Tolerability, Pharmacokinetics, and Serum Bactericidal Activity of Intravenous Dalbavancin in Healthy Volunteers

Abstract

Fifty-two healthy adult male and female volunteers were enrolled in this double-blind study to determine the maximum tolerated dose, characterize the pharmacokinetics, and obtain serum bactericidal activity (SBA) data for intravenous dalbavancin. Subjects were assigned to single-or multiple-dose groups and randomized to receive dalbavancin or placebo intravenously over 30 min. Doses started at 140 mg in the single-dose group and with a 300-mg loading dose (LD), followed by six daily 30-mg maintenance doses (MDs), in the multipledose cohort and escalated to a 1,120-mg single dose and a 1,000-mg LD and 100-mg MD regimen. Plasma, urine, and skin blister fluid aspirate drug concentrations were measured, and pharmacokinetic parameters were determined via noncompartmental methods. SBA against methicillin-resistant Staphylococcus aureus (MRSA) was determined at several time points. Adverse events and changes from the baseline for laboratory data, electrocardiograms, audiologic assessments, physical examinations, and vital signs were assessed. Concentrations increased in proportion to the dose. Steady-state concentrations were achieved by day 3 with the 10:1 LD-MD regimen. The half-life averaged 181 h, and the mean volume of distribution and clearance were 9.75 liters and 0.0473 liters/h, respectively. Mean values were similar in all groups and in males and females. The portion of the dose excreted renally averaged 33.5%. Bactericidal activity was demonstrated in serum at 7 days in all subjects receiving single doses of >500 mg. All doses were well tolerated. Dose-limiting toxicity was not encountered. No changes in auditory or vestibular function occurred. The long half-life and maintenance of SBA against MRSA for 1 week suggest that weekly dosing may be feasible.

Dalbavancin in the treatment of complicated skin and soft-tissue infections: a review

“…Investigators have demonstrated that elimination of dalbavancin occurs by both renal and non-renal routes (Leighton et al 2004;Cavaleri et al 2005). This is in contrast to vancomycin and teicoplanin which are eliminated primarily by the kidney.…”

“…This is in contrast to vancomycin and teicoplanin which are eliminated primarily by the kidney. In a Phase I trial, urine excretion of unaltered drug accounted for only 33.5% of the elimination of a single dose of dalbavancin which was similar to the 34.5% noted in an animal model (Leighton et al 2004;Cavaleri et al 2005). Additionally, mild renal impairment (creatinine clearance of 50 to 80 ml/min) does not appear to alter dalbavancin's pharmacokinetic parameters (Dowell et al 2003).…”

“…Additionally, in patients receiving a single dose of dalbavancin, the C max increased proportionately with the administered dose; and linear regression analysis of C max and AUC versus the given dose demonstrated linear dose-proportional pharmacokinetics. Taken together, this investigation supplied data supporting a once-weekly dosing regimen (Leighton et al 2004).…”

“…Despite a small free fraction in serum, dalbavancin appears to demonstrate bactericidal activity against S. aureus with MICs of 0.06 to 1.0 µg/mL (Bowker et al 2006). Dalbavancin demonstrates excellent tissue distribution and penetration in quantitative animal tissue distribution studies and in human trials (Leighton et al 2004;Cavaleri et al 2005;Nicolau et al 2007). Maximum drug concentration is achieved in most tissues within 24 hours of administration with the highest concentrations in the kidney and liver (Cavaleri et al 2005).…”

“…Initial in vivo studies using rat and rabbit models found extended interval dosing effective, suggesting that human trials could potentially utilize weekly dosing schedules (Cavaleri et al 2005). Data from a Phase I investigation provided further support of dalbavancin's once-weekly dosing regimen (Leighton et al 2004). In this trial, 52 healthy subjects were administered single parenteral doses of dalbavancin ranging from 140 mg to 1120 mg, and plasma drug concentrations were measured over time.…”