Pharmacokinetics of high-dose oseltamivir in healthy volunteers

Abstract

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.

Figures

FIG. 1.

Concentrations of OS (A) and OC (B) in plasma (median values) for all subjects by study block.

FIG. 2.

Relationship between the AUC0-∞ for plasma and the actual dose of OS (A) or OC (B) received. Data are from O and OL regimens, all doses. The filled circles are for the one subject with consistently impaired conversion of OS to OC.

FIG. 3.

Relationship between the estimated total amount of drug excreted in the urine and the dose of OS given.

FIG. 4.

(A) Relationship between AUCs (log scales) for OC in plasma and saliva. (B) Relationship between the relative increase in the AUC0-∞ for OC in saliva with the administration of probenecid [(OP group AUC0-∞ − O group AUC0-∞)/O group AUC0-∞)] and the AUC0-∞ for OC in saliva without the administration of probenecid. All doses were evaluated.