocardiogram is routinely examined by using conscious dogs. However, the results may be widely variable. The monkey, on the other hand, has scarcely been used for such studies; and as yet, there have not been reported studies on monkeys conducted at several facilities with a standard protocol. In the present study, we examined inter-facility variabilities in electrocardiographic and hemodynamic parameters as described below. We analyzed the data from 8 facilities (9 test groups) on dogs and 5 facilities (7 test groups) on monkeys. This data was obtained from the studies employing the following standard protocol: dl-Sotalol or a vehicle (0.5 w/v% methylcellulose solution) was given to animals; and the PR interval, QRS duration, QT interval, heart rate, and mean blood pressure were determined time-sequentially before and after administration of the vehicle or dl-sotalol in each test group. dl-Sotalol produced a prolongation of the maximum mean QTcF interval in conscious dogs and QTcB interval in conscious monkeys by more than 10% in every test group. No difference in the corrected QT interval among the test groups was observed in dogs, but a difference was observed in monkeys.