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

Abstract

ObjectivesThe 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.DesignRandomized placebo-controlled, double-blind single- and multiple-ascending dose studies and randomized open-label, crossover food effect and relative bioavailability studies.SettingClinical Research Units.ParticipantsHealthy subjects.InterventionStudy 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 ResultsPlasma 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 In the multiple-ascending dose study, 3 of 24 tedizolid subjects were withdrawn under prespecified stopping rules (one each of elevated alanine aminotransferase, low reticulocyte count, or low white blood cell count), as was 1 of 8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).ConclusionsOverall, 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.

In Vitro Susceptibility Testing of Tedizolid against Nontuberculous Mycobacteria

“…The in vitro MICs of TZD obtained in this and previous studies, along with the once-daily lower dosage for TZD and the potential for fewer and less serious adverse events associated with TZD compared with LZD, emphasize the potential for TZD in the treatment of infections caused by some species of NTM (3,8,17,19,20). Considering the data from this study and depending upon the determination of susceptibility breakpoints for TZD compared with those currently accepted for LZD against NTM, this new oxazolidinone may provide an effective therapeutic agent for the treatment of infections caused by NTM.…”

“…TZD has a high oral bioavailability and a longer half-life (11.0 h versus 5.0 h for LZD), thus allowing the clinician to easily modify the route from intravenous to oral and to use once-daily dosing, encouraging more patient compliance and outpatient usage (17,18). Moreover, although long-term usage has not been assessed, TZD appears to be better tolerated than LZD, especially in regard to hematological adverse events, including thrombocytopenia (3,15).…”

“…Studies also suggest that the 200-mg dose of tedizolid phosphate (150 mg TZD equivalent) has favorable pharmacokinetic, safety, and efficacy profiles and thus was selected for therapeutic dosing (3,16,17,20).…”

Nonclinical and Pharmacokinetic Assessments To Evaluate the Potential of Tedizolid and Linezolid To Affect Mitochondrial Function

“…Assuming that mitochondrion-related toxicities are driven by the time during which the free C min remains higher than the MPS IC 50 of a drug (12,48), our data help to explain why tedizolid may be safer than linezolid for clinical use, despite tedizolid having a lower MPS IC 50 (by molar value). An additional factor that may contribute to fewer mitochondrial effects with tedizolid than with linezolid might be the substantial drug accumulation (and increased plasma concentrations) with repeated administration of linezolid (25,51,52). In contrast, most tedizolid-treated patients stay within the desired exposure window, allowing mitochondrial recovery because of narrow PK variability and a lack of significant accumulation (43,52).…”

“…An additional factor that may contribute to fewer mitochondrial effects with tedizolid than with linezolid might be the substantial drug accumulation (and increased plasma concentrations) with repeated administration of linezolid (25,51,52). In contrast, most tedizolid-treated patients stay within the desired exposure window, allowing mitochondrial recovery because of narrow PK variability and a lack of significant accumulation (43,52). It is speculated that accumulation of linezolid is caused by impairment of hepatic mitochondria, leading to autoinhibition of its metabolism (53).…”