Pharmacodynamics of Abacavir in an In Vitro Hollow-Fiber Model System

AUTOR(ES)
FONTE

American Society for Microbiology

RESUMO

Abacavir is a potent new carbocyclic nucleoside analogue. We employed our hollow-fiber pharmacodynamic modeling system to examine the antiretroviral effects of different abacavir exposures, as well as the impact of the schedule of drug administration on efficacy. Dose ranging of abacavir revealed that a concentration of four times the 50% effective concentration (EC50) (approximately the EC95) was required to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) (strain MN) either in a continuous-infusion hollow-fiber experiment or in a classical tissue culture flask experiment. In contrast to earlier work with another drug class (HIV-1 protease inhibitors), addition of physiological amounts of the human drug binding proteins albumin and α1 acid glycoprotein revealed that there was little impact on the antiviral effect of the drug. Comparison of equivalent exposures (an area under the concentration-time curve [AUC] developed by approximately 500 mg per day of orally administered abacavir), either in a continuous-infusion mode or as a single oral dose of abacavir, demonstrated no difference in the ability to suppress either strain IIIB or strain MN. Comparison of administration of 250 mg every 12 h (q12h) versus once-daily administration of 500 mg for strain MN again showed no significant difference in suppressive effect. These experiments were carried out over 8 to 15 days. Because of these promising initial results, we extended the experiment to 30 days and examined three different schedules of administration that generated the same AUC at 24 h (AUC24): 300 mg q12h, 600 mg q24h, and 1,200 mg q48h. The aim of the last of these regimens was to definitively demonstrate schedule failure. There was little difference between the 1,200-mg q48h treatment group and the untreated control at 30 days. Likewise, there was little difference between the 600-mg q24h and 300-mg q12h treatment groups. However, at circa day 18 of the experiment, there was a small increase in viral output of p24 in the once-daily dosing unit. Examination of virus from all groups demonstrated no phenotypic or genotypic differences. The small difference in hollow-fiber unit p24 in the once-daily dosing group was not due to emergence of resistance over the 30-day single-drug exposure. We conclude that the dose of abacavir currently being studied in clinical trials (300 mg orally q12h) will be efficacious for the majority of sensitive clinical isolates of HIV-1. These in vitro data also suggest that this drug may be able to be administered to patients on a once-daily basis at a dose of 600 mg.

ACESSO AO ARTIGO

Documentos Relacionados