To assess the effect of a therapeutic and supratherapeutic intravenous dose of the neuraminidase inhibitor zanamivir on QT and rate-corrected QT intervals.Design
Randomized, placebo-controlled, single-dose, four-period, balanced crossover study.Setting
Clinical research unit.Subjects
Forty healthy adults were randomized to receive intravenous zanamivir at two dose levels, oral moxifloxacin, and placebo; 38 subjects completed all four study treatments.Intervention
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.Measurements and Main 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.Conclusion
Intravenous zanamivir does not affect cardiac repolarization. Accordingly, treatment with intravenous zanamivir does not require additional cardiac monitoring beyond the standard of care.