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Antimicrobial Agents and Chemotherapy, March 2004, p. 940-945, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.940-945.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Vicuron Pharmaceuticals, Inc., King of Prussia, Pennsylvania 19406,¹ Vicuron Pharmaceuticals, 21040 Gerenzano (Varese), Italy,² Clinical Research Center, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08903,³ Southern Illinois University School of Medicine, Springfield, Illinois 62794,⁴ Center for Speech and Hearing Sciences, East Brunswick, New Jersey 08816⁵

Received 24 April 2003/ Returned for modification 13 August 2003/ Accepted 11 November 2003

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 multiple-dose 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.

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