Chemical formula: C₁₂H₂₀N₄O₇ Molecular mass: 332.31 g/mol PubChem compound: 60855
Zanamivir is an inhibitor of influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells and promotes virus spread in the respiratory tract.
Neuraminidase inhibition occurred in vitro at very low zanamivir concentrations (50% inhibition at 0.64nM – 7.9nM against influenza A and B strains). Viral neuraminidase aids the release of newly formed virus particles from infected cells, and may facilitate access of virus through mucus to epithelial cell surfaces, to allow viral infection of other cells. The inhibition of this enzyme is reflected in both in vitro and in vivo activity against influenza A and B virus replication, and encompasses all of the known neuraminidase subtypes of influenza A viruses.
The activity of zanamivir is extracellular. It reduces the propagation of both influenza A and B viruses by inhibiting the release of infectious influenza virions from the epithelial cells of the respiratory tract. Influenza viral replication occurs in the superficial epithelium of the respiratory tract. The efficacy of topical administration of zanamivir to this site has been confirmed in clinical studies.
Neuraminidase inhibition occurred at very low zanamivir concentrations in vitro, with median inhibitory (IC50) values of 0.33 nM to 5.77 nM against influenza A and B strains respectively.
Resistance selection during zanamivir treatment is rare. Reduced susceptibility to zanamivir is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Neuraminidase substitutions conferring reduced susceptibility to zanamivir have emerged during treatment with zanamivir in human viruses and those with zoonotic potential: E119D, E119G, I223R, R368G, G370D, N434S (A/H1N1); N294S, T325I (A/H3N2); R150K (B); R292K (A/H7N9). The neuraminidase substitution Q136K (A/H1N1 and A/H3N2), confers high level resistance to zanamivir but is selected during adaptation to cell culture and not during treatment.
The clinical impact of reduced susceptibility in these viruses is unknown, and the effects of specific substitutions on virus susceptibility to zanamivir may be strain-dependent.
Cross-resistance between zanamivir and oseltamivir or peramivir has been observed in neuraminidase inhibition assays. A number of neuraminidase amino acid substitutions that arise during oseltamivir or peramivir treatment result in reduced susceptibility to zanamivir. The clinical impact of substitutions associated with reduced susceptibility to zanamivir and other neuraminidase inhibitors is variable and may be strain-dependent.
The H275Y substitution is the most common neuraminidase resistance substitution and is associated with reduced susceptibility to peramivir and oseltamivir. This substitution has no effect on zanamivir; therefore, viruses with the H275Y substitution retain full susceptibility to zanamivir.
Pharmacokinetic studies in humans have shown that the absolute oral bioavailability of the drug is low (mean (min, max) is 2% (1%, 5%)). Similar studies of orally inhaled zanamivir indicate that approximately 4-17% of the dose is systemically absorbed, with serum concentrations generally peaking within 1-2 hours. The poor absorption of the drug results in low systemic concentrations and therefore there is no significant systemic exposure to zanamivir after oral inhalation. There is no evidence of modification in the kinetics after repeated dosing with oral inhaled administration.
The serum pharmacokinetics of zanamivir administered intravenously have been studied in healthy volunteers receiving single escalating doses from 1 to 1200 mg and repeated doses of 600 mg twice daily for 5 days. Hospitalised patients with influenza also have received 300 mg or 600 mg twice daily for 5 to 10 days.
Dose proportionality was observed in zanamivir Cmax and AUC and no accumulation of zanamivir in serum was evident after repeated intravenous doses of up to 600 mg.
The plasma protein binding of zanamivir is very low (less than 10%). The volume of distribution of zanamivir in adults is approximately 16 litres, which approximates the volume of extracellular water.
After oral inhalation, zanamivir is widely deposited at high concentrations throughout the respiratory tract, thus delivering the drug to the site of influenza infection.
Following twice-daily administration of zanamivir solution for infusion, pulmonary epithelial lining fluid concentrations were 60-65% of the serum concentrations at the corresponding sampling time 12 hours after dosing. Following twice daily administration of 600 mg zanamivir solution for infusion, median trough zanamivir epithelial lining fluid concentrations ranged from 419 ng/mL to 584 ng/mL and were 47-66% of those in the initial bronchoalveolar sample following orally zanamivir inhalation powder 10 mg twice daily.
In vitro studies indicate that zanamivir is not an inhibitor or substrate of Breast Cancer Resistant Protein (BCRP), P-glycoprotein, Multidrug And Toxin Extrusion protein (MATE)1, MATE2-K, Organic Anion Transporter (OAT)1, OAT3, Organic Anion Transporting Polypeptide (OATP)1B1, OATP1B3 and Organic Cation Transporter (OCT)2 transporters.
Zanamivir has been shown to be renally excreted as unchanged drug, and does not undergo metabolism.
There is no evidence that intravenous zanamivir is metabolised.
Zanamivir is not an inhibitor of cytochrome P450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4. Zanamivir is not an inducer of CYP1A2 and 2B6 and, although induction of CYP3A4 in vitro was observed at 50-fold higher than the clinically relevant concentrations, no interaction with CYP3A4 substrates is expected based on physiologically based pharmacokinetic modelling.
