Microbiology

Mechanism of Action

Oseltamivir phosphate is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. Oseltamivir carboxylate is an inhibitor of influenza virus neuraminidase affecting release of viral particles.

Antiviral Activity

The antiviral activity of oseltamivir carboxylate against laboratory strains and clinical isolates of influenza virus was determined in cell culture assays. The concentrations of oseltamivir carboxylate required for inhibition of influenza virus were highly variable depending on the assay method used and the virus tested. The 50% and 90% effective concentrations (EC₅₀ and EC₉₀) were in the range of 0.0008 µM to > 35 µM and 0.004 µM to > 100 µM, respectively (1 µM=0.284 µg/mL). The relationship between the antiviral activity in cell culture and the inhibition of influenza virus replication in humans has not been established.

Resistance

Influenza A virus isolates with reduced susceptibility to oseltamivir carboxylate have been recovered by serial passage of virus in cell culture in the presence of increasing concentrations of oseltamivir carboxylate. Genetic analysis of these isolates showed that reduced susceptibility to oseltamivir carboxylate is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Resistance substitutions selected in cell culture in neuraminidase are I222T and H274Y in influenza A N1 and I222T and R292K in influenza A N2. Substitutions E119V, R292K and R305Q have been selected in avian influenza A neuraminidase N9. Substitutions A28T and R124M have been selected in the hemagglutinin of influenza A H3N2 and substitution H154Q in the hemagglutinin of a reassortant human/avian virus H1N9.

In clinical studies in the treatment of naturally acquired infection with influenza virus, 1.3% (4/301) of posttreatment isolates in adult patients and adolescents, and 8.6% (9/105) in pediatric patients aged 1 to 12 years showed emergence of influenza variants with decreased neuraminidase susceptibility in cell culture to oseltamivir carboxylate. Substitutions in influenza A neuraminidase resulting in decreased susceptibility were H274Y in neuraminidase N1 and E119V and R292K in neuraminidase N2. Insufficient information is available to fully characterize the risk of emergence of TAMIFLU resistance in clinical use.

In clinical studies of postexposure and seasonal prophylaxis, determination of resistance by population nucleotide sequence analysis was limited by the low overall incidence rate of influenza infection and prophylactic effect of TAMIFLU.

Cross-resistance

Cross-resistance between zanamivir-resistant influenza mutants and oseltamivir-resistant influenza mutants has been observed in cell culture. Due to limitations in the assays available to detect drug- induced shifts in virus susceptibility, an estimate of the incidence of oseltamivir resistance and possible cross-resistance to zanamivir in clinical isolates cannot be made. However, two of the three oseltamivir-induced substitutions (E119V, H274Y and R292K) in the viral neuraminidase from clinical isolates occur at the same amino acid residues as two of the three substitutions (E119G/A/D, R152K and R292K) observed in zanamivir-resistant virus.

Immune Response

No influenza vaccine interaction study has been conducted. In studies of naturally acquired and experimental influenza, treatment with TAMIFLU did not impair normal humoral antibody response to infection.

Pharmacokinetics

Absorption and Bioavailability

Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted predominantly by hepatic esterases to oseltamivir carboxylate. At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate. Exposure to oseltamivir is less than 5% of the total exposure after oral dosing (see Table 1).

Table 1: Mean (% CV) Pharmacokinetic Parameters of Oseltamivir and Oseltamivir Carboxylate After a Multiple 75 mg Capsule Twice Daily Oral Dose (n=20)

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