Source of support: Funding for this study was provided by GlaxoSmithKline.
Original Research Article
Effect of Intravenous Zanamivir on Cardiac Repolarization
Version of Record online: 3 APR 2013
© 2013 Pharmacotherapy Publications, Inc
Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy
Volume 33, Issue 7, pages 701–709, July 2013
How to Cite
(Pharmacotherapy 2013;33(7):701–709) doi: 10.1002/phar.1261
Conflict of interest: All authors are employees of GlaxoSmithKline and hold stock options.
Presented as a poster at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, September 9–12, 2012.
ClinicalTrials.gov identifier: NCT01353729
- Issue online: 1 JUL 2013
- Version of Record online: 3 APR 2013
- QT interval;
- cardiac conduction;
- neuraminidase inhibitor;
To assess the effect of a therapeutic and supratherapeutic intravenous dose of the neuraminidase inhibitor zanamivir on QT and rate-corrected QT intervals.
Randomized, placebo-controlled, single-dose, four-period, balanced crossover study.
Clinical research unit.
Forty healthy adults were randomized to receive intravenous zanamivir at two dose levels, oral moxifloxacin, and placebo; 38 subjects completed all four study treatments.
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.
Intravenous zanamivir does not affect cardiac repolarization. Accordingly, treatment with intravenous zanamivir does not require additional cardiac monitoring beyond the standard of care.