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

Abstract

MDCK cells transfected with the human ␤-galactoside ␣-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 a 1؋ 50% effective concentration (EC 50 ) exposure to oseltamivir by continuous infusion, one unit received the same AUC 0-24 (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 EC 50 s 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 AUC 0-24 /EC 50 ratio. This implies that it may be possible to treat influenza virus infection once daily with a dose of 150 mg/day.

Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza

“…In this regard, some authors have suggested a need to maintain high plasma trough concentrations or area-under-the-curve values for oseltamivir carboxylate relative to the 50% maximal inhibitory concentration of the influenza virus for optimal suppression of viral replication. 15,19 In view of the documented 50% maximal inhibitory concentration of the pandemic (H1N1) influenza virus, a regimen of oseltamivir 75 mg twice daily clearly results in trough concentrations and area-under-the-curve values for the carboxylate metabolite that are well above any likely pharmacodynamic threshold for maximal inhibition of the virus. Given this fact, it is not surprising that we found no correlation between trough plasma levels and area-under-thecurve values and main clinical outcomes (length of hospital stay and survival) (see Appendices 2 and 3, available at www .cmaj .ca /cgi /content /full /cmaj .092127 /DC1).…”

Pharmacokinetics and Diffusion into Sputum of Oseltamivir and Oseltamivir Carboxylate in Adults with Cystic Fibrosis

“…However, although these data about the diffusion of OC in sputum are encouraging, an in vitro hollow-fiber infection model has previously evidenced that the ratio of the AUC/ concentration reducing the number of PFU by 50% (the 50% effective concentration [EC 50 ]) is the variable correlated with anti-influenza virus A efficacy, with EC 50 s against the viral strains used ranging from 2 to 29 g/liter. Besides, the in vitro model has shown that the slope of the exposure/response curve was weak, so the concentrations providing the maximal efficacy are several times higher than the EC 50 (about 25 times the EC 50 ) (17), which would be far above the concentrations of OC in sputum that were observed in the present study. As it is unclear whether these EC 50 s are relevant in vivo, a prospective efficacy study performed in CF patients is therefore warranted to determine the adequate dosage regimen of oseltamivir.…”

Investigating Clinically Adequate Concentrations of Oseltamivir Carboxylate in End-Stage Renal Disease Patients Undergoing Hemodialysis Using a Population Pharmacokinetic Approach

“…Patients received 75 mg OP orally as a single dose 48 h before the start of their next HD session, 30 min after a standard meal. Serial blood samples for pharmacokinetic analysis were taken immediately before dosing and 0.5, 1, 1.5, 2, 3, 4, 5,6,8,10,12,15,24,36, and 48 h postdose. During HD (at 48.5, 49, 49.5, 50, 51, and 52 h postdose), additional blood samples were drawn from the dialyzer inflow and outflow.…”

“…Although we bridged the data by using C min , it is not fully clear which exposure metric (C min or AUC) is optimal for oseltamivir pharmacokinetic bridging for special populations. A hollow-fiber study by Drusano and colleagues (24) suggests AUC/EC 50 to be the pharmacodynamically linked variable. One pragmatic argument is that oseltamivir is generally safe and well tolerated, with a wide safety margin (2).…”