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

Abstract

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 In the multiple-ascending dose study, 3 of 24 tedizolid subjects were withdrawn under prespecified stopping rules (one each of elevated alanine aminotransferase, low reticulocyte count, or low white blood cell count), as was 1 of 8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.

Trial registration: ClinicalTrials.gov NCT00671359 NCT00671814 NCT00876655.

Keywords: TR-700; TR-701; TR-701 FA; food effect; pharmacokinetics; relative bioavailability; tedizolid phosphate disodium; tedizolid phosphate free acid.

© 2013 Trius Therapeutics. Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.

Figures

Figure 1

Mean plasma concentration-time profiles for tedizolid after a single oral dose of tedizolid phosphate disodium (TPD) at 200, 400, 600, 800, or 1200 mg. Subjects received a single administration of TPD (fasting) in the single-ascending dose arm of Study TR701-101.

Figure 2

Mean plasma concentration-time profiles for tedizolid after multiple oral doses of tedizolid phosphate at 200, 300, or 400 mg/day. Subjects received a single administration of tedizolid phosphate disodium (TPD) each morning after an overnight fast in the multiple-ascending dose arm of Study TR701-101. Plasma concentrations of tedizolid were determined on Day 15 for the 200 mg dose group, or on Day 21 (or last day of dosing in case of earlier withdrawal) for higher dose groups.

Figure 3

Relationship between dose of tedizolid phosphate disodium (TPD) and tedizolid plasma pharmacokinetics. Maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to infinity (AUC0–∞) were determined after a single dose of TPD in the single ascending dose arm of Study TR701-101 (six subjects per dose group). In the multiple ascending dose arm, Cmax was determined after the first dose of TPD, and AUC0–24 hr was determined at steady state. (A) Mean (± SD) Cmax versus dose. (B) Mean (± SD) AUC versus dose.

Figure 4

Mean plasma concentration-time profiles for tedizolid after a single administration of 600 mg of tedizolid phosphate under fed or fasted conditions. Results from Study TR701-103 are shown in linear (A, mean ± SD) and log (B) scales.

Figure 5

Mean plasma concentration-time profiles for tedizolid after a single administration of 150 mg of tedizolid from tedizolid phosphate disodium or tedizolid phosphate under fasted conditions. Results from Study TR701-108 are shown in linear (A, mean ± SD) and log (B) scales.

Figure 6

Pharmacokinetic parameter values for tedizolid for each subject after a single administration of 150 mg of tedizolid from tedizolid phosphate disodium or tedizolid phosphate under fasted conditions. Results from Study TR701-108 are shown for (A) area under the concentration-time curve from 0 to infinity (AUC0–∞) and (B) maximum plasma concentration (Cmax).