Pharmacokinetics of Tedizolid and Pseudoephedrine Administered Alone or in Combination in Healthy Volunteers

Abstract

Therapeutic doses of tedizolid phosphate, an oxazolidinone antibiotic, lack monoamine oxidase inhibition in vivo, potentially resulting in an improved safety profile versus other oxazolidinones. This randomized, double-blind, placebo-controlled, 2-period, 2-sequence, crossover, phase 1 study (NCT01577459) assessed the potential for pharmacokinetic (PK) interactions between tedizolid and pseudoephedrine. Eighteen healthy volunteers (age: 18⁻45 years) were block-randomized to 1 of 2 treatment sequences containing 2 treatment periods (tedizolid phosphate or placebo once daily for 4 days; single dose of pseudoephedrine 60 mg on day 5) separated by a 2-day washout. Median time to maximum plasma concentration for tedizolid and pseudoephedrine ranged from 3 to 4 h, regardless of treatment coadministration. Steady-state tedizolid had no effect on the PK of pseudoephedrine; geometric mean ratio and 90% confidence interval remained within the no-effect 0.8 to 1.25 boundaries. The maximum observed concentration of tedizolid decreased by approximately 14% when pseudoephedrine was coadministered; no changes in the area under the plasma concentration-time curve or the minimum observed plasma concentration occurred. All adverse events (AEs) were mild, and there were no serious AEs or study drug discontinuations. No meaningful PK interactions occurred between tedizolid and pseudoephedrine, and tedizolid was well tolerated when administered in conjunction with pseudoephedrine.

Keywords: acute bacterial skin infections; antibiotics; drug interactions; infectious disease; oxazolidinone; pharmacokinetics.

Conflict of interest statement

S.F. was an employee of Merck at the time of the study. P.P. was an employee and a stockholder of Merck at the time of the study. S.L.M. is a consultant to Merck and was compensated for supporting this research. The authors have no other funding or conflicts of interest to disclose.

Figures

Figure 1

By-participant display of PK parameter ratios. (A) Individual tedizolid Cmax, Cmin, and AUC0–24 treatment ratios (tedizolid + pseudoephedrine/tedizolid alone), GMRs, and corresponding 90% CIs; (B) Individual pseudoephedrine Cmax, AUC0–t, and AUC0–∞ treatment ratios (pseudoephedrine + tedizolid/pseudoephedrine + placebo), GMRs, and corresponding 90% CIs. Abbreviations: AUC0–t, area under the plasma concentration-time curve from hour 0 to last quantifiable time point; AUC0–24, area under the plasma concentration-time curve from hour 0 to hour 24; AUC0–∞, area under the plasma concentration-time curve from hour 0 extrapolated to infinity based on the apparent terminal rate constant; CI, confidence interval; Cmax, maximum observed concentration; Cmin, minimum observed concentration; GM, geometric mean; GMR, geometric mean ratio; PK, pharmacokinetic.