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Clinical Pharmacokinetics of the Prodrug Oseltamivir and its Active Metabolite Ro 64-0802

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Abstract

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 500mg 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.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Roche Global Development, 3401 Hillview Avenue, Palo Alto, California, USA

    George He

  2. Department of Clinical Pharmacology, Roche Global Development, Nutley, New Jersey, USA

    Joseph Massarella

  3. Department of Clinical Science, Roche Global Development, Welwyn, Hertfordshire, England

    Penelope Ward

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Correspondence to George He.

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He, G., Massarella, J. & Ward, P. Clinical Pharmacokinetics of the Prodrug Oseltamivir and its Active Metabolite Ro 64-0802. Clin Pharmacokinet 37, 471–484 (1999). https://doi.org/10.2165/00003088-199937060-00003

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