11th Conference on Retroviruses and Opportunistic Infections San Francisco, California - February 8 - 11, 2004

Conf Retroviruses Opportunistic Infect. 2004 Feb 8-11;11th:Abstract No. 535

G Hanna, J-H Yan*, W Fiske, T Masterson, D Zhang, and D Grasela
Bristol-Myers Squibb Co., Princeton, NJ, USA

BACKGROUND: BMS-488043 (043) is a novel, oral small-molecule inhibitor of HIV-1 entry that selectively prevents attachment of the exterior viral envelope protein gp120 to its cellular receptor CD4. A previously described member of the same class, BMS-378806, was well-tolerated but did not achieve target exposures after single doses in healthy adults.

METHODS: The safety, tolerability, and pharmacokinetics of 043 capsules was evaluated in 2 placebo-controlled studies in healthy adults. The first was an ascending single-dose study in which 6 groups of subjects (6 active/2 placebo per group) received 200-, 400-, 800-, 1200-, 1800-, or 2400-mg doses of 043. A second single dose was given as a solution (200-mg group), after ritonavir pretreatment (400-mg group), and after a high fat meal (800- and 1800-mg groups). The second was an ascending multiple-dose study in which 4 groups of subjects received 400-, 800-, 1200-, or 1800-mg doses of 043 every 12 hours for 14 days with either a high fat meal (n = 5 per group) or a light meal (n = 5 per group). Subjects were randomized with 4 active/1 placebo per group/meal type.

RESULTS: After single doses of 043 capsules under fasted conditions, median T_max was 1 to 2 hours and mean C_max was 662 to 1790 ng/mL for 200- to 2400-mg groups. C_max and AUC appeared to be dose related, but less than dose proportional, for doses of 200 to 800 mg with no significant increase in exposure at higher doses. Ritonavir pretreatment increased 043 exposure by 43%. Compared with the capsule under fasted condition, administration of the solution resulted in 3-fold increased exposure, and administration with food showed 3- to 5-fold increased exposure. On day 14 of dosing 400 to 1800 mg 043 every 12 hours with a high fat meal, median T_max was 3 to 4 hours after the morning dose, and mean C_max was 2494-7136 ng/mL; AUC (0 to 12 hours) was 10,643 to 34,986 ng h/mL; and C_min was 139 to 745 ng/mL. Accumulation indices (day 14:day 1) ranged from 1.1 to 1.6. Exposures were generally higher with high fat meal compared to light meal, were generally dose proportional over the dose range of 400 to 1200 mg (high fat meal) and 400 to 800 mg (light meal), but exposure did not significantly increase above these doses. 043 appeared generally safe and well-tolerated with no serious adverse events.

CONCLUSIONS: BMS-488043 demonstrated promising safety, tolerability and pharmacokinetics when administered to healthy adults for up to 14 days. A dose of 800 mg twice daily is expected to provide C_min levels adequate to suppress subtype B HIV-1 isolates.

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Copyright © 2004 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.