Oseltamivir phosphate (Tamiflu) is the ethyl ester pro-drug of oseltamivir carboxylate, an analogue of neur-aminic (sialic) acid that is a reversible competitive antagonist of influenza A and B neuraminidase. Neur-aminidase, like hemagglutinin, is a viral surface glyco-protein that interacts with host cell receptors containing terminal neuraminic acid residues. The binding of hemagglutinin to its cellular receptors initiates viral penetration and promotes the fusion of the viral enve-lope to the plasma membrane. Neuraminidase then de-stroys these hemagglutinin receptors by breaking the bond between the terminal neuraminic acid residue and its adjacent oligosaccharide. The cleavage of hemagglu-tinin receptors is required for the release of progeny virus from the host cell. It also facilitates the spread of infection by allowing viral particles to penetrate the neuraminic acid–rich respiratory mucus and by pre-venting the clumping of virus that results from the bind-ing of hemagglutinins to neuraminic acid residues on neighboring viral particles. Inhibition of neuraminidase activity prevents the release of progeny virus and inhibits viral spread. The active site of neuraminidase is highly conserved in influenza A and B viruses; thus, oseltamivir and other neuraminidase inhibitors (e.g., zanamivir) are effective against a variety of influenza strains.
Influenza virus resistant to oseltamivir has not been found in naturally acquired isolates but has been iso-lated from influenza patients who have undergone treatment with this drug. These resistant strains contain mutations in the active site of neuraminidase and are generally less virulent and infective than nonresistant virus. In vitro passage of influenza virus in the presence of oseltamivir carboxylate can produce mutations in hemagglutinin that decrease the overall dependence of viral replication on neuraminidase; however, the clinical relevance of this resistance mechanism is unknown.
Orally administered oseltamivir phosphate is rapidly ab-sorbed and converted by hepatic esterases to oseltamivir carboxylate. Approximately 80% of an oral dose reaches the systemic circulation as oseltamivir carboxylate, with peak plasma concentrations achieved within 2.5 to 5 hours. The plasma elimination half-life of oseltamivir carboxylate is 7 to 9 hours. Elimination of the parent drug and its active metabolite occurs primarily by active tubular secretion and glomerular filtration.
Oseltamivir is approved for the treatment of uncompli-cated acute influenza in patients aged 1 year and older. It decreases the duration of illness by 1 to 1.5 days when treatment is initiated within 48 hours of the onset of symptoms. Oseltamivir is also indicated for the prophy-laxis of influenza in individuals aged 13 and older. It re-duces infection rates to approximately 10 to 25% of that found in untreated populations; however, it is not in-tended to substitute for the early vaccination recom-mended by the CDC. Oseltamivir can be used as post-exposure prophylaxis in household contacts of infected patients, with infection rates of treated patients around 10% of placebo control levels.
The most frequently reported adverse effects of os-eltamivir are nausea and vomiting. These events are usu-ally mild to moderate, occur during the first 1 to 2 days of treatment, and can be lessened by taking the drug with food. Bronchitis, insomnia, and vertigo may also occur.
Oseltamivir may not be indicated for use in certain individuals. Its efficacy in patients with chronic cardiac or respiratory disease has not been established. In clin-ical trials, no difference in the incidence of complica-tions was seen between treatment and control groups. The efficacy of oseltamivir has not been demonstrated in immunocompromised patients, patients who begin treatment after 40 hours of symptoms, or patients given repeated prophylactic courses of therapy. Dosage ad-justment is recommended for individuals with renal in-sufficiency; the drug’s safety in patients with hepatic in-sufficiency is unknown.
No formal drug interaction studies of oseltamivir have been performed. Oseltamivir and its carboxylate metabolite do not interact with the cytochrome P450 system. Although probenecid decreases the elimination of oseltamivir, dosage adjustment is not required during coadministration of these drugs because of oseltamivir’s margin of safety. Oseltamivir does not interfere with an-tibody production in response to the influenza vaccine.
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