What is the mechanism of action of Oseltamivir (Tamiflu) in treating influenza?

Mechanism of Action of Oseltamivir (Tamiflu) in Treating Influenza

Oseltamivir is a neuraminidase inhibitor that works by blocking the viral neuraminidase enzyme, which is essential for the release of newly formed influenza virions from infected cells, thereby interrupting viral propagation within the respiratory tract. 1, 2

Pharmacological Mechanism

• Oseltamivir phosphate is an ethyl ester prodrug that requires ester hydrolysis for conversion to the active form, oseltamivir carboxylate 2
• The active metabolite (oseltamivir carboxylate) selectively inhibits neuraminidase glycoproteins found on both influenza A and B viruses 2, 3
• Neuraminidase is essential for viral replication as it facilitates:
  • De-aggregation and release of newly synthesized virions from infected cells 1
  • Spread of the virus through the respiratory tract 1
• Without functional neuraminidase, new viral particles remain bound to the host cell surface and to each other, limiting viral spread 1

Pharmacokinetics Related to Mechanism

• After oral administration, oseltamivir is extensively converted to oseltamivir carboxylate by hepatic esterases 2
• At least 75% of an oral dose reaches systemic circulation as the active metabolite (oseltamivir carboxylate) 2
• Less than 5% of the oral dose reaches circulation as unchanged oseltamivir 2
• The active metabolite has median IC50 values of 2.5 nM against influenza A/H1N1, 0.96 nM against influenza A/H3N2, and 60 nM against influenza B clinical isolates 2

Clinical Implications of Mechanism

• Oseltamivir is effective only during the viral replication phase, which explains why treatment must be initiated within 48 hours of symptom onset for maximum efficacy 4
• Earlier treatment correlates with greater clinical benefit:
  • Treatment within 12 hours after symptom onset reduces illness duration by an additional 74.6 hours compared to starting at 48 hours 4
  • Treatment within 24 hours reduces illness duration by an additional 53.9 hours compared to starting at 48 hours 4, 5
• The mechanism explains why oseltamivir is effective against both influenza A and B viruses, though it may be less effective against influenza B 1, 6

Efficacy Based on Mechanism

• By inhibiting viral release and spread, oseltamivir:
  • Reduces duration of influenza illness by approximately 30% (1-1.5 days) in otherwise healthy adults when started within 36-48 hours of symptom onset 3, 7
  • Decreases severity of illness by 35-38% compared to placebo 7
  • Reduces the risk of secondary complications such as pneumonia by approximately 50% 1, 3
  • Reduces viral shedding, which may decrease transmission 5

Resistance Considerations

• Resistance to oseltamivir can develop through mutations in the viral neuraminidase and/or hemagglutinin proteins 2
• Specific amino acid substitutions in the neuraminidase enzyme can reduce susceptibility to oseltamivir 2
• However, clinical resistance has been rarely observed and resistant strains often show reduced transmissibility and pathogenicity 4

Important Clinical Considerations

• The mechanism of action explains why oseltamivir is not effective against other respiratory viruses that do not use neuraminidase in their replication cycle 8
• The prodrug nature of oseltamivir allows for oral administration, unlike zanamivir which must be inhaled due to poor oral bioavailability 1
• Understanding the mechanism helps explain why treatment timing is critical - the drug can only work while viral replication is ongoing 4