Mechanism of Action
Zanamivir is an antiviral drug [see Clinical Pharmacology].
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•h/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/h. 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/h, mild/moderate 2.7 L/h, and severe 0.8 L/h; median values) and significant increases in half-life (normals 3.1 h, mild/moderate 4.7 h, and severe 18.5 h; 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 subjects with signs and symptoms of respiratory illness. Sixteen subjects, aged 6 to 12 years, received a single dose of 10 mg zanamivir dry powder via DISKHALER. Five subjects 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 subjects had Cmax median values of 43 ng/mL (range: 15 to 74) and AUC∞ median values of 167 ng•h/mL (range: 58 to 279). Low or undetectable serum concentrations were related to lack of measurable PIFR in individual subjects [see Use in Specific Populations Clinical Studies].
Geriatric Patients: The pharmacokinetics of zanamivir have not been studied in subjects older than 65 years [see Use in Specific Populations].
Gender, Race, and Weight: In a population pharmacokinetic analysis in patient trials, no clinically significant differences in serum concentrations and/or pharmacokinetic parameters (V/F, CL/F, ka, AUC0-3, 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.
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.
In an immunocompromised patient infected with influenza B virus, a variant virus emerged after treatment with an investigational nebulized solution of zanamivir for 2 weeks. Analysis of this variant showed a hemagglutinin substitution (T198I) which resulted in a reduced affinity for human cell receptors, and a substitution in the neuraminidase active site (R152K) which reduced the enzyme’s activity to zanamivir by 1,000-fold. Insufficient information is available to characterize the risk of emergence of zanamivir resistance in clinical use.
Cross-Resistance: Cross-resistance has been observed between some zanamivir-resistant and some oseltamivir-resistant influenza virus mutants generated in cell culture. However, some of the in cell culture zanamivir-induced resistance mutations, E119G/A/D and R292K, occurred at the same neuraminidase amino acid positions as in the clinical isolates resistant to oseltamivir, E119V and R292K. No trials have been performed to assess risk of emergence of cross-resistance during clinical use.
Influenza Vaccine Interaction Trial: An interaction trial (n = 138) was conducted to evaluate the effects of zanamivir (10 mg once daily) on the serological response to a single dose of trivalent inactivated influenza vaccine, as measured by hemagglutination inhibition titers. There was no difference in hemagglutination inhibition antibody titers at 2 weeks and 4 weeks after vaccine administration between zanamivir and placebo recipients.
Influenza Challenge Trials: Antiviral activity of zanamivir was supported for infection with influenza A virus, and to a more limited extent for infection with influenza B virus, by Phase I trials in volunteers who received intranasal inoculations of challenge strains of influenza virus, and received an intranasal formulation of zanamivir or placebo starting before or shortly after viral inoculation.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: In 2-year carcinogenicity studies conducted in rats and mice using a powder formulation administered through inhalation, zanamivir induced no statistically significant increases in tumors over controls. The maximum daily exposures in rats and mice were approximately 23 to 25 and 20 to 22 times, respectively, greater than those in humans at the proposed clinical dose based on AUC comparisons.
Mutagenesis: Zanamivir was not mutagenic in in vitro and in vivo genotoxicity assays which included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in mouse lymphoma, chromosomal aberration assays in human peripheral blood lymphocytes, and the in vivo mouse bone marrow micronucleus assay.
Impairment of Fertility: The effects of zanamivir on fertility and general reproductive performance were investigated in male (dosed for 10 weeks prior to mating, and throughout mating, gestation/lactation, and shortly after weaning) and female rats (dosed for 3 weeks prior to mating through Day 19 of pregnancy, or Day 21 post partum) at IV doses 1, 9, and 90 mg/kg/day. Zanamivir did not impair mating or fertility of male or female rats, and did not affect the sperm of treated male rats. The reproductive performance of the F1 generation born to female rats given zanamivir was not affected. Based on a subchronic study in rats at a 90 mg/kg/day IV dose, AUC values ranged between 142 and 199 mcg•h/mL (>300 times the human exposure at the proposed clinical dose).