Oseltamivir

Abstract

Oseltamivir is a prodrug of oseltamivir carboxylate (Ro 64-0802, GS4071), a potent and selective inhibitor of the neuraminidase glycoprotein essential for replication of influenza A and B viruses. Studies in volunteers with experimental human influenza A or B showed that administration of oral oseltamivir 20 to 200mg twice daily for 5 days reduced both the quantity and duration of viral shedding compared with placebo. Subsequent assessment of the drug at a dosage of 75mg twice daily for 5 days in otherwise healthy adults with naturally acquired febrile influenza showed that oseltamivir reduced the duration of the disease by up to 1.5 days and the severity of illness by up to 38% compared with placebo when initiated within 36 hours of symptom onset (earlier initiation of therapy was associated with faster resolution). The incidence of secondary complications and the use of antibacterials were also reduced significantly in oseltamivir recipients. A liquid formulation of oseltamivir (2 mg/kg twice daily for 5 days) has been shown to be effective in the treatment of children with influenza, and data presented in abstracts suggest that the drug may also be of use in high-risk populations such as the elderly or those with chronic cardiac or respiratory disease. In addition to treatment efficacy, the drug has demonstrated efficacy when used for seasonal or household prophylaxis. Oral oseltamivir (75mg once or twice daily for 6 weeks) during a period of local influenza activity significantly prevented the development of naturally acquired influenza by >70% compared with placebo in unvaccinated otherwise healthy adults. The drug also demonstrated efficacy when used adjunctively in previously vaccinated high-risk elderly patients (92% protective efficacy). Short term administration of oseltamivir (75mg once daily for 7 days) may significantly reduce the risk of illness in household contacts of infected persons when administered within 48 hours of symptom onset in the infected person. Oseltamivir 75mg twice daily for 5 days was well tolerated in clinical trials in healthy adults and high-risk patients, with nausea and vomiting being the most commonly reported events. Gastrointestinal events were mild and transient and both nausea and vomiting were less likely when oseltamivir was taken with food. Conclusions: Oseltamivir is a well tolerated orally active neuraminidase inhibitor which significantly reduces the duration of symptomatic illness and hastens the return to normal levels of activity when initiated promptly in patients with naturally acquired influenza. It therefore represents a useful therapeutic alternative to zanamivir (especially in patients who prefer oral administration or who have an underlying respiratory disorder) and the M₂ inhibitors amantadine and rimantadine (because of its broader spectrum of anti-influenza activity and lower likelihood of resistance) in patients with influenza. In addition, although annual vaccination remains the best means of influenza prevention, there may be a place for oseltamivir in providing household prophylaxis or adjunctive prophylaxis in high-risk vaccinated patients during an outbreak of the disease or for use in patients in whom vaccination is unsuitable or ineffective. Oseltamivir carboxylate (Ro 64-0802, GS4071), the active metabolite of oseltamivir, was a potent and selective inhibitor of neuraminidase (an influenza virus surface glycoprotein essential for influenza A and B virus replication) in cultured Madin-Darby canine kidney cells. IC₅₀ values (50% inhibitory concentrations) for oseltamivir carboxylate ranged from 0.0006 to 26.0 µmol/L for laboratory strains of influenza A and B virus and were similar to those reported with zanamivir (a neuraminidase inhibitor which has previously been shown to be a more potent inhibitor of influenza A and B strains than the antiviral agents amantadine, rimantadine and ribavirin). Oseltamivir carboxylate was at least 10⁶-fold more selective for influenza virus neuraminidases than for parainfluenza virus, Newcastle disease virus, Vibrio cholerae, Clostridium perfringens and human liver microsomes in vitro. Consistent with in vitro findings, oral oseltamivir demonstrated antiviral activity against influenza A and influenza B viral strains in animal studies (mice and ferrets) and volunteers with experimentally-induced influenza. The drug reduced the quantity and duration of viral shedding compared with placebo in volunteers with either strain of the virus. Viral resistance to oseltamivir carboxylate has emerged in vitro after sequential passages of influenza A (H3N2) virus in cell culture, but the likelihood of in vivo resistance to oseltamivir appears to be low (only a few cases of drug resistance have been reported in clinical trials). Finally, the drug appears to have low cytotoxicity relative to its antiviral activity, and does not alter the human immune response to influenza. Oseltamivir is rapidly absorbed from the gastrointestinal tract after oral administration and is then extensively metabolised, predominantly by hepatic esterases, to its only active metabolite oseltamivir carboxylate. Plasma concentrations of oseltamivir carboxylate were detected within 30 minutes of an oral oseltamivir dose in volunteers and peaked within ≈3 to 4 hours at steady state. Oseltamivir has high (79%) oral bioavailability relative to an intravenous dose of oseltamivir carboxylate and its absorption is not significantly affected by the presence of food. Oseltamivir carboxylate was rapidly distributed to the primary site of influenza virus replication (surface epithelial cells of the respiratory tract) after oral administration of oseltamivir in preclinical studies, and to the middle ear and sinuses in volunteers. Oseltamivir carboxylate is eliminated by a first-order process, primarily by glomerular filtration and renal tubular...