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Bevirimat (BVM; formerly known as PA-457) is a novel inhibitor of human immunodeficiency virus (HIV)maturation that is being developed for the treatment of HIV infection. The pharmacokinetics of this agent in healthy male volunteers were studied in a randomized, double-blind study in which the participants received single oral doses of placebo (n ‫؍‬ 8) or escalating doses of BVM at 25, 50, 100, or 250 mg (n ‫؍‬ 6 per dose); escalation was performed only after the pharmacokinetics and safety of the preceding dose had been evaluated. Plasma was collected over 480 h after dosing and urine was collected over 48 h after dosing for determination of the values of pharmacokinetic parameters. BVM was well absorbed after oral administration, with peak plasma concentrations being achieved 1 to 3 h after dosing. The half-life was 60 to 80 h. The exposure assessed by determination of the peak concentration and the area under the concentration-time curve was dose proportional. Single oral doses of BVM were well tolerated: there were no dose-limiting toxicities, and no serious adverse events were reported. These findings suggest that that BVM offers a favorable pharmacokinetic profile, with predictable pharmacokinetics following the oral administration of single doses. The long half-life of BVM may facilitate once-daily dosing.Although the introduction of highly active antiretroviral therapy regimens has significantly improved the prognosis for people infected with human immunodeficiency virus (HIV) type 1 (HIV-1) (2, 9), the development of viral resistance presents a major clinical challenge. It is estimated that up to 78% of individuals with HIV-1 infection harbor drug-resistant strains (10) and that 5 to 10% of strains are resistant to all classes of reverse transcriptase and viral protease inhibitors (4). The growing problem of resistance necessitates the development of new agents and regimens for the control of HIV infection (1). One response to this need has been to investigate therapeutic targets other than reverse transcriptase and viral protease, which have traditionally been the targets of highly active antiretroviral therapy regimens.Bevirimat (BVM; formerly known as PA-457) [3-O-(3Ј,3Ј-dimethylsuccinyl)betulinic acid] (Fig. 1) is the first of a new class of antiretroviral agents that inhibit HIV-1 replication by disrupting virus maturation. BVM inhibits the final step in the Gag processing cascade, resulting in defective core condensation and the release of noninfectious virus particles from HIV-1-infected cells, thus blocking the spread of the infection to new cells (5). Due to this novel mechanism of action, BVM shows potent activity against HIV-1 strains that are resistant to all currently approved classes of antiretroviral agent (3).In vitro studies have shown that BVM does not undergo oxidative metabolism in human microsomes, does not inhibit the cytochrome P450 system, and does not interact with human Pgp (6). It is a substrate for UDP-glucuronosyltransferases, and since it contains two carboxylic acid moiet...

Bevirimat shows dose-proportional pharmacokinetics during repeated dosing for 10 days. Its accumulation is approximately 4-fold greater on day 10 compared with day 1. Repeated dosing with bevirimat is well tolerated. These properties make bevirimat potentially suitable for inclusion in highly active antiretroviral therapy regimens.

Bevirimat is a first in class, orally active, potent and selective inhibitor of HIV-1. It may have utility for the treatment of HIV-1-infected patients who are failing current regimens because of the development of drug resistance. In earlier studies in HIV-1-infected patients, an immediate-release tablet formulation exhibited a relative bioavailability (F(rel)) of 50% or greater and a higher intersubject variability than an oral solution. The purpose of this study was to determine whether this pharmacokinetic profile is attributable to a narrow permeability-dependent absorption window within the gastrointestinal tract. Three groups of subjects completed an open-label, 2-way crossover, randomized pharmacoscintigraphic study. Subjects received a 25-mg bevirimat oral immediate-release solution plus 25 mg bevirimat solution delivered to the proximal small bowel, distal small bowel, or colon via the Enterion capsule. The results indicate that the permeability of bevirimat throughout the small intestine was excellent and suggest that the variability observed for the immediate release tablet was not related to the presence of an absorption window in the small intestine.

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