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 g/ml, respectively, and steady-state area-under-the-curve values were 700, 1,033, and 1,165 g ⅐ h/ml, respectively. The elimination half-life ranged from 6.9 to 9.1 h following the administration of doses >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. , abstr. F-2108, 2003). Data from in vitro and animal studies indicate that telavancin has superior activity to ␤-lactams, older glycopeptides (e.g., vancomycin), and the oxazolidinone linezolid (6). This antimicrobial agent is rapidly bactericidal against staphylococci, with Ͼ99.9% killing achieved within 4 h of exposure at concentrations achievable in vivo (8).Unlike most glycopeptides, telavancin has multiple mechanisms of action. In addition to inhibiting peptidoglycan synthesis by blocking the transglycosylation step, telavancin also interacts with the bacterial membrane, dissipating the membrane potential and effecting changes in cell permeability. The multiple mechanisms of action may lead to a lower frequency of resistance (Debavov et al., 43rd ICAAC; K. Krause, D. Debabov, J. Pace, and K. Kaniga, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. C1-1810, 2003). The rapid bactericidal activity of this agent may result in a reduction in the duration of therapy and improved clinical outcomes. This paper reports the results of a two-part, randomized, double-blind, placebo-controlled study of sequentially ascending doses of telavancin with healthy adult male subjects. The study objectives were to assess the safety, pharmacokinetics, and pharmacodynamics (serum inhibitory and bactericidal titers) of intravenous (i.v.) telavancin. Study subjects. Eligible male subjects (age, 18 to 50 years; weight, 50 to 100 kg) with no clinically relevant abnormal physical or laboratory findings and normal electrocardiograms (ECGs), blood pressure, and heart rate were included in the study. Subjects had to be able to comply with the study requirements and to provide written inf...

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

“…For example, telavancin and daptomycin display bactericidal activity against Gram-positive organisms despite being highly protein bound, 93 and 92%, respectively (21,23,125). Various factors have been proposed to explain these observations.…”

Telavancin: A Review of its Use in Treating Gram-Positive Infections

“…24,25 Telavancin has a linear profile when infused over 30 to 120 minutes at a dose range of 7.5 to 15 mg/kg. It takes three to four days to achieve a steady state and there is no evidence of tissue accumulation.…”

Telavancin in the treatment of Staphylococcus aureus hospital-acquired and ventilator-associated pneumonia: clinical evidence and experience

“…In a single dose of TLV at the FDA-approved adult dose (10 mg/kg), the mean C max was 87.5 μg/ml, AUC0-24 was 762 (± 81) μg h/ml, half-life was 7.5 (± 2.28) h, clearance was 11.8 (± 1.4) ml/h/kg and the volume of distribution was 115 (± 6) ml/kg [Vibativ, 2015;Shaw et al 2005].…”

“…The activity of the drug in vitro is rapidly bactericidal and concentration dependent, with the ratio of area under the time concentration curve to minimum inhibitory concentration (AUC/MIC) as the best predictor of activity in animal models [Nannini and Stryjewski, 2008;Shaw et al 2005]. The recommended dosing for TLV is 10 mg/kg administered over a 60-min period in patients 18 years of age or older by intravenous infusion once every 24 h for 7-21 days [Vibativ, 2015].…”