Influenza remains an important cause of morbidity and mortality, and incurs substantial economic costs due to hospitalization – particularly for the elderly aged 65 years or more, and among those with high-risk medical conditions. While influenza vaccination is considered the most effective control measure for both healthy populations and the chronically ill, it is less effective in the elderly and immunocompromised patients.
Thus effective drugs for influenza are still necessary, and neuraminidase inhibitors represent the mainstay of anti-influenza treatment today. Oseltamivir, the most famous neuraminidase inhibitor, has become a drug of public health importance since it was included in influenza pandemic management plans. Many systematic reviews and meta-analyses of oseltamivir efficacy in treatment and prophylaxis have been published in peer-reviewed journals.
Drug chemistry and mechanism of action
Oseltamivir (also known under a brand name Tamiflu) is the orally-active ethyl ester prodrug of oseltamivir carboxylate [(3R, 4R, 5S)-4-acetylamino-5-amino-3(1-ethylpropoxyl)-1-cyclohexene-1-carboxylic acid], which is a potent selective inhibitor of influenza A and B virus neuraminidases. The conversion of oseltamivir to oseltamivir carboxylate occurs via carboxylesterases which are located predominantly in the liver.
The first structure determination of oseltamivir phosphate was achieved by single crystal X-ray diffraction with synchrotron radiation. The synthesis of this drug requires shikimic acid, which is extracted from the pods of Chinese star anise. A 10-step process of complex chemical reactions is required in order to synthesize oseltamivir.
This drug binds to the active site of influenza virus neuraminidase, preventing the cleavage of N-acetylneuraminic acid (sialic acid) from the hemagglutinin receptor on epithelial cells. By leaving this receptor intact, viral aggregation ensues, which in turn prevents the virus from entering into epithelial cells. Intact hemagglutinin receptors also cause aggregation of new virus particles on the cell surface.
Oral oseltamivir is absorbed rapidly and, as mentioned, cleaved by carboxylesterases in the liver and gastrointestinal tract to the active carboxylate. The bioavailability of the carboxylate is estimated to be approximately 80%, and the time to maximum plasma concentration of the carboxylate is between 2.5 and 5 hours.
The volume of distribution of oseltamivir carboxylate is heavily influenced by its polar physicochemical characteristics and lies between 23 and 26 liters, with approximately 3% of the drug bound to plasma proteins. Concentrations in the lung have been reported as high as five times higher than corresponding plasma levels, and the drug is also well distributed to the nasal mucosa and the tissues of the middle ear.
Oseltamivir shows dose-linear kinetics, with an elimination half-life of approximately 7.7 hours in healthy individuals. Oseltamivir carboxylate is eliminated primarily by kidney via glomerular filtration and tubular secretion, with an average half-life of 6-10 hours. Both clearance and tissue distribution are reduced by probenecid. Less than 20% of an oral dose of oseltamivir is eliminated in the feces.
Young children (between one and twelve years of age) clear the active metabolite oseltamivir carboxylate at a faster pace when compared to older children and adults. On the other hand, exposure to the active metabolite is about 25% higher in elderly than in young individuals; however, this does not necessitate dosage adjustments.
- Ebadi M. Desk Reference of Clinical Pharmacology, Second Edition. CRC Press, 2007; pp. 526-528
- Smith DA. Metabolism, Pharmacokinetics, and Toxicity of Functional Groups: Impact of the Building Blocks of Medicinal Chemistry in ADMET. Royal Society of Chemistry, 2010; pp. 427-431.