Oseltamivir

Oseltamivir
(3R,4R,5S)-4-acetylamino-5-amino-3- (1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester
Empirical formula	C₁₆H₂₈N₂O₄
Molecular weight	312.4
Bioavailability (Oral)	75%
Metabolism	hepatic, to GS4071
Half life	6-10 hours
Excretion	renal (GS4071)
Pregnancy category	B1 (Australia)

Oseltamivir is an antiviral drug, a neuraminidase inhibitor used in the treatment of and prophylaxis of both influenza A and influenza B. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed. It was developed by Gilead Sciences and is currently marketed by Hoffman-La Roche (Roche) under the trade name Tamiflu®.

Oseltamivir is a prodrug (usually administered as phosphate), it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071).

Like zanamivir, oseltamivir acts as a transition-state analogue inhibitor of influenza neuraminidase.

Use in avian influenza

Oseltamivir was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. In response to the epidemic, various governments – including those of the United Kingdom, United States and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic. Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries.

Toward the end of May 2005, Roche stated that demand for oseltamivir was in excess of production capacity, with extended delays expected for new supplies. In order to satisfy U.S. demand, Roche planned to open a new production plant in North America during the second half of 2005.

Resistance

As with other antivirals, resistance to the agent was expected with widespread use of oseltamivir, though the emergence of resistant viruses was expected to be less frequent than with amantadine or rimantadine. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme. (Ward et al., 2005)

Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir. (Kiso et al., 2004) This rate was similar to another study where resistant isolates of H1N1 influenza virus were found in 16.3% of another cohort of Japanese children. It has been proposed that the higher-than-expected resistance rate in these two studies was as a result of the underexposure to oseltamivir in the children. (Ward et al., 2005)

Partial resistance has also been detected in several isolates of H5N1 avian influenza isolated in Vietnam. (World Health Organization, 2005)

Other actions

Tamiflu also appears to be active against canine parvovirus, feline panleukopenia, the canine respiratory complex known as "kennel cough," and the emerging disease dubbed "canine flu," an equine virus that began affecting dogs in 2005. Veterinary investigation of its use for canine parvo [1] and canine flu [2]is ongoing, but many shelters and rescue groups have reported great success employing Tamiflu in the early stages of these illnesses.

References

Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759-65. PMID 15337401
Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother 2005;55(Suppl 1): i5-i21. PMID 15709056
World Health Organization. WHO inter-country-consultation: influenza A/H5N1 in humans in Asia: Manila, Philippines, 6-7 May 2005. (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.)

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