title: Lack of an effect of standard and supratherapeutic doses of linezolid on QTc interval prolongation.
abstract: A double-blind, placebo-controlled, four-way crossover study was conducted in 40 subjects to assess the effect of linezolid on corrected QT (QTc) interval prolongation. Time-matched, placebo-corrected QT intervals were determined predose and at 0.5, 1 (end of infusion), 2, 4, 8, 12, and 24 h after intravenous dosing of linezolid 600 and 1,200 mg. Oral moxifloxacin at 400 mg was used as an active control. The pharmacokinetic profile of linezolid was also evaluated. At each time point, the upper bound of the 90% confidence interval (CI) for placebo-corrected QTcF values (i.e., QTc values adjusted for ventricular rate using the correction methods of Fridericia) for linezolid 600 and 1,200-mg doses were <10 ms, which indicates an absence of clinically significant QTc prolongation. At 2 and 4 h after the moxifloxacin dose, corresponding to the population T(max), the lower bound of the two-sided 90% CI for QTcF when comparing moxifloxacin to placebo was >5 ms, indicating that the study was adequately sensitive to assess QTc prolongation. The pharmacokinetic profile of linezolid at 600 mg was consistent with previous observations. Systemic exposure to linezolid increased in a slightly more than dose-proportional manner at supratherapeutic doses, but the degree of nonlinearity was small. At a supratherapeutic single dose of 1,200 mg of linezolid, no treatment-related increase in adverse events was seen compared to 600 mg of linezolid, and no clinically meaningful effects on vital signs and safety laboratory evaluations were noted.
authors.affiliation: Pfizer, Inc., 235 East 42nd St., New York, NY 10017, USA. bharat.damle@pfizer.com
authors.forename: Bharat
authors.initials: B
authors.lastname: Damle
authors.forename: Robert R
authors.initials: RR
authors.lastname: Labadie
authors.forename: Cheryl
authors.initials: C
authors.lastname: Cuozzo
authors.forename: Christine
authors.initials: C
authors.lastname: Alvey
authors.forename: Heng Wee
authors.initials: HW
authors.lastname: Choo
authors.forename: Steve
authors.initials: S
authors.lastname: Riley
authors.forename: Deborah
authors.initials: D
authors.lastname: Kirby
mesh_terms: D000081:Acetamides / Q000009:adverse effects* / Q000627:therapeutic use; D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D001372:Aza Compounds / Q000009:adverse effects / Q000627:therapeutic use; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D024841:Fluoroquinolones; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D006801:Humans; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D023303:Oxazolidinones / Q000009:adverse effects* / Q000627:therapeutic use; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000081:Acetamides; D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D023303:Oxazolidinones; D011804:Quinolines; D000069349:Linezolid; D000077266:Moxifloxacin