AbstractThe purpose of this study was to measure oritavancin's electrocardiographic effects at a supratherapeutic dose of 1600 mg given intravenously (IV) over 3 hours. A cohort of 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 milliseconds 1 hour after infusion. Linear PK‐PD modeling predicted a 3.2‐millisecond change in the PR interval for the Cmax (138 μg/mL) observed in pivotal phase 3 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, or 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.