Mechanism of Action

Zanamivir is an antiviral drug [see CLINICAL PHARMACOLOGY].

Pharmacokinetics

Absorption and Bioavailability: Pharmacokinetic studies of orally inhaled zanamivir indicate that approximately 4% to 17% of the inhaled dose is systemically absorbed. The peak serum concentrations ranged from 17 to 142 ng/mL within 1 to 2 hours following a 10 mg dose. The area under the serum concentration versus time curve (AUC∞) ranged from 111 to 1,364 ng•hr/mL.

Distribution: Zanamivir has limited plasma protein binding ( < 10%).

Metabolism: Zanamivir is renally excreted as unchanged drug. No metabolites have been detected in humans.

Elimination: The serum half-life of zanamivir following administration by oral inhalation ranges from 2.5 to 5.1 hours. It is excreted unchanged in the urine with excretion of a single dose completed within 24 hours. Total clearance ranges from 2.5 to 10.9 L/hr. Unabsorbed drug is excreted in the feces.

Impaired Hepatic Function: The pharmacokinetics of zanamivir have not been studied in patients with impaired hepatic function.

Impaired Renal Function: After a single intravenous dose of 4 mg or 2 mg of zanamivir in volunteers with mild/moderate or severe renal impairment, respectively, significant decreases in renal clearance (and hence total clearance: normals 5.3 L/hr, mild/moderate 2.7 L/hr, and severe 0.8 L/hr; median values) and significant increases in half-life (normals 3.1 hr, mild/moderate 4.7 hr, and severe 18.5 hr; median values) and systemic exposure were observed. Safety and efficacy have not been documented in the presence of severe renal insufficiency. Due to the low systemic bioavailability of zanamivir following oral inhalation, no dosage adjustments are necessary in patients with renal impairment. However, the potential for drug accumulation should be considered.

Pediatric Patients: The pharmacokinetics of zanamivir were evaluated in pediatric patients with signs and symptoms of respiratory illness. Sixteen patients, 6 to 12 years of age, received a single dose of 10 mg zanamivir dry powder via DISKHALER. Five patients had either undetectable zanamivir serum concentrations or had low drug concentrations (8.32 to 10.38 ng/mL) that were not detectable after 1.5 hours. Eleven patients had Cmax median values of 43 ng/mL (range 15 to 74) and AUC∞ median values of 167 ng•hr/mL (range 58 to 279). Low or undetectable serum concentrations were related to lack of measurable PIFR in individual patients [see Use in Specific Populations, Clinical Studies ].

Geriatric Patients:The pharmacokinetics of zanamivir have not been studied in patients over 65 years of age [see Use in Specific Populations].

Gender, Race, and Weight: In a population pharmacokinetic analysis in patient studies, no clinically significant differences in serum concentrations and/or pharmacokinetic parameters (V/F, CL/F, ka, AUC_0-3, Cmax, Tmax, CLr, and % excreted in urine) were observed when demographic variables (gender, age, race, and weight) and indices of infection (laboratory evidence of infection, overall symptoms, symptoms of upper respiratory illness, and viral titers) were considered. There were no significant correlations between measures of systemic exposure and safety parameters.

Microbiology

Mechanism of Action: Zanamivir is an inhibitor of influenza virus neuraminidase affecting release of viral particles.

Antiviral Activity: The antiviral activity of zanamivir against laboratory and clinical isolates of influenza virus was determined in cell culture assays. The concentrations of zanamivir required for inhibition of influenza virus were highly variable depending on the assay method used and virus isolate tested. The 50% and 90% effective concentrations (EC₅₀ and EC₉₀) of zanamivir were in the range of 0.005 to 16.0 μM and 0.05 to > 100 μM, respectively (1 μM = 0.33 mcg/mL). The relationship between the cell culture inhibition of influenza virus by zanamivir and the inhibition of influenza virus replication in humans has not been established.

Resistance: Influenza viruses with reduced susceptibility to zanamivir have been selected in cell culture by multiple passages of the virus in the presence of increasing concentrations of the drug. Genetic analysis of these viruses showed that the reduced susceptibility in cell culture to zanamivir is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Resistance mutations selected in cell culture which result in neuraminidase amino acid substitutions include E119G/A/D and R292K. Mutations selected in cell culture in hemagglutinin include: K68R, G75E, E114K, N145S, S165N, S186F, N199S, and K222T.

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