QT PRODACT: Inter-facility Variability in Electrocardiographic and Hemodynamic Parameters in Conscious Dogs and Monkeys

Abstract

Abstract. 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. Supplementary material (Appendix): available only at http://dx

QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation

“…Moreover, in the light cycle, the scattering of the QTcB intervals from the control baseline values in 4 animals in different testing facilities was within 10% (12). This observation supports the results that a more than 10% change in the QTcB interval compared with the control baseline is considered to be caused by a test compound.…”

QT PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT Interval Prolongation by Human Pharmaceuticals

“…After completion of the series of experiments, the vehicle and dl-sotalol hydrochloride (sotalol), a common positive compound, were administered to the same animals to investigate the interfacility variability. The results are reported by Sasaki et al (7) in this issue.…”

A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A & B regulatory submissions

“…By publishing the data and providing recommendations on its use, it is hoped that this will be regarded as a reference guide for other researchers and scientific reviewers within regulatory agencies. Previous examples of publications on interlaboratory concordance in safety pharmacology-related studies include those on the functional observational battery (FOB; Moser, Becking, MacPhail, & Kulig, 1997) and on QTc effects detected using dog cardiovascular telemetry (Sasaki, Shimizu, Suganami, & Yamamoto, 2005).…”