Electrocardiographic Effects of a Supratherapeutic Dose of Oritavancin.
Clin Pharmacol Drug Dev. 2016 May 3;
Authors: Mason JW, Bellibas SE, Huang NY, Sanabria CR, Darpo B
The purpose of this study was to measure oritavancin's electrocardiographic effects at a supratherapeutic dose of 1600 mg I.V. over 3 hours. 150 healthy volunteers were randomized to receive placebo, oritavancin or oral moxifloxacin 400 mg in a parallel designed thorough QT study. A supratherapeutic mean maximum oritavancin concentration (Cmax) of 232 μg/ml was achieved. There was no significant effect on baseline and placebo corrected (dd) QTcF, QRS or heart rate. ddPR was slightly increased at most time points, with a maximum mean change of 7.7 msec 1 hour after infusion. Linear PK-PD modelling predicted a 3.2 msec change in the PR interval for the Cmax (138 μg/ml) observed in pivotal Phase III studies after 1200 mg of oritavancin. Moxifloxacin produced the expected increase in ddQTcF, validating assay sensitivity. At plasma concentrations above the clinical exposures of oritavancin, no clinically or statistically significant effect on QTcF, QRS and heart rate was observed. The increase in PR is considered clinically insignificant, given the rapid decline in initial plasma concentration of oritavancin after infusion and the expected lower Cmax in patients. A therapeutic 1200 mg single dose of oritavancin is not anticipated to cause any clinically significant effect on cardiac electrophysiology. This article is protected by copyright. All rights reserved.
PMID: 27138652 [PubMed - as supplied by publisher]