title: Electrocardiographic Effects of a Supratherapeutic Dose of Oritavancin.
abstract: The 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 Cmaxin patients. A therapeutic 1200-mg single dose of oritavancin is not anticipated to cause any clinically significant effect on cardiac electrophysiology.
authors.affiliation: University of Utah Division of Cardiology, Salt Lake City, UT, USA.|Spaulding Clinical Research, West Bend, WI, USA.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Mason
authors.affiliation: The Medicines Company, Parsippany, NJ, USA.
authors.forename: S Eralp
authors.initials: SE
authors.lastname: Bellibas
authors.affiliation: The Medicines Company, Parsippany, NJ, USA.
authors.forename: Nuo-Yu
authors.initials: NY
authors.lastname: Huang
authors.affiliation: Spaulding Clinical Research, West Bend, WI, USA.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Sanabria
authors.affiliation: Karolinska Institute Division of Cardiovascular Medicine, Stockholm, Sweden.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D006020:Glycopeptides / Q000009:adverse effects* / Q000493:pharmacokinetics; D006207:Half-Life; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D016014:Linear Models; D000077427:Lipoglycopeptides; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D055815:Young Adult; D014640:Vancomycin / Q000031:analogs & derivatives
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D006020:Glycopeptides; D000077427:Lipoglycopeptides; D000077266:Moxifloxacin; C100708:oritavancin; D014640:Vancomycin
keywords: PR interval; QT interval; oritavancin; thorough QT study