title: Antiviral activity, pharmacokinetics, and safety of BMS-488043, a novel oral small-molecule HIV-1 attachment inhibitor, in HIV-1-infected subjects.
abstract: BMS-488043 is a novel and unique oral small-molecule inhibitor of the attachment of human immunodeficiency virus type 1 (HIV-1) to CD4(+) lymphocytes. The antiviral activity, pharmacokinetics, viral susceptibility, and safety of BMS-488043 were evaluated in an 8-day monotherapy trial. Thirty HIV-1-infected study subjects were randomly assigned to sequential, safety-guided dose panels of 800 and 1,800 mg BMS-488043 or a matched placebo in a 4:1 ratio, and the drug was administered every 12 h with a high-fat meal for 7 days and on the morning of day 8. Dose-related, albeit less-than-dose-proportional, increases in plasma BMS-488043 concentrations were observed. Mean plasma HIV-1 RNA decreases from the baseline for the BMS-488043 800- and 1,800-mg dose groups on day 8 were 0.72 and 0.96 log(10) copies/ml, respectively, compared with 0.02 log(10) copies/ml for the placebo group. A lower baseline BMS-488043 50% effective concentration (EC(50)) in the active-treatment groups was predictive of a greater antiviral response. Although absolute drug exposure was not associated with an antiviral response, the trough concentration (C(trough)), adjusted by the baseline EC(50) (C(trough)/EC(50)), was associated with antiviral activity. During dosing, four subjects experienced >10-fold reductions in viral susceptibility to BMS-488043, providing further support of the direct antiviral mechanism of BMS-488043. BMS-488043 was generally safe and well tolerated. These results suggest that further development of this novel class of oral HIV-1 attachment inhibitors is warranted.
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Hanna
authors.forename: Jacob
authors.initials: J
authors.lastname: Lalezari
authors.forename: James A
authors.initials: JA
authors.lastname: Hellinger
authors.forename: David A
authors.initials: DA
authors.lastname: Wohl
authors.forename: Richard
authors.initials: R
authors.lastname: Nettles
authors.forename: Anna
authors.initials: A
authors.lastname: Persson
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.forename: Pinfang
authors.initials: P
authors.lastname: Lin
authors.forename: Richard
authors.initials: R
authors.lastname: Colonno
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D023581:HIV Fusion Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007211:Indoles; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019289:Pyruvic Acid; D012367:RNA, Viral / Q000097:blood; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D023581:HIV Fusion Inhibitors; D007211:Indoles; D010879:Piperazines; D012367:RNA, Viral; D019289:Pyruvic Acid; C509651:BMS-488043