title: 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).
authors.affiliation: Trius Therapeutics, Inc., San Diego, California, USA. sflanagan@triusrx.com
authors.forename: S
authors.initials: S
authors.lastname: Flanagan
authors.forename: K
authors.initials: K
authors.lastname: Bartizal
authors.forename: S L
authors.initials: SL
authors.lastname: Minassian
authors.forename: E
authors.initials: E
authors.lastname: Fang
authors.forename: P
authors.initials: P
authors.lastname: Prokocimer
mesh_terms: D000081:Acetamides / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D051379:Mice; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D010755:Organophosphates / Q000378:metabolism / Q000494:pharmacology*; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology*; D023303:Oxazolidinones / Q000378:metabolism / Q000494:pharmacology*; D054199:Pseudoephedrine / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000378:metabolism / Q000494:pharmacology*; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology; D014439:Tyramine / Q000378:metabolism; D055815:Young Adult
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D008996:Monoamine Oxidase Inhibitors; D010755:Organophosphates; D010080:Oxazoles; D023303:Oxazolidinones; D018490:Serotonin Agents; D013777:Tetrazoles; D012701:Serotonin; D054199:Pseudoephedrine; C546016:tedizolid; D008995:Monoamine Oxidase; D000069349:Linezolid; C515040:tedizolid phosphate; D014439:Tyramine