916

Abstract

Introduction: Some antibiotics used for treating ventilator-associated bacterial pneumonia (VABP) are associated with mitochondrial toxicity that can manifest as serious optic and/or peripheral neuropathy. Tedizolid phosphate (TZP), a novel antibiotic prodrug currently in clinical development for VABP, may have reduced potential for mitochondrial toxicity. This study was conducted to evaluate the potential for drug-induced optic and peripheral neuropathies with TZP at the 200 mg once daily dose used in the VABP Phase 3 program. Methods: This was a Phase 1 open-label study in healthy male and female volunteers (18-65 years old) who received oral TZP 200 mg once daily for 10 days and underwent extensive ophthalmologic and neurologic assessments before and after study drug administration and 2 - 4 weeks after the last dose. Ophthalmologic assessments included optical coherence tomography, best corrected distance visual acuity, dilated fundoscopy, color vision testing (Roth 28), dilated and non-dilated slit lamp examination, visual field testing (Haag-Streit Octopus 300), and optic nerve photography. Neurologic assessments included cranial nerve, sensory, motor, reflex, coordination, and gait evaluations. Results: A total of 72 subjects were enrolled; 67 completed the study (i.e., received all 10 doses of study drug and underwent all study visits). Five subjects withdrew from the study for personal reasons. There were no discontinuations or withdrawals due to treatment emergent adverse events (TEAEs). All subjects had normal neurologic assessments at all study time points. Minor changes in ophthalmologic examinations were observed, but none were deemed clinically meaningful. TEAEs were reported in approximately 30% of subjects. The most common TEAEs were headache, musculoskeletal pain, nausea, diarrhea, and nasal congestion. All TEAEs were mild in severity; there were no serious AEs or deaths. Conclusions: There was no evidence of neurologic and ophthalmologic changes suggestive of peripheral or optic neuropathy in healthy volunteers who received oral TZP 200 mg once daily for 10 days. These results add to the cumulative evidence supporting the ongoing clinical development of TZP for critically ill patients.