Safety and Efficacy of Once Daily Intranasal Zanamivir in Preventing Experimental Human Influenza a Infection

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Abstract
Zanamivir, a potent inhibitor of influenza A and B virus neuraminidases, is protective against experimental human influenza when given intranasally twice daily. We conducted two studies to assess the pharmacokinetics and protective efficacy of a reduced frequency dosing regimen of topical zanamivir. In the first study, 36 uninfected volunteers received a single dose of zanamivir by intranasal spray (6.4 mg), intranasal drops (16 mg) or dry powder oral inhalation (10 mg). At 4 h, median nasal wash concentrations were 50-fold higher after intranasal dosing than after inhalation. Substantial levels (spray group, median 4596 ng/ml; drop group, 1239 ng/ml) were detected in nasal wash 48 h after intranasal dosing. In the double-blinded efficacy study, 47 sero-susceptible volunteers were randomized to receive either placebo or zanamivir intranasal spray (6.4 mg). Among the 43 subjects evaluated, decreases in viral shedding occurred in the group receiving one dose of zanamivir 4 h prior to inoculation, whereas no significant benefit was observed in those receiving a single dose 48 h prior to challenge. In the group given three daily doses, reductions were seen in viral shedding and infection. In the two regimens providing zanamivir 4 h prior to inoculation, significant reductions in nasal mucus weight were observed. Decreases in total symptom scores and the incidence of upper respiratory illness also occurred, but they did not reach statistical significance. The efficacy of a single dose of zanamivir given 4 h prior to inoculation supports the hypothesis that influenza virus neuraminidase is essential for initial virus spread through respiratory secretions. These findings indicate that once daily dosing of zanamivir is protective against experimental influenza A infection.

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