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The effects of loading doses and probenecid coadministration on oseltamivir pharmacokinetics at four increasing dose levels in groups of eight healthy adult Thai volunteers (125 individual series) were evaluated. Doses of up to 675 mg were well-tolerated. The pharmacokinetics were dose linear. Oseltamivir phosphate (OS) was rapidly and completely absorbed and converted (median conversion level, 93%) to the active carboxylate metabolite. Median elimination half-lives (and 95% confidence intervals [CI]) were 1.0 h (0.9 to 1.1 h) for OS and 5.1 h (4.7 to 5.7 h) for oseltamivir carboxylate (OC). One subject repeatedly showed markedly reduced OS-to-OC conversion, indicating constitutionally impaired carboxylesterase activity. The coadministration of probenecid resulted in a mean contraction in the apparent volume of distribution of OC of 40% (95% CI, 37 to 44%) and a reduction in the renal elimination of OC of 61% (95% CI, 58 to 62%), thereby increasing the median area under the concentration-time curve (AUC) for OC by 154% (range, 71 to 278%). The AUC increase for OC in saliva was approximately three times less than the AUC increase for OC in plasma. A loading dose 1.25 times the maintenance dose should be given for severe influenza pneumonia. Probenecid coadministration may allow considerable dose saving for oseltamivir, but more information on OC penetration into respiratory secretions is needed to devise appropriate dose regimens.

Original publication

DOI

10.1128/AAC.00588-08

Type

Journal article

Journal

Antimicrob Agents Chemother

Publication Date

03/2009

Volume

53

Pages

945 - 952

Keywords

Administration, Oral, Adult, Antiviral Agents, Area Under Curve, Asian Continental Ancestry Group, Biological Availability, Dose-Response Relationship, Drug, Drug Interactions, Female, Half-Life, Humans, Influenza A Virus, H5N1 Subtype, Influenza, Human, Male, Metabolic Clearance Rate, Models, Biological, Nausea, Oseltamivir, Probenecid, Saliva, Thailand, Urinalysis, Vomiting