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Population Pharmacokinetics of Oseltamivir When Coadministered With Probenecid

From F. Hoffmann-La Roche Ltd, Basel, Switzerland (Dr Rayner, Dr Chanu, Dr Gieschke); Roche Products Ltd, Welwyn Garden City, United Kingdom (Dr Boak); and Exprimo NV, Mechelen, Belgium (Dr Jonsson).

Oseltamivir is a potent, selective, oral neuraminidase inhibitor for the treatment and prophylaxis of influenza. Plasma concentrations of the active metabolite, oseltamivir carboxylate, are increased in the presence of probenecid, suggesting that the combination could allow for the use of reduced doses of oseltamivir. To investigate this proposal, we developed a population pharmacokinetic model and simulated the pharmacokinetics of candidate combination regimens of oral oseltamivir (45 mg and 30 mg twice a day) plus oral probenecid (500 mg/6 hourly). Probenecid plus oseltamivir 45 mg achieved all the pharmacokinetic parameters expected of oseltamivir alone, but combination with oseltamivir 30 mg and dose interval extension approaches did not. An oseltamivir–probenecid combination may compromise tolerability and enhance the potential for drug interactions. In addition, increased dosing requirements may affect compliance and attainment of optimal oseltamivir exposure, potentially facilitating the emergence of viral strains with reduced susceptibility to oseltamivir. These factors, set alongside increased capacity for oseltamivir production, should be carefully considered before an oseltamivir–probenecid combination is used.

Key Words: Pandemic influenza • oseltamivir • probenecid • pharmacokinetics

Address for reprints: Craig R. Rayner, F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Bldg. 015/1.006, CH-4070 Basel, Switzerland; e-mail: craig.rayner{at}roche.com.

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