aids therapies: effective dose range for once-daily protease inhibitor determined

AIDS Weekly Plus AIDS Therapies: Effective Dose Range For Once-Daily Protease Inhibitor Determined Michael Greer, Staff Medical Writer
May 7, 2001

- Further study of the Bristol-Myers Squibb's once-daily anti-HIV compound BMS-232632 has determined effective concentrations of the drug designed to ease patients' rigorous dose schedules. "BMS-232632 is a potent [HIV] protease inhibitor with a half-life that allows for once-daily dosing," explained G.L. Drusano and colleagues at Albany Medical College in New York. Drusano et al. were able to determine the amount of BMS-232632 necessary to provide nearly complete viral inhibition. Moreover, they also identified a potential pitfall for in vitro experiments measuring the efficacy of this compound. A continuous infusion of BMS-232632 at levels four times that of drug's 50% effective concentration (EC₅₀) almost totally shut down viral replication, the researchers said. In vitro experiments showed that this dose would have to be quadrupled again to provide the same degree of HIV inhibition when administered once a day. The accuracy of these in vitro investigations was enhanced after the discovery that human binding protein activity significantly inflated the drug's EC₅₀, Drusano et al. noted. The presence of these proteins raised the effective dose of BMS-232632 by more than 13-fold. Simulations adjusted for the effects of protein binding showed that between 60% and 70% of patients would respond to a 400- to 600-milligram BMS-232632 dose, if its EC₅₀ could be kept under 1 nM ("Hollow-fiber unit evaluation of a new human immunodeficiency virus type 1 protease inhibitor, BMS-232632, for determination of the linked pharmacodynamic variable," J Infect Dis. 2001 Apr 1;183(7):1126-9. "These experiments demonstrated that concentration above a threshold (time > 4 x EC₅₀) is the pharmacodynamically linked variable for this HIV 1 protease inhibitor," Drusano and colleagues concluded. At the Eighth Conference on Retroviruses and Opportunistic Infections, held in Chicago, Illinois, during February 2001, University of Southern California researcher Kathleen Squires reported Phase I safety and effectiveness data on BMS-232632 (see NewsRx's AIDS Weekly, February 19-26, 2001). The corresponding author for the Journal of Infectious Diseases paper is G.L. Drusano, Albany Medical College, Clinical Research Institute, Division of Clinical Pharmacology, Albany, NY 12208 USA. A search at NewsRx.net using the search term "AIDS and HIV therapy" yielded over 1,290 articles in six specialized reports. Key points reported in this study include: BMS-232632 is an HIV protease inhibitor designed for once-daily dosing When given as a continuous infusion, this drug almost totally blocks viral replication at a dose four times its EC₅₀ If given once a day, the dose would have to be quadrupled again to produce this level of efficacy Human protein binding activity significantly inflated the compound's EC₅₀ This article was prepared by AIDS Weekly editors from staff and other reports.

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