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Antimicrobial Agents and Chemotherapy, June 2009, p. 2375-2381, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.00167-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Prediction of the Pharmacodynamically Linked Variable of Oseltamivir Carboxylate for Influenza A Virus Using an In Vitro Hollow-Fiber Infection Model System{triangledown}

James J. McSharry, Qingmei Weng, Ashley Brown, Robert Kulawy, and George L. Drusano*

Antiviral Pharmacodynamics Laboratory, Center for Emerging Infections and Host Defense, Ordway Research Institute, Center for Medical Sciences, 150 New Scotland Avenue, Albany, New York 12208

Received 6 February 2009/ Returned for modification 18 March 2009/ Accepted 1 April 2009

MDCK cells transfected with the human β-galactoside {alpha}-2,6-sialyltransferase 1 gene (AX-4 cells) were used to determine the drug susceptibility and pharmacodynamically linked variable of oseltamivir for influenza virus. For dose-ranging studies, five hollow-fiber units were charged with 102 A/Sydney/5/97 (H3N2) influenza virus-infected AX-4 cells and 108 uninfected AX-4 cells. Each unit was treated continuously with different oseltamivir carboxylate concentrations in virus growth medium for 6 days. For dose fractionation studies, one hollow-fiber unit received no drug, one unit received a 1x 50% effective concentration (EC50) exposure to oseltamivir by continuous infusion, one unit received the same AUC0-24 (area under the concentration-time curve from 0 to 24 h) by 1-h infusion every 24 h, one unit received the same total exposure in two equal fractions every 12 h, and one unit received the same total exposure in three equal fractions every 8 h. Each infusion dose was followed by a no-drug washout, producing the appropriate half-life for this drug. The effect of the drug on virus replication was determined by sampling the units daily, measuring the amount of released virus by plaque assay, and performing a hemagglutination assay. The drug concentration in the hollow-fiber infection model systems was determined at various times by liquid chromatography-tandem mass spectrometry. The dose-ranging study showed that the EC50s for oseltamivir carboxylate for the A/Sydney/5/97 strain of influenza virus was about 1.0 ng/ml. The dose fractionation study showed that all treatment arms suppressed virus replication to the same extent, indicating that the pharmacodynamically linked variable was the AUC0-24/EC50 ratio. This implies that it may be possible to treat influenza virus infection once daily with a dose of 150 mg/day.

* Corresponding author. Mailing address: Antiviral Pharmacodynamics Laboratory, Center for Emerging Infections and Host Defense, Ordway Research Institute, Center for Medical Sciences, 150 New Scotland Avenue, Albany, NY 12208. Phone: (518) 641-6410. E-mail: gdrusano{at}ordwayresearch.org

{triangledown} Published ahead of print on 13 April 2009.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2375-2381, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.00167-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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