Pharmacokinetics, serum inhibitory and bactericidal activity, and safety of telavancin in healthy subjects

Abstract

The pharmacokinetics, tolerability, and serum inhibitory and bactericidal titers of telavancin, a new rapidly bactericidal lipoglycopeptide with multiple mechanisms of action against gram-positive pathogens, were assessed in a two-part, randomized, double-blind, placebo-controlled, ascending-dose study with 54 healthy men. In part 1, single ascending intravenous doses of 0.25 to 15 mg/kg of body weight were studied. In part 2, multiple ascending doses (30-min infusions of 7.5 to 15 mg/kg/day) were studied over 7 days. Following the administration of multiple doses, steady state was achieved by days 3 to 4. At day 7 after the administration of telavancin at 7.5, 12.5, and 15 mg/kg/day, peak concentrations in plasma were 96.7, 151.3, and 202.5 microg/ml, respectively, and steady-state area-under-the-curve values were 700, 1,033, and 1,165 microg x h/ml, respectively. The elimination half-life ranged from 6.9 to 9.1 h following the administration of doses > or =5 mg/kg. Most adverse events were mild in severity. At 24 h postinfusion, serum from subjects given telavancin demonstrated potent bactericidal activity against methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae strains. The results suggest that telavancin may be an effective once-daily therapy for serious bacterial infections caused by these pathogens.

Figures

FIG. 1.

Mean (standard deviation) concentrations in plasma following a 120-min i.v. administration of telavancin at 0.25 to 12.5 mg/kg.

FIG. 2.

Dose linearity analysis for Cmax (A) and AUC (B) for 120-min infusions of telavancin at 1 to 12.5 mg/kg.

FIG. 3.

Comparison of mean (standard deviation) concentration-time course of telavancin in plasma on days 1 and 7 at 7.5 mg/kg/day (A), 12.5 mg/kg/day (B), and 15 mg/kg/day (C).