AG1343, a potent inhibitor of human immunodeficiency virus type 1 (HIV-1)
protease (Ki = 2 nM), was designed by
protein structure-based
drug design techniques.
AG1343 has potent
antiviral activity (95% effective dose = 0.04 microgram/ml) against a number of HIV-1 strains in acute and chronic models of
infection. As part of its preclinical development, the oral bioavailability of
AG1343 in rats, dogs, monkeys, and marmosets was determined and its tissue distribution in rats was evaluated. There were no major interspecies differences in
AG1343 pharmacokinetics. Following
intravenous administration, the elimination half-life of
AG1343 ranged from 1 to 1.4 hr. The total volume of distribution (2 to 7 liters/kg) exceeded the volume of total body water, indicating extensive tissue distribution. Systemic clearance of
AG1343 (1 to 4 liters/kg) in the different species corresponded to hepatic blood flow, suggesting possible hepatic involvement in the elimination of
AG1343. Following
oral administration, peak levels in plasma ranged from 0.34 microgram/ml
after treatment with 10 mg/kg of
body weight in the dog to 1.7 micrograms/ml after dosing with 50 mg/kg in the rat. Because of the slow absorption of
AG1343, plasma concentrations of
AG1343 exceeding that required for 95% inhibition of HIV-1 replication were maintained for up to 7 h after a single oral dose in all species evaluated. Average oral bioavailability of
AG1343 ranged from 17% in the marmoset to 47% in the dog. Studies of distribution to tissue in the rat after
oral administration of 14C-AG1343 established extensive distribution with concentrations in most tissues exceeding that found in plasma. Of particular significance were high levels of
AG1343 equivalent in mesenteric lymph nodes (32.05 micrograms/g) and spleen tissue (9.33 micrograms/g). The major excretory route for
AG1343 was via feces, with 100% of the dose recovered by 48 h. Results from these studies demonstrate that
AG1343 is orally bioavailable and that levels in plasma in the therapeutic range are achievable and are maintained for prolonged periods in the animal models tested. On the basis of these and other findings,
AG1343 was developed for further testing in human subjects.