The serum half-life of zanamivir following administration by oral inhalation ranges from 2.6 to 5.05 hours. It is eliminated entirely through renal filtration. Total clearance ranges from 2.5 to 10.9 L/h as approximated by urinary clearance. Renal elimination is completed within 24 hours.
Zanamivir is eliminated unchanged in urine by glomerular filtration following intravenous administration. In adults with normal renal function, the elimination half-life is approximately 2-3 hours.
At the therapeutic daily dose of 20 mg orally inhaled, bioavailability is low (4-17%), and as a result there is no significant systemic exposure of patients to zanamivir. Any alteration of pharmacokinetics that may occur with age is unlikely to be of clinical consequence and no dose modification is recommended.
The pharmacokinetics in elderly subjects was similar to young adult subjects after intravenous administration. In the population pharmacokinetic analysis, age had no significant effect on the pharmacokinetics of zanamivir.
In an open-label single-dose study the pharmacokinetics of zanamivir was evaluated in 16 paediatric subjects, aged 6 to 12 years, using dry powder (10 mg) inhalation formulation (Diskhaler device). The systemic exposure was similar to 10 mg of inhaled powder in adults, but the variability was large in all age groups and more pronounced in the youngest children. Five patients were excluded due to undetectable serum concentrations at all time points or 1.5 hours post-dose, suggesting inadequate drug delivery.
The pharmacokinetics of zanamivir following a twice daily intravenous dose of 14 mg/kg for paediatric patients between 6 months and <6 years and 12 mg/kg for those between 6 years and <18 years of age were similar to those seen in adults who received 600 mg twice daily intravenously. The pharmacokinetics of zanamivir in subjects 6 months to <18 years of age (administered standard dose of 12 mg/kg, 14 mg/kg or 600 mg according to age and body weight) and in adult subjects (administered standard dose of 600 mg) was similar.
Pharmacokinetic parameters in paediatric and adult subjects:
| Age Group | Dose | N | Cmax (μg/mL) | AUC(0-∞) (μg.h/mL) | Cmin (μg/mL) | T1/2 (h) | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| GM | %CV | GM | %CV | GM | Range | GM | %CV | |||
| 6 months - <1 year | 14 mg/kg | 7 | 36.2 | 21 | 75.3 | 23 | NA | NA | 1.84 | 19 |
| 1 - <2 years | 14 mg/kg | 6 | 37.8 | 24 | 72.4 | 14 | 0.305 | NA | 2.49 | 118 |
| 2 - <6 years | 14 mg/kg | 12 | 41.5 | 23 | 80.3 | 38 | 0.277 | 0.133 – 0.984 | 1.60 | 34 |
| 6 - <13 years | 12 mg/kg | 16 | 44.2 | 47 | 107 | 41 | 0.564 | 0.111 – 2.31 | 2.57 | 55 |
| 13 - <18 years | 600 mg | 13 | 34.5 | 27 | 91.1 | 27 | 0.211 | 0.104 – 0.428 | 2.06 | 47 |
| >18 years | 600 mg | 67 | 32.8 | 34 | 82.9 | 36 | 0.82 | 0.1 – 11.4 | 2.39 | 31 |
%CV = percent coefficient of variation, GM = Geometric Mean, NA = Not available
Inhaled zanamivir results in approximately 4-17% of the inhaled dose being absorbed. In the severe renal impairment group from the single IV zanamivir dose trial subjects were sampled after a dose of 2 mg or twice to four times the expected exposure from inhalation. Using the normal dosing regimen (10 mg bid), the predicted exposure at Day 5 is 40-fold lower than what was tolerated in healthy subjects after repeated iv administration. Given the importance of local concentrations, the low systemic exposure, and the previous tolerance of much higher exposures no dose adjustment is advised.
The serum half-life of intravenous zanamivir increases to approximately 12-20 hours in patients with severe renal impairment (creatinine clearance <30 mL/min). Zanamivir has not been studied in patients with end-stage renal disease.
There are limited data on zanamivir exposure during concomitant continuous renal replacement therapy and very limited data with dialysis.
Zanamivir is not metabolised, therefore no effect of hepatic impairment is expected.
Pharmacokinetic studies in Thai, Chinese and Japanese healthy subjects did not identify any clinically relevant differences in the pharmacokinetics of zanamivir in these populations compared with Caucasians.
General toxicity studies did not indicate any significant toxicity of zanamivir. Zanamivir was not genotoxic and no clinically relevant findings were observed in long term carcinogenicity studies in rats and mice.
No drug-related malformations, maternal toxicity or embryotoxicity were observed in pregnant rats or rabbits or their foetuses following intravenous administration of zanamivir at doses up to 90 mg/kg/day. Following subcutaneous administration of zanamivir in an additional rat embryofoetal development study, there was an increase in the incidence rates of a variety of minor skeletal and visceral alterations and variants in the exposed offspring at the highest dose 80 mg/kg, three times daily (240 mg/kg/day; total daily dose), most of which remained within the background rates of the historical occurrence in the strain studied. Based on AUC measurements, the 80 mg/kg dose (240 mg/kg/day) produced an exposure approximately 1000 times the human exposure at the clinical inhaled dose. In the peri- and post-natal developmental study conducted in rats, there was no clinically meaningful impairment of development of offspring.
Intravenous doses of up to 90mg/kg/day zanamivir produced no effect on fertility and reproductive function of the treated or subsequent generation in male and female rats.
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