Tigecycline Does Not Prolong Corrected QT Intervals in Healthy Subjects

Abstract

We evaluated the effect of tigecycline (50-mg and 200-mg doses) on corrected QT (QTc) intervals and assessed safety and tolerability in a randomized, placebo-controlled, four-period crossover study of 48 (44 male) healthy volunteers aged 22 to 53 years. Fed subjects received tigecycline (50 mg or 200 mg) or placebo in a blinded fashion or an open-label oral dose of moxifloxacin (400 mg) after 1 liter of intravenous fluid. Serial electrocardiograms were recorded before, and for 96 h after, dosing. Blood samples for tigecycline pharmacokinetics were collected after each recording. QTc intervals were corrected using Fridericia's correction (QTcF). Pharmacokinetic parameters were calculated using noncompartmental methods with potential relationships examined using linear mixed-effects modeling. Adverse events were recorded. The upper limits of the 90% confidence interval for the mean difference between both tigecycline doses and placebo for all time-matched QTcF interval changes from baseline were <5 ms. The tigecycline concentrations initially declined rapidly and then more slowly. In the group given 50 mg of tigecycline, the pharmacokinetic parameters and means were as follows: maximum concentration of drug in serum (C max ), 432 ng/ml; area under the concentration-time curve from time zero extrapolated to infinity (AUC 0 -ؕ ), 2,366 ng · h/ml; clearance ( T igecycline is a broad-spectrum glycylcycline that binds to the 30S ribosomal subunit blocking entry of amino-acyl tRNA and preventing peptide chain elongation. Tigecycline overcomes two major mechanisms of tetracycline resistance, ribosomal protection and efflux; however, resistance via nonspecific multidrug efflux pumps has been demonstrated (1). Its in vitro spectrum of activity includes many Gram-positive and Gram-negative organisms, anaerobes, atypical organisms, and some multidrug-resistant pathogens (2-5). These attributes suggest a role for tigecycline in the empirical treatment of susceptible and resistant pathogens and the definitive treatment of tigecycline-susceptible resistant bacteria.Tigecycline is approved for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, and community-acquired bacterial pneumonia (6). The efficacy and safety of tigecycline for these indications have been demonstrated in phase 3 clinical trials (7-12). The recommended treatment regimen for tigecycline includes an initial infusion of 100-mg dose followed by 50 mg every 12 h (6), although in practice some clinicians have acknowledged using higher doses (13).In a pooled analysis of phase 3 and 4 studies in patients with a variety of infections, an increase in all-cause mortality was found in tigecycline-treated patients versus comparators. In some other classes of antibiotics, such as macrolides and fluoroquinolones, mortality rates may be adversely affected by prolongation of the cardiac QTc (corrected QT) interval (14,15).Thorough QT studies were not routinely performed at the time of the clinical development of tigecycli...

The Development of Third-Generation Tetracycline Antibiotics and New Perspectives

“…No adverse cardiovascular reactions are known for tigecycline. A study in healthy subjects showed that this compound has no significant effect on the QT interval [169].…”