In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions

Abstract

Tedizolid phosphate is a novel oxazolidinone prodrug whose active moiety, tedizolid, has improved potency against Gram-positive pathogens and pharmacokinetics, allowing once-daily administration. Given linezolid warnings for drug-drug and drug-food interactions mediated by monoamine oxidase (MAO) inhibition, including sporadic serotonergic toxicity, these studies evaluated tedizolid for potential MAO interactions. In vitro, tedizolid and linezolid were reversible inhibitors of human MAO-A and MAO-B; the 50% inhibitory concentration (IC50) for tedizolid was 8.7 μM for MAO-A and 5.7 μM for MAO-B and 46.0 and 2.1 μM, respectively, with linezolid. Tedizolid phosphate was negative in the mouse head twitch model of serotonergic activity. Two randomized placebo-controlled crossover clinical studies assessed the potential of 200 mg/day tedizolid phosphate (at steady state) to enhance pressor responses to coadministered oral tyramine or pseudoephedrine. Sensitivity to tyramine was determined by comparing the concentration of tyramine required to elicit a ≥ 30-mmHg increase in systolic blood pressure (TYR30) when administered with placebo versus tedizolid phosphate. The geometric mean tyramine sensitivity ratio (placebo TYR30/tedizolid phosphate TYR30) was 1.33; a ratio of ≥ 2 is considered clinically relevant. In the pseudoephedrine study, mean maximum systolic blood pressure was not significantly different when pseudoephedrine was coadministered with tedizolid phosphate versus placebo. In summary, tedizolid is a weak, reversible inhibitor of MAO-A and MAO-B in vitro. Provocative testing in humans and animal models failed to uncover significant signals that would suggest potential for hypertensive or serotonergic adverse consequences at the therapeutic dose of tedizolid phosphate. Clinical studies are registered at www.clinicaltrials.gov as NCT01539473 (tyramine interaction study conducted at Covance Clinical Research Center, Evansville, IN) and NCT01577459 (pseudoephedrine interaction study conducted at Vince and Associates Clinical Research, Overland Park, KS).

Figures

Fig 1

Spectrum of clinical findings. Manifestations of the serotonin syndrome range from mild to life threatening. The vertical arrows suggest the approximate point at which clinical findings initially appear in the spectrum of the disease, but all findings may not be consistently present in a single patient with serotonin syndrome. Severe signs may mask other clinical findings. For example, muscular hypertonicity can overwhelm tremor and hyperreflexia. Reprinted from reference with permission from Massachusetts Medical Society.

Fig 2

Blood pressure response to 60 mg pseudoephedrine in placebo- and tedizolid phosphate-pretreated study populations. Patients (n = 18) were randomized to oral placebo or oral tedizolid phosphate doses of 200 mg per day for 4 days; on the fifth day, 60 mg pseudoephedrine was administered with the morning dose of placebo or tedizolid phosphate, and blood pressure was recorded over the subsequent 24 h. Blood pressure was measured within 15 min prior to drug administration (Pre), every hour for 8 h after study drug administration, and at 10, 12, and 24 h.

Fig 3

Mouse head twitch rate following tedizolid phosphate, linezolid, fluoxetine, or moclobemide treatment. Twitch frequency is shown as means ± SD (n = 8 mice/group). Tedizolid refers to tedizolid phosphate. *, P < 0.05 versus the control group.