Oseltamivir is an ethyl
ester prodrug of
Ro 64-0802, a selective inhibitor of influenza virus
neuraminidase.
Oral administration of
oseltamivir delivers the active
antiviral Ro 64-0802 to the bloodstream, and thus all sites of
influenza infection (lung, nasal mucosa, middle ear) are accessible. The pharmacokinetic profile of
oseltamivir is simple and predictable, and twice daily treatment results in effective
antiviral plasma concentrations over the entire administration interval. After
oral administration,
oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite. The absolute bioavailability of the active metabolite from orally administered
oseltamivir is 80%. The active metabolite is detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours. After peak plasma concentrations are attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours.
Oseltamivir is eliminated primarily by conversion to and renal excretion of the active metabolite. Renal clearance of both compounds exceeds glomerular filtration rate, indicating that renal tubular secretion contributes to their elimination via the anionic pathway. Neither compound interacts with
cytochrome P450 mixed-function oxidases or glucuronosyltransferases. The pharmacokinetic profile of the active metabolite is linear and dose-proportional, with less than 2-fold accumulation over a dosage range of
oseltamivir 50 to 500 mg twice daily. Steady-state plasma concentrations are achieved within 3 days of twice daily administration, and at a dosage of 75mg twice daily the steady-state plasma trough concentrations of active metabolite remain above the minimum inhibitory concentration for all
influenza strains tested. Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary. In patients with renal impairment, metabolite clearance decreases linearly with
creatinine clearance. A dosage reduction to 75mg once daily is recommended for patients with
creatinine clearance <30 ml/min (1.8 L/h). The pharmacokinetics in patients with
influenza are qualitatively similar to those in healthy young adults. In vitro and in vivo studies indicate no clinically significant drug interactions. Neither
paracetamol (
acetaminophen) nor
cimetidine altered the pharmacokinetics of
Ro 64-0802. Coadministration of
probenecid resulted in a 2.5-fold increase in exposure to
Ro 64-0802; however, this competition is unlikely to result in clinically relevant effects. These properties make
oseltamivir a suitable candidate for use in the prevention and treatment of
influenza.