Abstract
Tedizolid phosphate is a novel antibacterial prodrug with potent activity against Gram-positive pathogens. In vitro and in vivo studies demonstrated that the prodrug is rapidly converted by nonspecific phosphatases to the biologically active moiety tedizolid. Single oral dose radiolabeled 14C-tedizolid phosphate kinetic studies in human subjects (100 µCi in 204 mg tedizolid phosphate free acid) confirmed a rapid time to maximum tedizolid concentration (Tmax, 1.28 hours), a long terminal half-life (10.6 hours), and a Cmax of 1.99 µg/ml. Metabolite analysis of plasma, fecal, and urine samples from rats, dogs, and humans confirmed that tedizolid is the only measurable metabolite in plasma after intravenous (in animals only) or oral administration and that tedizolid sulfate is the major metabolite excreted from the body. Excellent mass balance recovery was achieved and demonstrated that fecal excretion is the predominant (80–90%) route of elimination across species, primarily as tedizolid sulfate. Urine excretion accounted for the balance of drug elimination but contained a broader range of minor metabolites. Glucuronidation products were not detected. Similar results were observed in rats and dogs after both intravenous and oral administration. The tedizolid metabolites showed less potent antibacterial activity than tedizolid. The observations from these studies support once daily dosing of tedizolid phosphate and highlight important metabolism and excretion features that differentiate tedizolid phosphate from linezolid.
Footnotes
- Received December 20, 2013.
- Accepted May 29, 2014.
This study was sponsored by Cubist.
Employees of the study sponsor were involved in study design, data collection, data analysis, interpretation of the results, and review/writing of the manuscript. All authors had full access to the data. The authors had final responsibility for the decision to submit for publication. V. Ong, S. Flanagan, E. Fang, H.J. Dreskin, J.B. Locke, K. Bartizal, and P. Prokocimer are employees of Cubist. Medical writing support was provided by Bill Jacobs (Strategic HealthCom, Somerville, NJ), funded by Cubist.
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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