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Antimicrobial Agents and Chemotherapy, August 2004, p. 2799-2807, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2799-2807.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Daptomycin

Barry Dvorchik,^1* Robert D. Arbeit,^1, Julia Chung,² Susan Liu,² William Knebel,² and Helen Kastrissios²

Cubist Pharmaceuticals, Inc., Lexington, Massachusetts 02421,¹ GloboMax Holdings LLC, Hanover, Maryland 21076²

Received 9 November 2003/ Returned for modification 26 January 2004/ Accepted 4 April 2004

Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30 covariates were considered. A two-compartment model with first-order elimination provided the best fit for data on daptomycin concentrations in plasma over time. In the final population PK model, daptomycin plasma clearance (CL) was a function of renal function, body temperature, and sex. Of these factors, renal function contributed most significantly to interindividual variability. CL varied linearly with the estimated creatinine clearance. CL among dialysis subjects was approximately one-third that of healthy subjects (0.27 versus 0.81 liter/h). CL in females was 80% that in males; however, in clinical trials, the outcome was not affected by sex and therefore this effect is not considered clinically meaningful. The relationship with body temperature should be interpreted cautiously since the analysis included only a limited number of subjects who were hyperthermic. The volume of distribution of the peripheral compartment (V₂) and intercompartmental clearance (Q) were linearly related to body weight. V₂ increased approximately twofold in the presence of an acute infection. No factors were identified that significantly impacted V₁. This analysis supports the dosing of daptomycin on a milligram-per-kilogram-of-body-weight basis and suggests that modified dosing regimens are indicated for patients with severe renal disease and for those undergoing dialysis.

Present address: Paratek Pharmaceuticals, Boston, MA 02111.

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