Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Export

@article{citeulike:5636294, 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.}, author = {Wattanagoon, Y. and Stepniewska, K. and Lindeg\r{a}rdh, N. and Pukrittayakamee, S. and Silachamroon, U. and Piyaphanee, W. and Singtoroj, T. and Hanpithakpong, W. and Davies, G. and Tarning, J. and Pongtavornpinyo, W. and Fukuda, C. and Singhasivanon, P. and Day, N. P. and White, N. J.}, citeulike-article-id = {5636294}, citeulike-linkout-0 = {http://dx.doi.org/10.1128/AAC.00588-08}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19104028}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19104028}, doi = {10.1128/AAC.00588-08}, issn = {1098-6596}, journal = {Antimicrobial agents and chemotherapy}, keywords = {h1n1, influenza, oseltamivir, pharmacokinetics}, month = {March}, number = {3}, pages = {945--952}, posted-at = {2009-08-24 23:36:27}, priority = {4}, title = {Pharmacokinetics of high-dose oseltamivir in healthy volunteers.}, url = {http://dx.doi.org/10.1128/AAC.00588-08}, volume = {53}, year = {2009} }

TY - JOUR ID - citeulike:5636294 L3 - citeulike-article-id:5636294 N2 - 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. IS - 3 JF - Antimicrobial agents and chemotherapy SN - 1098-6596 EP - 952 TI - Pharmacokinetics of high-dose oseltamivir in healthy volunteers. VL - 53 SP - 945 KW - h1n1 KW - influenza KW - oseltamivir KW - pharmacokinetics AU - Wattanagoon, Y AU - Stepniewska, K AU - Lindegårdh, N AU - Pukrittayakamee, S AU - Silachamroon, U AU - Piyaphanee, W AU - Singtoroj, T AU - Hanpithakpong, W AU - Davies, G AU - Tarning, J AU - Pongtavornpinyo, W AU - Fukuda, C AU - Singhasivanon, P AU - Day, NP AU - White, NJ PY - 2009/03// UR - http://dx.doi.org/10.1128/AAC.00588-08 ER -