NDLI: Prediction of the Pharmacodynamically Linked Variable of Oseltamivir Carboxylate for Influenza A Virus Using an In Vitro Hollow-Fiber Infection Model System▿

Content Provider	PubMed Central
Author	Mcsharry, James J. Weng, Qingmei Brown, Ashley Robert, Kulawy Drusano, George L.
Abstract	MDCK cells transfected with the human β-galactoside α-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 1× 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.
Related Links	http://dx.doi.org/10.1128/AAC.00167-09
Starting Page	2375
File Format	PDF
ISSN	10986596
e-ISSN	10986596
Journal	Antimicrobial Agents and Chemotherapy
Issue Number	6
Volume Number	53
Language	English
Publisher	American Society for Microbiology (ASM)
Publisher Date	2009-06-01
Access Restriction	Open
Rights Holder	American Society for Microbiology (ASM)
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases Pharmacology Pharmacology (medical)

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