Population analysis of the pharmacokinetics and pharmacodynamics of RWJ-270201 (BCX-1812) in treating experimental influenza A and B virus in healthy volunteers.

Abstract

Our objective was to assess the pharmacokinetics and pharmacodynamics of RWJ-270201 (BCX-1812), an oral neuraminidase inhibitor for the treatment of influenza A and B virus in healthy volunteers. This was a double-blind, randomized, placebo-controlled, parallel group study. A total of 80 adult male and female subjects were enrolled for the influenza A challenge study. This was a 5-arm study (100 mg/qd, 200 mg/qd, 200 mg/bid, 400 mg/qd, and placebo). In the challenge B virus model, 60 subjects were enrolled for a 3-arm study (800 mg on Day 1 followed by 400 mg on Days 2-5; 800 mg on Days 1-5; and placebo). The pharmacokinetics of RWJ-270201 (BCX-1812) were characterized with the use of a population approach and were described by a 2-compartmental model with first-order absorption and elimination. The pharmacodynamic data, mean log viral titers, were described with the use of an empirical equation relating the viral growth and the effect of drug on changes in viral titers. Pharmacokinetic analyses show that weight was the most significant covariate for all estimated pharmacokinetic parameters. The pharmacodynamic data, mean log viral titers showed a decrease in viral titers with increase in plasma exposure. The decrease in viral titer started to occur 12 hours following the drug dosing, and viral suppression lasted 72 hours to 96 hours. The exposures associated with a 50% decrease in viral titers were 1089 ng-h/mL and 1898 ng-h/mL, respectively. A PK/PD model was well utilized to characterize the effect of RWJ-270201 (BCX-1812) on the influenza A and B virus. The results from this model showed that both the loading dose and the standard dose regimens are efficacious against A and B virus. RWJ-270201 (BCX-1812) is under clinical development for the treatment of influenza A and B infections in adult and high-risk populations. It is a potent and selective inhibitor of both influenza A and B virus neuraminidases and inhibits the viral cleavage of sialic acid from cell surface glycoproteins and glycolipids. Consequently, RWJ-270201 (BCX-1812) prevents infection by stopping the release of newly formed virus from the surface of infected cells and preventing viral spread across the mucous lining of the respiratory tract. It therefore represents an attractive agent for antiviral therapy.