Zanamivir

Abstract

Zanamivir is a novel inhibitor of the enzyme neuraminidase, a surface glycoprotein essential for the replication of type A and B influenza viruses. Statistically significant reductions in median time to alleviation of major symptoms of influenza were reported in phase II and III studies of zanamivir. Benefit was seen with early treatment (within 30 or 36 hours of onset of illness) in phase II trials. Median times to alleviation of major (or ‘clinically significant’) symptoms were reduced by 1 to 2.5 days after treatment with zanamivir 10mg twice daily by oral inhalation for 5 days in 3 phase III studies. Benefit of zanamivir treatment in terms of time to return to normal activities and reductions in consumption of paracetamol (acetaminophen), and reductions in the level of interference of influenza with sleep, work, leisure and recreational activities, were reported. Reductions relative to placebo of 2.5 to 3.25 days were observed in median time to alleviation of major symptoms in high-risk patients. Available data also indicate potential of zanamivir in the prophylaxis of influenza. A statistically significant reduction in the incidence of influenza A was reported with zanamivir 10mg by oral inhalation once daily for 4 weeks in a double-blind study in 1107 persons in 2 university communities. Prophylactic benefit of zanamivir in influenza A and B outbreaks has also been suggested by data from a nursing home community. Adverse event profiles in patients receiving zanamivir therapeutically or prophylactically appear similar to those in patients receiving placebo. The most commonly reported adverse events in therapeutic trials have been nasal signs and symptoms, diarrhoea, nausea, headache, bronchitis and cough. Conclusions: Prompt treatment with zanamivir in patients with naturally acquired influenza is associated with significant reductions in duration of symptomatic illness, accelerated return to normal levels of activity and reduced consumption of antibiotics for influenza-related complications. While vaccination in selected populations remains the seasonal intervention of choice for prophylaxis, the efficacy, good tolerability and lack of resistance seen with zanamivir are likely to make the drug a valuable treatment option, particularly in individuals not covered or inadequately protected by vaccination, and in those at high risk of influenza-related complications. Confirmation of the prophylactic efficacy of zanamivir would indicate a major potential role for the drug in this setting, especially in persons for whom vaccination is not suitable or fully effective, in closed communities (e.g. nursing homes) and in individuals at high risk. Concentrations of zanamivir required for 50% inhibition of in vitro plaque for mation (IC₅₀) in plaque reduction assays in Madin-Darby canine kidney (MDCK) cells ranged from 0.004 to 0.014 µmol/L in a range of laboratory-passaged strains of influenza A and B. A wider range of IC50 values (0.002 to 16 µmol/L) was reported in assays of clinical isolates, but higher concentrations of amantadine, rimantadine and ribavirin were needed to inhibit replication of all strains tested. Zanamivir was also effective in the inhibition of influenza A and B strains in yield reduction assays in human respiratory epithelium: concentrations required for 90% inhibition of viral replication (IC90) were max) of zanamivir are attained within 1 to 2 hours of a single dose of dry powder inhaled via the Diskhaler® device. Serum elimination half-life values were 5.05 and 4.14 hours after single inhaled doses of 5 and 10mg, respectively, and C_max was attained within 1 hour of administration after 1 and 7 days’ treatment. 12 and 17% of the administered dose was excreted in the urine and median renal clearances were 6.45 and 10.87 L/h on days 1 and 7, respectively. Lung scintigraphy showed 13.2% of the inhaled 10mg dose to be deposited in the bronchi and lungs, with 77.6% being deposited in the oropharynx. High concentrations of zanamivir are retained in tracheal and bronchial epithelium for up to 24 hours after a single inhaled dose of 10mg. Impairment of renal function has no effect on C_max values or time to C_max, although increases in area under the curve of serum drug concentration versus time have been reported. Current data indicate no likelihood of interaction between zanamivir and other drugs. Pooled data from 2 phase II studies conducted in North America and Europe showed a 1-day reduction...