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Antimicrobial Agents and Chemotherapy, April 2003, p. 1318-1323, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1318-1323.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Daptomycin Pharmacokinetics and Safety following Administration of Escalating Doses Once Daily to Healthy Subjects

Barry H. Dvorchik,* David Brazier, Michael F. DeBruin, and Robert D. Arbeit

Cubist Pharmaceuticals, Inc., Lexington, Massachusetts

Received 6 May 2002/ Returned for modification 26 July 2002/ Accepted 25 November 2002

The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight (~20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life (~9 h), volume of distribution (~0.1 liters/kg), systemic clearance (~8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h (~54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.

* Corresponding author. Mailing address: Cubist Pharmaceuticals, Inc., 65 Hayden Ave., Lexington, MA 02421. Phone: (781) 860-8333. Fax: (781) 861-0556. E-mail: bdvorchik{at}cubist.com.

Antimicrobial Agents and Chemotherapy, April 2003, p. 1318-1323, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1318-1323.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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