Lack of an effect of linezolid on QTc interval prolongation
Abstract number: P1578
Damle B., LaBadie R., Cuozzo C., Alvey C., Chong C., Choo H., Kirby D.
Objective: To demonstrate the lack of an effect of single intravenous (IV) infusion doses of linezolid (600 and 1200 mg), relative to placebo, on the QTc interval.
Methods: This was a randomized, 4-way crossover, double-blind (for linezolid/placebo; open label for moxifloxacin) study in 40 healthy subjects. Treatments included 1-h IV infusion of linezolid 600 and 1200 mg, placebo, and oral moxifloxacin 400 mg (positive control), each separated by a washout of 96 h. Pharmacokinetic (PK) samples and triplicate 12-lead ECG were collected as follows: predose [-1 and -0.5 h for ECG, and 0 h for ECG and PK], and 30 min, and at 1 (end of infusion), 2, 4, 8, 12 and 24 h after dosing. PK were determined by noncompartmental analyses. Time-matched, placebo-subtracted change in QT intervals with Fridericia's (QTcF) correction were determined for linezolid and moxifloxacin using a repeated measure mixed effect model with appropriate terms for the given design and baseline as a covariate.
Results: The figure provides time-matched adjusted differences of QTcF for each treatment compared to placebo values as obtained from the statistical model. For both linezolid doses, the upper bound of the 90% CI at every time point postdose was below 10 msec, thus satisfying the criteria for a negative thorough QT/QTc study. Using the same repeated-measures model, at population Tmax for moxifloxacin (between 2 and 4 h) the 2-sided 90% CI when comparing moxifloxacin to placebo was greater than 5 msec indicating that the study was sensitive to assess QTc prolongation. An increase in linezolid dose from 600 to 1200 mg resulted in an increase in mean Cmax and AUCinf values of 104% and 134%, respectively. Mean clearance of linezolid was 13.7% lower for the 1200 mg compared with the 600 mg dose. Median Tmax values and mean Vss values were comparable across doses but mean half-life slightly increased with dose. A total of 29 treatment-emergent adverse events (AEs) were reported by 24 subjects. The most common AE was nausea occurring in 4 subjects receiving 1200 mg linezolid. Other AEs were headache and dysmenorrhoea, reported by 2 subjects each.
Conclusions: Therapeutic and supratherapeutic doses of linezolid did not have a clinically relevant effect on QT/QTc interval. Linezolid exposure increased in a more than dose proportional manner from 600 to 1200 mg dose. Single doses of linezolid up to 1200 mg were well tolerated.
|Session name:||Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases|
|Location:||Vienna, Austria, 10 - 13 April 2010|
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