In Vitro , In Vivo , and Clinical Studies of Tedizolid To Assess the Potential for Peripheral or Central Monoamine Oxidase Interactions

Abstract

bTedizolid 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 drugfood 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 (IC 50 ) for tedizolid was 8.7 M for MAO-A and 5.7 M for MAO-B and 46.0 and 2.1 M, 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 (TYR 30 ) when administered with placebo versus tedizolid phosphate. The geometric mean tyramine sensitivity ratio (placebo TYR 30 /tedizolid phosphate TYR 30 ) 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

Absorption, Distribution, Metabolism, and Excretion of the Novel Antibacterial Prodrug Tedizolid Phosphate

“…Tedizolid distribution in bone was of particular interest, because hematologic abnormalities are a noted adverse effect associated with linezolid use (Stalker and Jungbluth, 2003). Similarly, the lower tissue-to-plasma concentration in brain is consistent with the lower risk for central nervous system-related monoamine oxidase interactions previously observed in animal models that compared tedizolid and linezolid (Flanagan et al, 2013). Tedizolid was the only metabolite consistently observed in plasma samples after intravenous or oral administration of tedizolid phosphate.…”

Comparative Efficacies of Tedizolid Phosphate, Vancomycin, and Daptomycin in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis

“…Thirteen untreated control rabbits and 9 tedizolid phosphate treated at 2 mg/kg, 11 tedizolid phosphate treated at 4 mg/kg, 10 tedizolid phosphate treated at 8 mg/kg, and 8 vancomycin treated were included in this experiment. Mean values of the AUC 0 -24 for tedizolid were 19.0, 42.8, and 76.3, respectively, for the 2-, 4-, and 8-mg/kg doses ( Table 2) (16).…”

New Gram-Positive Agents: the Next Generation of Oxazolidinones and Lipoglycopeptides

“…Among patients with normal baseline alanine aminotransferase (ALT) levels, more patients were found to have postbaseline ALT elevations greater than three times the upper limit of normal with dalbavancin treatment (0.8%) versus vancomycin-linezolid treatment (0.2%). These elevations were reversible in all patients (16,25). Severe hypersensitivity reactions to dalbavancin have been reported, necessitating caution in patients with an allergy to other glycopeptides, such as vancomycin.…”

“…As such, it has a low potential for drug-drug interactions (16). Of note, although nephrotoxicity was only rarely reported in either arm of the phase III DISCOVER trials, careful evaluation of the potential for this adverse effect with dalbavancin is warranted as this agent continues to transition into clinical practice.…”

“…During studies designed to evaluate MAO inhibition, tedizolid phosphate did not produce hypertensive or serotonergic-related adverse reactions in humans or animal models. Therefore, tedizolid phosphate may not have clinically significant interactions with serotonergic compounds (16). However, patients receiving serotonergic agents, such as SSRIs, were excluded from phase III clinical trials, making it difficult to completely rule out the possibility of tedizolid interactions with these agents (13,14).…”