Giuseppe
Emeritus
Antimicrob Agents Chemother. 2009 Apr 13. [Epub ahead of print]
Prediction of the Pharmacodynamically-linked Variable of Oseltamivir Carboxylate for Influenza A Virus Using an In Vitro Hollow Fiber Infection Model System.
McSharry JJ, Weng Q, Brown A, Kulawy R, Drusano GL. - 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.
MDCK cells transfected with human beta-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 10(2) A/Sydney/5/97 (H3N2) influenza virus-infected AX-4 cells and 10(8) 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 1 X EC50 exposure of oseltamivir by continuous infusion, one unit received the same AUC0-24 by bolus every 24 hr, one unit received the same total exposure in two equal fractions every 12 hr, and one unit received the same total exposure in three equal fractions every 8 hr. Each bolus dose was followed by a no drug washout producing the appropriate half-life for this drug.
The effect of drug on virus replication was determined by sampling the units daily, measuring the amount of released virus by plaque assay and hemagglutination assay.
The drug concentration in the HFIM systems was determined at various times by LC/MS/MS. The dose ranging study showed that the EC50 values 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 by the same extent indicating the pharmacodynamically-linked variable was the AUC0-24hr/EC50 ratio.
This implies it may be possible to treat influenza virus infection once-daily with a dose of 150 mg/day.
PMID: 19364864 [PubMed - as supplied by publisher]
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Prediction of the Pharmacodynamically-linked Variable of Oseltamivir Carboxylate for Influenza A Virus Using an In Vitro Hollow Fiber Infection Model System.
McSharry JJ, Weng Q, Brown A, Kulawy R, Drusano GL. - 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.
MDCK cells transfected with human beta-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 10(2) A/Sydney/5/97 (H3N2) influenza virus-infected AX-4 cells and 10(8) 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 1 X EC50 exposure of oseltamivir by continuous infusion, one unit received the same AUC0-24 by bolus every 24 hr, one unit received the same total exposure in two equal fractions every 12 hr, and one unit received the same total exposure in three equal fractions every 8 hr. Each bolus dose was followed by a no drug washout producing the appropriate half-life for this drug.
The effect of drug on virus replication was determined by sampling the units daily, measuring the amount of released virus by plaque assay and hemagglutination assay.
The drug concentration in the HFIM systems was determined at various times by LC/MS/MS. The dose ranging study showed that the EC50 values 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 by the same extent indicating the pharmacodynamically-linked variable was the AUC0-24hr/EC50 ratio.
This implies it may be possible to treat influenza virus infection once-daily with a dose of 150 mg/day.
PMID: 19364864 [PubMed - as supplied by publisher]
-