Tamiflu (Oseltamivir)
Classification:
Antiinfective Agents
Description: Tamiflu (Oseltamivir) (GS 4104) is an oral neuraminidase inhibitor. It is a prodrug that is metabolized to its active form, oseltamivir carboxylate (GS 4071). As opposed to amantadine and rimantadine that have activity against influenza A only, Tamiflu (Oseltamivir) has activity against influenza A and B. In two phase III trials, Tamiflu (Oseltamivir) reduced the median time to improvement in influenza-infected patients by 1.3 days (30%) compared to patients receiving placebo. Of the influenza-infected patients, 95% were infected with influenza A and 3% with influenza B. There was no increase in efficacy in patients receiving Tamiflu (Oseltamivir) doses > 150 mg/day. Tamiflu (Oseltamivir) treatment should be started within 48 hours of the onset of flu symptoms; there are no data to support Tamiflu (Oseltamivir) efficacy if treatment is started > 40 hours after the onset of symptoms. However, Tamiflu (Oseltamivir) is not considered a substitute for annual influenza virus vaccination. Instead, antiviral drugs are considered adjuncts to the prevention and control of influenza; annual influenza vaccination remains the main option for reducing the impact of influenza. The FDA approved Tamiflu (Oseltamivir) for adults and adolescents for the treatment and prevention of uncomplicated infections due to influenza virus A or B in October 1999 and November 2000, respectively. In December 2000, the FDA approved Tamiflu ™ oral suspension for the treatment of influenza in children >= 1 year of age. Due to concerns resulting from preclinical data (animal data); the manufacturer issued recommendations against the drug’s use in infants < 1 year of age in December 2003.
Mechanism of Action: Tamiflu (Oseltamivir) is activated to oseltamivir carboxylate, which acts as a neuraminidase (sialidase) inhibitor. Oseltamivir carboxylate selectively inhibits the neuraminidases of influenza A and B, and does not significantly inhibit human lysosomal neuraminidase. Influenza virus neuraminidase is a surface glycoprotein that catalyzes the cleavage of the linkage between a terminal sialic acid and adjacent sugar residue. This action promotes the spread of virus in the respiratory tract by several mechanisms. Viral neuraminidase promotes the release of virions from infected cells; promotes the penetration of virus into respiratory epithelial cells; prevents the formation of viral aggregates; prevents viral inactivation by respiratory mucus; induces cellular apoptosis by activating transforming growth factor beta; and induces cytokines including interleukin-1 and tumor necrosis factor. Oseltamivir carboxylate acts extracellularly and binds to an unoccupied area of influenza neuraminidase that results in competitive inhibition of the enzyme.
In vitro studies show that oseltamivir carboxylate and zanamivir have a similar EC50 (50% effective inhibitory concentration) to influenza virus A and B. It would appear that mechanisms of resistance would be similar for the two agents; cross-resistance has been observed in vitro. Genetic analysis show that reduced susceptibility to oseltamivir carboxylate is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemaglutinin or both. In challenge studies of human subjects infected with influenza virus, 3% of the post-treatment isolates showed emergence of influenza variants with decreased neuraminidase susceptibility to oseltamivir carboxylate. In clinical studies of naturally acquired influenza infection, 1.3% of post-treatment isolates showed emergence of influenza variants with decreased neuraminidase susceptibility to oseltamivir carboxylate. The actual risk of resistance to Tamiflu (Oseltamivir) during clinical use cannot be determined from these small, initial reports.
Pharmacokinetics: Tamiflu (Oseltamivir) is administered orally. Tamiflu (Oseltamivir) is extensively converted to oseltamivir carboxylate by hepatic estrases. At least 75% of an Tamiflu (Oseltamivir) oral dose reaches the systemic circulation as oseltamivir carboxylate; < 5% of the total dose reaches the systemic circulation as Tamiflu (Oseltamivir). Administration with food has no affect on the Cmax or AUC values for oseltamivir carboxylate. The binding of oseltamivir carboxylate to plasma proteins is low (3%). Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms. Oselatamivir has an elimination half-life of 1-3 hours and > 90% of oseltamivir is eliminated by conversion to oseltamivir carboxylate. Oseltamivir carboxylate is not further metabolized and is eliminated in the urine. The elimination half-life of oseltamivir carboxylate is 6-10 hours. Oseltamivir carboxylate undergoes renal secretion in addition to glomerular filtration.
Special Populations: In patients with decreased renal function, oseltamivir carboxylate exposure is inversely proportional to declining renal function. Dosage adjustment is recommended for patients with a creatinine clearance < 30 ml/min. There are no data available in patients with renal failure (creatinine clearance < 10 ml/min). In elderly patients (age 65-78 years), the steady-state AUC was 25-35% higher compared to younger patients given comparable doses. However, no dosage adjustments are required. In pediatric patients < 12 years of age, both oseltamivir and oseltamivir caboxylate are cleared faster than in adults resulting in a lower exposure for a given mg/kg dose. The pharmacokinetics of patients > 12 years are similar to adult patients.
Related entries
Monthly Archives
Syndicate
Allergies
