title: Effect of intravenous zanamivir on cardiac repolarization.
abstract: OBJECTIVE
  To assess the effect of a therapeutic and supratherapeutic intravenous dose of the neuraminidase inhibitor zanamivir on QT and rate-corrected QT intervals.
  
  
  METHODS
  Randomized, placebo-controlled, single-dose, four-period, balanced crossover study.
  
  
  METHODS
  Clinical research unit.
  
  
  METHODS
  Forty healthy adults were randomized to receive intravenous zanamivir at two dose levels, oral moxifloxacin, and placebo; 38 subjects completed all four study treatments.
  
  
  METHODS
  Subjects were randomized to receive a single intravenous dose of zanamivir 600 mg (therapeutic dose) with oral moxifloxacin placebo, a single intravenous dose of zanamivir 1200 mg (supratherapeutic dose) with oral moxifloxacin placebo, oral moxifloxacin 400 mg (positive control) with intravenous zanamivir placebo, or intravenous zanamivir placebo with oral moxifloxacin placebo. Subjects crossed over to all other treatments, with each treatment separated by a 7-day washout period.
  
  
  RESULTS
  Zanamivir pharmacokinetics were dose proportional; the pharmacokinetic exposure from zanamivir 1200 mg was 2 times higher than that from 600 mg, the maximum dose under clinical evaluation. For both 600-mg and 1200-mg doses of intravenous zanamivir, the upper limit of the 90% confidence interval (CI) for the placebo-adjusted mean change from baseline of the QT interval corrected for heart rate using Fridericia's formula (ΔΔQTcF) was less than 10 msec at all time points. The sensitivity of the study to detect modest increases in QT interval was established with the positive control, moxifloxacin. The maximum ΔΔQTcF value for zanamivir 1200 mg was 1.73 msec (90% CI -0.40 to 3.87 msec), which was observed within 30 minutes after dosing, and 11.21 msec (90% CI 8.81-13.60) for moxifloxacin, observed at 4 hours after dosing. No relationship was observed between zanamivir serum concentration and ΔΔQTcF. Zanamivir was generally well tolerated, with very few adverse events; none were serious or severe.
  
  
  CONCLUSIONS
  Intravenous zanamivir does not affect cardiac repolarization. Accordingly, treatment with intravenous zanamivir does not require additional cardiac monitoring beyond the standard of care.
authors.affiliation: Infectious Diseases Medicines Discovery and Development, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.forename: Jianjun
authors.initials: J
authors.lastname: Gan
authors.forename: Amanda
authors.initials: A
authors.lastname: Peppercorn
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gould
authors.forename: Steve
authors.initials: S
authors.lastname: Weller
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Piscitelli
authors.forename: Parul
authors.initials: P
authors.lastname: Patel
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000009:adverse effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D000077266:Moxifloxacin; D011804:Quinolines / Q000009:adverse effects; D013997:Time Factors; D055815:Young Adult; D053243:Zanamivir / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D053243:Zanamivir; D000077266:Moxifloxacin
keywords: QT interval; cardiac conduction; influenza; neuraminidase inhibitor; zanamivir