Tamiflu
Metabolism of the influenza neuraminidase inhibitor prodrug oseltamivir in the rat.

Sweeny DJ, Lynch G, Bidgood AM, Lew W, Wang KY, Cundy KC.

Gilead Sciences, Inc., Foster City, California 94404, USA. David_Sweeney Gilead.com

The metabolism of [2-acetyl-(14)C]oseltamivir (GS4104, Ro 64-0796), the prodrug of the novel influenza neuraminidase inhibitor GS4071 (Ro 64-0802), was examined in rats after oral dosing. Intact oseltamivir was observed only in lung and urine, accounting for 37 and 15% of the total radioactivity in these samples, respectively. GS4071 was the major metabolite in plasma, tissues, and urine, and accounted for 32 to 56% of the radioactivity present in these samples. The second most abundant peak in these samples (13-24% of radioactivity) was a novel metabolite (M3). This metabolite was purified from urine of rats dosed orally with oseltamivir and was identified by liquid chromatography-mass spectrometry and NMR as the (R)-omega-carboxylic acid metabolite of oseltamivir. The omega-carboxylic acid metabolite of oseltamivir could not be produced in vitro. However, omega-hydroxylated products of oseltamivir were produced by rat liver microsomes. Both the (R)- and (S)-omega-hydroxylated products were observed, but formation of the (R)-isomer predominated. These data indicated that in the rat, oseltamivir was primarily metabolized to the active influenza neuraminidase inhibitor GS4071 and, to a lesser extent, to an (R)-omega-carboxylic acid metabolite.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10859145&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Characterization of recombinant influenza B viruses with key neuraminidase inhibitor resistance mutations.

Jackson D, Barclay W, Zurcher T.

School of Animal and Microbial Sciences, University of Reading, Whiteknights, PO Box 228, Reading RG6 6AJ.

Objectives and methods: An influenza B virus plasmid-based rescue system was used to introduce site-specific mutations, previously observed in neuraminidase (NA) inhibitor-resistant viruses, into the NA protein of six recombinant viruses. Three mutations observed only among in vitro selected zanamivir-resistant influenza A mutants were introduced into the B/Beijing/1/87 virus NA protein, to change residue E116 to glycine, alanine or aspartic acid. Residue E116 was also mutated to valine, a mutation found in the clinic among oseltamivir-resistant viruses. An arginine to lysine change at position 291 (292 N2 numbering) mimicked that seen frequently in influenza A N2 clinical isolates resistant to oseltamivir. Similarly, an arginine to lysine change at position 149 (152 in N2 numbering) was made to reproduce the change found in the only reported zanamivir-resistant clinical isolate of influenza B virus. In vitro selection and prolonged treatment in the clinic leads to resistance pathways that require compensatory mutations in the haemagglutinin gene, but these appear not to be important for mutants isolated from immunocompetent patients. The reverse genetics system was therefore used to generate mutants containing only the NA mutation. RESULTS AND CONCLUSIONS: With the exception of a virus containing the E116G mutation, mutant viruses were attenuated to different levels in comparison with wild-type virus. This attenuation was a result of altered NA activity or stability depending on the introduced mutation. Mutant viruses displayed increased resistance to zanamivir, oseltamivir and peramivir, with certain viruses displaying cross-resistance to all three drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15665027&dopt=Abstract oseltamivir Tamiflu



Tamiflu
[Control of hospital infection of influenza: administration of neuraminidase inhibitor and cohort isolation of influenza patients]

[Article in Japanese]

Kosugi Y, Ishikawa T, Chimura Y, Annaka M, Shibazaki S, Adachi K, Higuchi H, Shinkai T, Sadamasu K, Masuda Y, Inamatsu T.

Department of Infectious Disease, Tokyo Metropolitan Geriatric Medical Center.

