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Comparative Study
. 1995 Mar 28;92(7):2484-8.
doi: 10.1073/pnas.92.7.2484.

ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans

D J Kempf  1 , K C Marsh, J F Denissen, E McDonald, S Vasavanonda, C A Flentge, B E Green, L Fino, C H Park, X P Kong, et al.
Affiliations
Comparative Study

ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans

D J Kempf et al. Proc Natl Acad Sci U S A. .

Abstract

Examination of the structural basis for antiviral activity, oral pharmacokinetics, and hepatic metabolism among a series of symmetry-based inhibitors of the human immunodeficiency virus (HIV) protease led to the discovery of ABT-538, a promising experimental drug for the therapeutic intervention in acquired immunodeficiency syndrome (AIDS). ABT-538 exhibited potent in vitro activity against laboratory and clinical strains of HIV-1 [50% effective concentration (EC50) = 0.022-0.13 microM] and HIV-2 (EC50 = 0.16 microM). Following a single 10-mg/kg oral dose, plasma concentrations in rat, dog, and monkey exceeded the in vitro antiviral EC50 for > 12 h. In human trials, a single 400-mg dose of ABT-538 displayed a prolonged absorption profile and achieved a peak plasma concentration in excess of 5 micrograms/ml. These findings demonstrate that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease.

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