The pharmacokinetic and safety profiles of zanamivir after single and repeat intravenous administration in healthy Japanese males

Abstract

Neuraminidase inhibitors are important options for the treatment of infection by the influenza virus. For the treatment of severe influenza, parenteral administration of a neuraminidase inhibitor may be desirable. This study was conducted to evaluate the pharmacokinetic and safety profiles of intravenous zanamivir, an influenza viral neuraminidase inhibitor, in Japanese subjects to further characterize these profiles particularly following relatively high-doses when compared with inhalation doses and to provide reassurance that there are no marked differences with profiles reported for other ethnically different populations. Single doses of 100, 300, 600mg zanamivir were administered to healthy Japanese men in a randomized, double-blind, ascending dose, placebo-controlled, incomplete three-period cross-over study. In period 3, subjects were given 600mg of zanamivir on day 1, followed by a 60h washout period and then a 5-day course of 600mg zanamivir twice daily. Each subjects received two of three active dosages of zanamivir from 100, 300 and 600mg, and placebo. Adverse events reported in the study were all mild in intensity and resolved without any treatment. The mean AUC0-∞ values after single intravenous administration of 100, 300 and 600mg were 16768, 53462 and 100400ng·h/mL, respectively, demonstrating dose proportionality. No accumulation or time variance was observed after 5days of twice-daily administration of 600mg zanamivir. Urinary concentrations of zanamivir after single doses ranging from 100 to 600mg indicated that over 94% of the zanamivir administered was excreted in urine within 24h. Single and 5-day BID repeat dosing of 600mg were safely administered in Japanese healthy subjects. The pharmacokinetic profile of zanamivir after intravenous administration was consistent with previously reported findings in non-Japanese subjects.