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Antimicrobial Agents and Chemotherapy, March 2009, p. 945-952, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.00588-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of High-Dose Oseltamivir in Healthy Volunteers{triangledown}

Y. Wattanagoon,1 K. Stepniewska,1,2 N. Lindegårdh,2,1 S. Pukrittayakamee,1 U. Silachamroon,1 W. Piyaphanee,1 T. Singtoroj,1 W. Hanpithakpong,1 G. Davies,1 J. Tarning,1 W. Pongtavornpinyo,1 C. Fukuda,1 P. Singhasivanon,1 N. P. J. Day,1,2 and N. J. White1,2*

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand,1 Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford OX3 7LJ, United Kingdom2

Received 5 May 2008/ Returned for modification 18 September 2008/ Accepted 10 December 2008

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.

* Corresponding author. Mailing address: Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand. Phone: (66) 2 203 6333. Fax: (66) 2 354 9169. E-mail: nickw{at}tropmedres.ac

{triangledown} Published ahead of print on 22 December 2008.

Antimicrobial Agents and Chemotherapy, March 2009, p. 945-952, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.00588-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hoffmann, G., Funk, C., Fowler, S., Otteneder, M. B., Breidenbach, A., Rayner, C. R., Chu, T., Prinssen, E. P. (2009). Nonclinical Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in the Central Nervous System. Antimicrob. Agents Chemother. 53: 4753-4761 [Abstract] [Full Text]  


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