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

• Published in: Pharmacotherapy Vol. 34; no. 9; pp. 891 - 900
• Main Authors: Flanagan, Shawn, Fang, Edward, Muñoz, Kelly A., Minassian, Sonia L., Prokocimer, Philippe G.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-09-2014; Wiley Subscription Services, Inc; BlackWell Publishing Ltd
• Subjects: Administration, Oral; Adult; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacokinetics; Biological Availability; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Injections, Intravenous; intravenous; Male; Organophosphates - administration & dosage; Organophosphates - adverse effects; Organophosphates - pharmacokinetics; Original s; Oxazoles - administration & dosage; Oxazoles - adverse effects; Oxazoles - pharmacokinetics; pharmacokinetics; Pilot Projects; tedizolid phosphate; Young Adult; tedizolid phosphate; pharmacokinetics; intravenous
• ISSN: 0277-0008; 1875-9114
• DOI: 10.1002/phar.1458

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.