Improved pharmacokinetics of the novel oxazolidinone antibiotic tedizolid phosphate compared with linezolid in healthy subjects

Purpose: Tedizolid phosphate disodium salt (TR-701) is a novel oxazolidinone prodrug that is rapidly converted to the microbiologically active molecule tedizolid (TR-700). TR-700 is active against gram-positive organisms. TR-701 FA (free acid) is currently in phase 3 trials for the treatment of acute bacterial skin and skin structure infections. The objective of this study was to compare the pharmacokinetics (PK) and safety of 200 mg TR-701 and the current label-approved dose of linezolid in healthy adults. 

Methods: This study evaluated the single and multiple dose PK of TR-700, compared with linezolid in healthy adults. Each cohort of 10 subjects (8 active and 2 placebo) received oral 200 mg TR-701 once-daily, or oral 600 mg linezolid twice-daily for 21 days.   TR700 and linezolid plasma concentrations were determined using validated tandem mass spectrometry assays and PK was determined with standard noncompartmental methods using WinNonlin. 

Results:

• Mean TR-700 half-life was approximately 2-fold longer than that of linezolid, thus supporting once-daily administration
• The pharmacokinetics of TR-700 after a single dose of TR-701 well predicted the exposure after repeat administration (linearity ratio = 0.94)
• Day 21 pharmacokinetics of linezolid exhibited nonlinearities (linearity ratio= 1.55) following multiple twice-daily dosing
• Moderate accumulation of TR-700 (approximately 28%) and marked accumulation of linezolid (approximately 72%) was observed after 21 days 

Conclusion:

• After 21 days of TR-701 treatment, TR-700 exhibited consistent and predictable exposure
• Nonlinear linezolid kinetics were observed with increased exposure after repeat administration
• Both drugs were safe and well tolerated