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. The median IC50 values of oseltamivir against influenza A/H1N1, influenza A/H3N2, and influenza B clinical isolates were 2.5 nM (range 0.93 to 4.16 nM, N=74), 0.96 nM (range 0.13 to 7.95 nM, N=774), and 60 nM (20 to 285 nM, N=256), respectively, in a neuraminidase assay with a fluorescently labeled MUNANA substrate.

Antiviral Activity

The antiviral activity of oseltamivir carboxylate against laboratory strains and clinical isolates of influenza virus was determined in cell culture. The concentrations of oseltamivir carboxylate required for inhibition of influenza virus in cell culture 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 micromolar to greater than 35 micromolar and 0.004 micromolar to greater than 100 micromolar, respectively (1 micromolar=0.284 microgram per mL). The relationship between the antiviral activity in cell culture, inhibitory activity in the neuraminidase assay, and the inhibition of influenza virus replication in humans has not been established.

Resistance

Cell culture studies: 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. Reduced susceptibility of influenza virus to inhibition by oseltamivir carboxylate may be conferred by amino acid substitutions in the viral neuraminidase and/or hemagglutinin proteins.

Clinical studies: Reduced susceptibility isolates have been obtained during treatment with oseltamivir and from sampling during community surveillance studies. Changes in the viral neuraminidase that have been associated with reduced susceptibility to oseltamivir carboxylate are summarized in Table 8. The clinical impact of this reduced susceptibility is unknown.

Hemagglutinin (HA) substitutions selected in cell culture and associated with reduced susceptibility to oseltamivir include (influenza virus subtype-specific numbering) A11T, K173E, and R453M in H3N2; and H99Q in influenza B virus (Yamagata lineage). In some cases, HA substitutions were selected in conjunction with known NA resistance substitutions and may contribute to reduced susceptibility to oseltamivir; however, the impact of HA substitutions on antiviral activity of oseltamivir in humans is unknown and likely to be strain-dependent.

Table 8: Neuraminidase Amino Acid Substitutions Associated with Reduced Susceptibility to Oseltamivir

Selection of influenza A viruses resistant to oseltamivir can occur at higher frequencies in children. Oseltamivir treatment-associated resistance in pediatric treatment studies has been detected at frequencies of 27% to 37% and 3% to 18% (3/11 to 7/19 and 1/34 to 9/50 post-treatment isolates, respectively) for influenza A/H1N1 virus and influenza A/H3N2 virus, respectively.

In immunocompromised adults and pediatrics (1 year of age and older), selection of influenza viruses resistant to oseltamivir can occur at higher frequencies than in the otherwise healthy population. In a treatment study of immunocompromised subjects, treatment‐associated genotypic resistance was detected in 27% (8/30), 12% (6/52), and 0% (0/42) of influenza A/H1N1, A/H3N2, and B virus infections, respectively. Treatment‐emergent resistance was observed at a higher frequency in hematopoietic stem cell transplant recipients (32%; 6/19).

The frequency of resistance selection to oseltamivir and the prevalence of such resistant virus vary seasonally and geographically.

Circulating seasonal influenza strains expressing neuraminidase resistance-associated substitutions have been observed in individuals who have not received oseltamivir treatment. The oseltamivir resistance-associated substitution H275Y was found in more than 99% of US-circulating 2008 H1N1 influenza virus isolates. The 2009 H1N1 influenza virus (“swine flu”) was almost uniformly susceptible to oseltamivir; however, the frequency of circulating resistant variants can change from season to season. Prescribers should consider available information from the CDC on influenza virus drug susceptibility patterns and treatment effects when deciding whether to use oseltamivir phosphate.

Cross-resistance

Cross-resistance between oseltamivir and zanamivir has been observed in neuraminidase biochemical assays. The H275Y (N1 numbering) or N294S (N2 numbering) oseltamivir resistance-associated substitutions observed in the N1 neuraminidase subtype, and the E119V or N294S oseltamivir resistance-associated substitutions observed in the N2 subtype (N2 numbering), are associated with reduced susceptibility to oseltamivir but not zanamivir. The Q136K and K150T zanamivir resistance-associated substitutions observed in N1 neuraminidase, or the S250G zanamivir resistance-associated substitutions observed in influenza B virus neuraminidase, confer reduced susceptibility to zanamivir but not oseltamivir. The R292K oseltamivir resistance-associated substitution observed in N2, and the I222T, D198E/N, R371K, or G402S oseltamivir resistance-associated substitutions observed in influenza B virus neuraminidase, confer reduced susceptibility to both oseltamivir and zanamivir. These examples do not represent an exhaustive list of cross resistance-associated substitutions and prescribers should consider available information from the CDC on influenza drug susceptibility patterns and treatment effects when deciding whether to use oseltamivir phosphate.

No single amino acid substitution has been identified that could confer cross-resistance between the neuraminidase inhibitor class (oseltamivir, zanamivir) and the M2 ion channel inhibitor class (amantadine, rimantadine). However, a virus may carry a neuraminidase inhibitor-associated substitution in neuraminidase and an M2 ion channel inhibitor-associated substitution in M2 and may therefore be resistant to both classes of inhibitors. The clinical relevance of phenotypic cross-resistance evaluations has not been established.

Immune Response

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