Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid

Abstract

Objectives: Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate.

Design: Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies.

Setting: Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010.

Participants: Ninety healthy volunteers.

Intervention: Single intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100-400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days.

Measurements and main results: A dose-dependent increase was observed in the maximum plasma concentration (1.2-5.1 μg/ml) and the area under the concentration-time curve (17.4-58.7 μg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100-400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores.

Conclusion: These results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the need for dose adjustment when switching administration routes.

Trial registration: ClinicalTrials.gov NCT00983255.

Keywords: intravenous; pharmacokinetics; tedizolid phosphate.

© 2014 Cubist Pharmaceuticals. Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.

Figures

Figure 1

Study design. IV = intravenous.

Figure 2

Mean plasma tedizolid phosphate or tedizolid concentrations during a 1-hour intravenous (IV) infusion of tedizolid phosphate 200 mg (n=8). These data are from the IV portion of the crossover bioavailability phase of the study. Error bars denote standard deviations.

Figure 3

Mean tedizolid plasma concentration after a single dose of intravenous (IV) tedizolid phosphate, plotted on a (A) linear or (B) log time scale (n=9, 9, 8, and 9 for 100-, 200-, 300-, and 400-mg doses, respectively). Postinfusion data from subjects with 1-hour infusions were offset by 1 hour to match postinfusion times of subjects having 2-hour infusions. Mean tedizolid plasma concentration after 7 days of IV tedizolid phosphate 200 mg/day, plotted on a (C) linear or (D) log time scale (n=8). Mean tedizolid plasma concentration after a single dose of IV or oral 200 mg tedizolid phosphate, plotted on a (E) linear or (F) log time scale (n=8). Error bars denote standard deviations.

Figure 4

(A) Maximum plasma concentration (Cmax) for tedizolid after single or first multiple dose of intravenous (IV) tedizolid phosphate. (B) Area under the concentration-time curve (AUC) for tedizolid after single (AUC0–∞) and multiple (AUC0–24) doses of IV tedizolid phosphate. There were 9, 26, 8, and 9 individuals in the 100-, 200-, 300-, and 400-mg cohorts, respectively. Error bars denote standard deviations.