title: Effects of therapeutic and supratherapeutic doses of oral tedizolid phosphate on cardiac repolarisation in healthy volunteers: a randomised controlled study.
abstract: Drug-induced prolongation of the QT interval on the electrocardiogram (ECG) infrequently results in Torsades de pointes, a potentially fatal arrhythmia. Therefore, thorough QT analysis of new drugs is a regulatory requirement. The objective of this phase 1 study was to assess the effects of oral tedizolid phosphate on the QT interval corrected with Fridericia's formula (QTcF) in healthy adult subjects. A single therapeutic dose (200 mg) and a supratherapeutic dose (1200 mg) of tedizolid phosphate were administered to characterise QTc changes following typical systemic exposure and with markedly higher exposures, respectively. This was a four-way crossover study with 48 subjects randomly assigned to receive therapeutic and supratherapeutic doses of tedizolid phosphate, moxifloxacin (positive control for QT interval prolongation) and placebo (negative control). A continuous 12-lead ECG was recorded from 1 h before drug administration to 23 h after administration. Adverse events, which were generally mild, occurred most frequently with moxifloxacin or with a supratherapeutic dose of tedizolid phosphate; however, all treatments were well tolerated. This study demonstrated that therapeutic or supratherapeutic doses of the antibacterial tedizolid had no clinically significant effect on QT interval in healthy adults [ClinicalTrials.gov registration no.: NCT01461460].
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ 07033, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Flanagan
authors.affiliation: eResearch Technology, Inc., 1818 Market Street, Philadelphia, PA 19103, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Litwin
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ 07033, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Fang
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ 07033, USA. Electronic address: philippe.prokocimer@merck.com.
authors.forename: Philippe
authors.initials: P
authors.lastname: Prokocimer
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000009:adverse effects; D064368:Healthy Volunteers; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010755:Organophosphates / Q000008:administration & dosage* / Q000009:adverse effects*; D010080:Oxazoles / Q000008:administration & dosage* / Q000009:adverse effects*; D010919:Placebos / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D010755:Organophosphates; D010080:Oxazoles; D010919:Placebos; C515040:tedizolid phosphate; D000077266:Moxifloxacin
keywords: Antibacterial; ECG; Heart; Oxazolidinone; QT prolongation; Safety