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Antimicrobial Agents and Chemotherapy, September 2008, p. 3013-3021, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00047-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics and Tolerability of Oseltamivir Combined with Probenecid ^,

Mark Holodniy,^1,2,3* Scott R. Penzak,⁴ Timothy M. Straight,⁵ Richard T. Davey,⁶ Kelvin K. Lee,^3,7 Matthew Bidwell Goetz,^8,9 Dennis W. Raisch,¹⁰ Francesca Cunningham,¹¹ Emil T. Lin,¹² Noemi Olivo,³ and Lawrence R. Deyton^1,13

Office of Public Health and Environmental Hazards, U.S. Department of Veterans Affairs, Washington, DC,¹ Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California,² VA Palo Alto Health Care System, Palo Alto, California,³ Clinical Pharmacokinetics Research Laboratory, National Institutes of Health, Bethesda, Maryland,⁴ Department of Clinical Investigation, Brooke Army Medical Center, Ft. Sam Houston, Texas,⁵ CRS/LIR/NIAID, National Institutes of Health, Bethesda, Maryland,⁶ VA Cooperative Studies Program Coordinating Center, Palo Alto, California,⁷ Greater Los Angeles Health Care System, Los Angeles, California,⁸ Infectious Diseases Section, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California,⁹ VA Cooperative Studies Program, Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico,¹⁰ Pharmacy Benefits Management Group, U.S. Department of Veterans Affairs, Hines, Illinois,¹¹ Department of Biopharmaceutical Sciences, UCSF, San Francisco, California,¹² George Washington University School of Medicine and Health Sciences, Washington, DC,¹³

Received 14 January 2008/ Returned for modification 25 April 2008/ Accepted 6 June 2008

Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P < 0.05 for both comparisons by analysis of variance). The (arithmetic) mean concentration at 48 h for group 2 was not significantly different from the mean concentration at 24 h for group 1 (42 ± 76 and 81 ± 54 ng/ml, respectively; P = 0.194), but the mean concentration at 48 h for group 3 was significantly less than the mean concentration at 24 h for group 1 (23 ± 26 and 81 ± 54 ng/ml, respectively; P = 0.012). Alternate-day dosing of oseltamivir plus dosing with probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further.

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* Corresponding author. Mailing address: Public Health Research Center, VA Palo Alto Health Care System, 3801 Miranda Ave. (132), Palo Alto, CA 94304. Phone: (650) 852-3408. Fax: (650) 858-3978. E-mail: Holodniy{at}stanford.edu

Published ahead of print on 16 June 2008.

The ClinicalTrials.gov identifier for this report is NCT00304434.

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Antimicrobial Agents and Chemotherapy, September 2008, p. 3013-3021, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00047-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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