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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  TR 701‐101 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  TR 701‐103 was a food‐effect study in 12 subjects administered 600 mg  TPD . Study  TR 701‐108 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 (C max ). Tedizolid half‐life values were approximately 2‐fold greater compared with linezolid.  TPD  administration with food delayed tedizolid absorption and reduced C max  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 In the multiple‐ascending dose study, 3 of 24 tedizolid subjects were withdrawn under prespecified stopping rules (one each of elevated alanine aminotransferase, low reticulocyte count, or low white blood cell count), as was 1 of 8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.

pharmacotherapy: the journal of human pharmacology and drug therapy

Pharmacokinetics of Tedizolid Following Oral Administration: Single and Multiple Dose, Effect of Food, and Comparison of Two Solid Forms of the Prodrug