title: In vitro and clinical investigation of the relationship between CCR5 receptor occupancy and anti-HIV activity of Aplaviroc.
abstract: Aplaviroc (GW873140) binds specifically to human cellular CC chemokine receptor 5 (CCR5) and demonstrates potent anti-human immunodeficiency virus activity in vitro in the subnanomolar range. In vitro studies show that aplaviroc selectively inhibits the binding of a particular monoclonal antibody, 45531, to CCR5. Based on this observation, a flow cytometry-based assay was developed to determine percentage CCR5 receptor occupancy (RO). CCR5 receptor occupancy was aplaviroc concentration-dependent and related to anti-human immunodeficiency virus activity in vitro. In the clinical setting, CCR5 receptor occupancy in peripheral blood was >98% in all subjects within 2 to 3 hours of dosing, which is consistent with the peak plasma concentrations of drug. Longitudinal analysis in the drug washout period revealed the time to 50% CCR5 receptor occupancy averaged >100 hours, in both human immunodeficiency virus-positive and human immunodeficiency virus-negative subjects, substantially longer than the plasma pharmacokinetic half-life of 3 hours. The duration of CCR5 receptor occupancy appeared to be dose-dependent and associated with antiviral activity as measured by plasma human immunodeficiency virus RNA nadir following 10 days of multiple dose administration. These data demonstrate that the analysis of CCR5 receptor occupancy, in addition to conventional plasma-based pharmacokinetic measures, provides an informative tool to assist in evaluating the pharmacodynamic and antiviral effects of cellular CC chemokine receptor antagonists.
authors.affiliation: GlaxoSmith Kline Virology, Research Triangle Park, NC 27709, USA. james.f.demarest@gsk.com
authors.forename: James F
authors.initials: JF
authors.lastname: Demarest
authors.forename: Sara S
authors.initials: SS
authors.lastname: Sparks
authors.forename: Kathleen
authors.initials: K
authors.lastname: Schell
authors.forename: Shiro
authors.initials: S
authors.lastname: Shibayama
authors.forename: Charlene B
authors.initials: CB
authors.lastname: McDanal
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Adkison
authors.forename: Anne
authors.initials: A
authors.lastname: Shachoy-Clark
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Piscitelli
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005434:Flow Cytometry; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012367:RNA, Viral / Q000097:blood / Q000187:drug effects; D019713:Receptors, CCR5 / Q000187:drug effects* / Q000378:metabolism; D013141:Spiro Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D001565:Benzoates; D054659:Diketopiperazines; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D012367:RNA, Viral; D019713:Receptors, CCR5; D013141:Spiro Compounds; C499671:aplaviroc