title: ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans.
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.
authors.affiliation: Department of Anti-Infective Research, Abbott Laboratories, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: J F
authors.initials: JF
authors.lastname: Denissen
authors.forename: E
authors.initials: E
authors.lastname: McDonald
authors.forename: S
authors.initials: S
authors.lastname: Vasavanonda
authors.forename: C A
authors.initials: CA
authors.lastname: Flentge
authors.forename: B E
authors.initials: BE
authors.lastname: Green
authors.forename: L
authors.initials: L
authors.lastname: Fino
authors.forename: C H
authors.initials: CH
authors.lastname: Park
authors.forename: X P
authors.initials: XP
authors.lastname: Kong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts / Q000502:physiology; D001665:Binding Sites; D001682:Biological Availability; D002214:Capsules; D005260:Female; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir; D013607:Tablets; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D002214:Capsules; D017320:HIV Protease Inhibitors; D011725:Pyridines; D013607:Tablets; D013844:Thiazoles; C092970:A 80987; D016333:HIV Protease; D014633:Valine; D019438:Ritonavir