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

Shawn Flanagan,Philippe Prokocimer,Sonia Minassian

doi:10.3390/jcm7060150

Shawn Flanagan, Philippe Prokocimer + Show 1 more

Open Access

https://doi.org/10.3390/jcm7060150

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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.

Highlights

Agents approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI) are generally efficacious, but toxicity and microbial resistance may limit their use [1,2]
The oxazolidinone antibiotic linezolid, an inhibitor of monoamine oxidase (MAO), is approved for the treatment of uncomplicated and complicated skin and skin structure infections; significant safety concerns have emerged since its approval [4]
Clinical studies have demonstrated that linezolid increases blood pressure in patients who have uncontrolled hypertension and in those who are taking sympathomimetic drugs such as pseudoephedrine [4,5], which are associated with increases in systolic blood pressure (SBP) and heart rate (HR) [6]

Summary

Introduction

Agents approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI) are generally efficacious, but toxicity and microbial resistance may limit their use [1,2]. Given the increasing prevalence of multidrug-resistant, gram-positive pathogens, there is a need for new and effective antibiotics with proven antibacterial activity [2,3]. Oxazolidinones are one such class of antibacterial agents. The oxazolidinone antibiotic linezolid, an inhibitor of monoamine oxidase (MAO), is approved for the treatment of uncomplicated and complicated skin and skin structure infections; significant safety concerns have emerged since its approval [4]. Coadministration of linezolid with other MAO inhibitors, adrenergic drugs, or serotonergic drugs is restricted because it may produce cardiovascular (e.g., hypertension) or neurologic (i.e., serotonin syndrome) treatment-emergent adverse events (AEs) that can be fatal in some patients [3,4]. Clinical studies have demonstrated that linezolid increases blood pressure in patients who have uncontrolled hypertension and in those who are taking sympathomimetic drugs such as pseudoephedrine [4,5], which are associated with increases in systolic blood pressure (SBP) and heart rate (HR) [6]

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