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Abstract

Introduction: Tedizolid phosphate (TZP) is in Phase III clinical development globally for infections caused by Gram-positive bacteria, including MRSA. The pharmacokinetic (PK) properties of the active moiety tedizolid after intravenous (IV) and oral (PO) administration of TZP had previously been evaluated in healthy American subjects. This Phase I study assessed the PK profile of tedizolid in healthy Japanese adults prior to its Phase III investigation for nosocomial pneumonia. Methods: In this two-way crossover study, subjects were randomized to receive IV placebo (saline, n=4) or 200 mg TZP (n=8) in 250 ml infusion over 60 minutes. After a 7-day washout period, subjects randomly received an oral dose of either placebo (n=4) or 200 mg TZP (n=8) with 240 mL water. Plasma samples were collected at baseline and at subsequent time points up to 72 hours after administration. The concentration of tedizolid was determined by LC-MS/MS assay and PK parameters were calculated. Data are expressed as (arithmetic) mean ± standard deviation. Results: Due to a mild adverse event, TZP infusion was discontinued in one subject, who was then excluded from the entire PK analysis. After IV administration of TZP, the plasma concentration of tedizolid reached a Cmax of 3.45 ± 0.60 μg/mL within ~1 hour (Tmax=1.08h) and decreased with a half-life (t1/2) of 10.8 ± 1.37 hours. The total drug exposure (AUC) was 34.4 ± 7.9 μg•h/mL. After PO administration of TZP, the tedizolid plasma concentration reached a Cmax of 2.38 ± 0.59 μg/mL within ~3 hours, then it decreased with a t1/2 of 10.7 ± 0.99 hours; the AUC was 28.6 ± 8.2 μg•h/mL. Conclusions: The PK profile of the active moiety tedizolid was similar after IV and PO administration of TZP in healthy Japanese adults and was comparable to the profile previously observed in American subjects in a similar study (IV: Cmax=2.48 ± 0.41 μg/mL, t1/2=11.4 ± 2.00 h, AUC=29.0 ± 6.14 μg•h/mL; PO: Cmax=1.91 ± 0.44 μg/mL, t1/2=11.1 ± 2.12 h, AUC=26.7 ± 6.0 μg•h/mL), with slightly higher exposures (Cmax, AUC) even after correcting for body weight. In summary, no major differences in the PK profile of tedizolid were observed due to subject ethnicity and no TZP dose adjustment is recommended for Japanese adults.