ABT-538 is a Potent Inhibitor of Human Immunodeficiency Virus Protease and has High Oral Bioavailability in Humans

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 7; pp. 2484 - 2488
• Main Authors: Kempf, Dale J., Marsh, Kennan C., Denissen, Jon F., McDonald, Edith, Vasavanonda, Sudthida, Flentge, Charles A., Green, Brian E., Fino, Lynnmarie, Park, Chang H., Kong, Xiang-Peng, Wideburg, Norman E., Saldivar, Ayda, Ruiz, Lisa, Kati, Warren M., Sham, Hing L., Robins, Terry, Stewart, Kent D., Hsu, Ann, Plattner, Jacob J., Leonard, John M., Norbeck, Daniel W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 28.03.1995; National Acad Sciences; National Academy of Sciences
• Subjects: Acquired immune deficiency syndrome; Administration, Oral; AIDS; AIDS/HIV; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - pharmacokinetics; Antivirals; Bile - metabolism; Bile Ducts - physiology; Binding Sites; Bioavailability; Biological Availability; Blood plasma; Capsules; Dosage; Drug therapy; Female; HIV; HIV Protease - chemistry; HIV Protease Inhibitors - administration & dosage; HIV Protease Inhibitors - pharmacokinetics; HIV-1 - drug effects; HIV-2 - drug effects; Human immunodeficiency virus; human immunodeficiency virus 1; Humans; Injections, Intravenous; Macaca fascicularis; Male; Medical research; Metabolic Clearance Rate; Metabolism; Models, Molecular; Molecular Structure; Pharmacokinetics; Pharmacology; Pyridines - administration & dosage; Pyridines - pharmacokinetics; Rats; Rats, Sprague-Dawley; Ritonavir; Solubility; Tablets; Thiazoles - administration & dosage; Thiazoles - pharmacokinetics; Thiazoles - pharmacology; Tissue Distribution; Valine - administration & dosage; Valine - analogs & derivatives; Valine - pharmacokinetics; Valine - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.7.2484

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 μM] and HIV-2 (EC50= 0.16 μM). Following a single 10-mg/kg oral dose, plasma concentrations in rat, dog, and monkey exceeded the in vitro antiviral EC50for > 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 μg/ml. These findings demonstrate that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease.