Characterization of Neurologic and Ophthalmologic Safety of Oral Administration of Tedizolid for Up to 21 Days in Healthy Volunteers.

BACKGROUND: Antibacterials that inhibit protein synthesis may be associated with mitochondrial toxicity, manifested as serious optic or peripheral neuropathy or myelosuppression. Tedizolid is a novel oxazolidinone antibacterial that may have reduced the potential for mitochondrial toxicity. STUDY QUESTION: Based on the results of 2 studies (NCT01623401 and NCT00671814) conducted early in the tedizolid development program, what is the potential for drug-induced optic and peripheral neuropathies with tedizolid treatment? METHODS: Two phase-1 studies were conducted in healthy volunteers. The first was an open-label study in which subjects received 200 mg of oral tedizolid phosphate once daily for 10 days. The second was a double-blind, placebo- and active-controlled, dose-escalating (multiple-administration) study in which subjects received 200, 300, or 400 mg of oral tedizolid phosphate once daily or 600 mg of oral linezolid twice daily or oral placebo for 21 days. Overall safety and tolerability were assessed, and extensive ophthalmologic and neurologic assessments were performed in both studies. RESULTS: In these 2 studies in healthy subjects, tedizolid administered for up to 21 days was not associated with drug-related ophthalmologic or neurologic adverse events. Incidences of adverse events involving the eye or the nervous system were generally low, and no clinically meaningful changes in ophthalmologic or neurologic test results were recorded during either study. CONCLUSIONS: Using an extensive battery of ophthalmologic tests and detailed neurologic clinical examination, there was no evidence of clinical or subclinical neurologic or ophthalmologic changes suggestive of peripheral or optic neuropathy in healthy volunteers who received therapeutic and supratherapeutic doses of oral tedizolid for periods of up to 21 days.

Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid.

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.

Pharmacokinetics of tedizolid following oral administration: single and multiple dose, effect of food, and comparison of two solid forms of the prodrug.

OBJECTIVES: The single- and multiple-dose pharmacokinetics (PK) of tedizolid were examined after oral administration of tedizolid phosphate disodium (TPD), including the effect of food on PK. The relative bioavailability of TPD to the free acid tedizolid phosphate was determined to bridge the results of these and other studies to the solid form of the prodrug selected for further development. DESIGN: Randomized placebo-controlled, double-blind single- and multiple-ascending dose studies and randomized open-label, crossover food effect and relative bioavailability studies. SETTING: Clinical Research Units. PARTICIPANTS: Healthy subjects. INTERVENTION: Study TR701-101 enrolled 40 subjects in single-ascending dose (200-1200 mg TPD or placebo) and 40 subjects in 21-day multiple-ascending dose (200, 300, or 400 mg TPD once/day; 600 mg linezolid twice/day; or placebo) arms. Study TR701-103 was a food-effect study in 12 subjects administered 600 mg TPD. Study TR701-108 was a relative bioavailability study in 12 subjects administered 150-mg tedizolid equivalents as TPD or tedizolid phosphate. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of the prodrug tedizolid phosphate, its active moiety tedizolid, and/or linezolid were collected. After administration of 200 to 600 mg TPD, tedizolid values increased approximately dose proportionally in area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ). Tedizolid half-life values were approximately 2-fold greater compared with linezolid. TPD administration with food delayed tedizolid absorption and reduced Cmax relative to the fasted state but did not alter AUC. Minimal accumulation was predicted and observed for tedizolid, whereas observed accumulation of linezolid exceeded predictions based on single-dose PK. Comparable PK of tedizolid was observed following oral administration of either TPD or tedizolid phosphate. In the multiple-ascending dose study, 3 of 24 tedizolid subjects were withdrawn under prespecified stopping rules (one each of elevated alanine aminotransferase, low reticulocyte count, or low white blood cell count), as was 1 of 8 linezolid subjects (low reticulocyte count). CONCLUSIONS: Overall, tedizolid has a favorable PK profile, a half-life that supports once daily administration, and no nonlinearities at steady state. Tedizolid phosphate can be administered without regard to food.