title: Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers.
abstract: OBJECTIVE
  To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies.
  
  
  METHODS
  Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations.
  
  
  RESULTS
  Mean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin.
  
  
  CONCLUSIONS
  Both levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies. This study has demonstrated the utility of levofloxacin on the assay in measuring mean QTc changes around 5 ms.
authors.affiliation: Richmond Pharmacology Ltd, St George's University of London, UK.
authors.forename: Jorg
authors.initials: J
authors.lastname: Taubel
authors.forename: Asif
authors.initials: A
authors.lastname: Naseem
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Harada
authors.forename: Duolao
authors.initials: D
authors.lastname: Wang
authors.forename: Radivoj
authors.initials: R
authors.lastname: Arezina
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lorch
authors.forename: A John
authors.initials: AJ
authors.lastname: Camm
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001372:Aza Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D064704:Levofloxacin; D008297:Male; D000077266:Moxifloxacin; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012015:Reference Standards; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D064704:Levofloxacin; D015242:Ofloxacin; D000077266:Moxifloxacin
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