A phase 2 randomized, double-blind, dose-ranging study evaluating the safety, tolerability, population pharmacokinetics, and efficacy of oral torezolid phosphate in patients with complicated skin and skin structure infections

P Prokocimer, P Bien, J Surber, P Mehra, C DeAnda, Jurgen Bulitta, G R Corey

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Abstract

Torezolid (TR-700) is the active moiety of the prodrug torezolid phosphate (TP, TR-701), a second generation oxazolidinone with 4- to 16-fold greater potency than linezolid against gram positive species including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind Phase 2 study evaluated three levels (200, 300, or 400mg) of oral, once daily TP over 5-7 days for complicated skin and skin structure infections (cSSSI). Patients 18-75 years with cSSSI suspected or confirmed gram positive pathogens were randomized 1:1:1. Of 188 treated patients, 76.6 had abscesses, 17.6 had extensive cellulitis, and 5.9 had wound infections. S. aureus, the most common pathogen, was isolated in 90.3 of patients (139/154) with a baseline pathogen; 80.6 were MRSA. Cure rates in clinically evaluable patients were 98.2 at 200mg, 94.4 at 300mg, and 94.4 at 400mg. Cure rates were consistent across diagnoses, regardless of lesion size or the presence of systemic signs of infection. Clinical cure rates in patients with S. aureus isolated at baseline was 96.6 overall and 96.8 for MRSA. TP was safe and well tolerated at all dose levels. No patients discontinued treatment due to an adverse event. Three- stage hierarchical population pharmacokinetic modeling yielded a geometric mean clearance of 8.28L/h (between patient variability 32.3 ), volume of central compartment 71.4L (24.0 ), and of peripheral compartment 27.9L (35.7 ). Results of this study show a high degree of efficacy at all three dose levels without significant differences in the safety profile, and support the continued evaluation of TP for the treatment of cSSSI in Phase 3 trials.
Original languageEnglish
Pages (from-to)583 - 592
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume55
Issue number2
DOIs
Publication statusPublished - 2011

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