Single- and Multiple-Dose Pharmacokinetics and Absolute Bioavailability of Tedizolid

ObjectivesTedizolid 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. DesignDouble-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies. SettingSingle center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010. ParticipantsNinety healthy volunteers. InterventionSingle intravenous (IV) doses of tedizolid phosphate 50mg (lead-in) and 100-400mg. Single oral and IV dose of tedizolid phosphate 200mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300mg for up to 7days. Measurements and Main ResultsA dose-dependent increase was observed in the maximum plasma concentration (1.2-5.1g/ml) and the area under the concentration-time curve (17.4-58.7gxhr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100-400mg. Administration of IV tedizolid phosphate 200mg once/day for 7days 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 200mg and placebo were similarly tolerated, based on visual infusion phlebitis scores. ConclusionThese results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200mg with both the oral and IV formulations, without the need for dose adjustment when switching administration routes.