Influenza can spread rapidly to patients and staff in hospitals when influenza is introduced by visitors, staff, or patients. In order to prevent and control outbreaks of influenza in hospitals, systematic management is important. This consists of a rapid diagnostic test, cohort isolation and administration of neuraminidase inhibitor. In the 2002-2003 season, 53 elderly patients were admitted to our hospital under the control of the system. The mean age was 78.8 years. We set 2 isolation rooms (10 beds) for influenza patients. Patients were isolated in the room for three days, administered oseltamivir immediately. Oral oseltamivir was well tolerated. Mean hospital stay was 10.7 days. 36 cases developed complications requiring antibiotics, and one patient developed a catheter related infection. Under the system, we could avoid cross infection of influenza. In two cases, nose swabs were taken for virus isolation every 12 hours and a rapid decline in virus shedding was observed after treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15678974&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Pharmacoeconomic assessment of oseltamivir in treating influenza--the case of otherwise healthy Danish adolescents and adults.

Vindt Holm M, Gyldmark M, Holme Hansen E.

Department of Social Pharmacy, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark. mvindtholm hotmail.com

OBJECTIVE: To assess the pharmacoeconomics of treating influenza with oseltamivir in healthy Danish adolescents and adults. METHOD: Cost-effectiveness and cost-utility analyses were used to compare oseltamivir to usual care (symptomatic treatment with over the counter (OTC) medicine), considering both the societal and health care payer's perspectives. The population group studied was otherwise healthy adolescents and adults, aged 13 to 64. Danish data were collected to simulate results that are specific to Denmark. The economic model included first- and second-order Monte Carlo simulations. Sensitivity analyses were conducted to test the robustness of the analyses. MAIN OUTCOME MEASURE: The cost-effectiveness study was expressed as gain in cost per day to return to normal activity, and the cost-utility study as cost per QALY (quality adjusted life years) gained. RESULTS: From a societal perspective, oseltamivir was a dominant treatment compared to usual care. From a health care payer's perspective, the cost-effectiveness ratio was 12.3 euros per gain in day to return to normal activity and 5,063 euros/QALY gained. A sensitivity analysis leaving out hospitalisation, complications, and mortality showed increased cost-effectiveness and cost-utility ratios. However, treatment with oseltamivir remained cost-effective, assuming a willingness to pay for health benefits at 26,174 euros/QALY. CONCLUSION: Pharmacoeconomic analyses of influenza treatment with oseltamivir in an otherwise healthy Danish adolescent/adult population show that this treatment saves money for society and is associated with a relatively low cost from a health care payer's perspective. Treatment of influenza with oseltamivir would be cost-effective for healthy adolescents/adults in Denmark.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15683104&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Oseltamivir (Tamiflu(R)) and its potential for use in the event of an influenza pandemic.

Ward P, Small I, Smith J, Suter P, Dutkowski R.

Roche Products Ltd, Welwyn Garden City, Herts, UK.

Recent cross species transmission of avian influenza has highlighted the threat of pandemic influenza. Oseltamivir (Tamiflu((R))) has been shown to be effective in the treatment and prevention of epidemic influenza infection in adults, adolescents and children (>/= 1 year). Although oseltamivir has not been approved for prophylactic use in children, it has been shown to be effective. Oseltamivir is also active against avian influenza virus strains. Evidence suggests that lower doses or shorter durations of treatment/chemoprophylaxis other than those approved may not be effective and may contribute to emergence of viral resistance. Safety data from dose ranging studies show that 5 day courses of 150 mg twice daily for treatment and 6 week courses of 75 mg twice daily for prophylaxis were as well tolerated as the approved dose regimens. The use of oseltamivir in a pandemic is influenced by the goals of the pandemic plan developed by the responsible Government and Health Authority. To optimize use of antiviral medications, processes will be needed to collect, collate and report outcome data from treated patients and/or from use for chemoprophylaxis of pandemic influenza during the first-wave outbreaks. If oseltamivir is included in a national or regional pandemic plan, stockpiling of the material, either in the form of capsules or the bulk active pharmaceutical ingredient will be necessary. In the absence of a stockpile, there is no guarantee that an adequate supply of oseltamivir will be available.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15709056&dopt=Abstract oseltamivir Tamiflu