Background:  GW873140 is a novel CCR5 receptor antagonist that binds specifically to human CCR5 and demonstrates potent in vitro anti-HIV activity. GW873140 binds to human CCR5 with a unique profile as evidenced by the selective inhibition of monoclonal antibody binding.  

Methods:  A double blind, randomized, placebo-controlled single and multiple oral dose escalation study was conducted in 70 fasted subjects (57 males, 13 females). During single dose escalation, 3 cohorts of 10 subjects (8 active / 2 placebo) received doses of 50, 200, 400, 800, 1200 mg, or 400 mg + standard breakfast in an alternating panel design. During multiple dose escalation, 4 cohorts (8 active / 2 placebo) received doses of 200, 400, 600, or 800 mg as a single dose on day 1 and then twice daily for 7 days. In vivo CCR5 occupancy was evaluated during the multiple dose phase and analyzed directly using samples of whole blood collected at baseline and at timepoints following single or multiple doses. Flow cytometric analysis was used to determine percentage CCR5 occupancy using 3 CCR5 monoclonal antibodies, each with unique binding specificity. Laboratory safety tests, vital signs, ECG, and pharmacokinetic sampling were performed at regular intervals.

Results:  Preliminary data indicated that GW873140 was well tolerated with no serious adverse events and no grade 3 or 4 adverse events. Mild to moderate side effects included abdominal cramping, nausea, and diarrhea. No specific trends in laboratory parameters and no clinically significant ECG changes were noted. Median GW873140 AUC and C_max ranged from 127 ng*h/mL and 24 ng/mL at 200 mg twice daily to 329 ng*h/mL and 100 ng/mL at 800 mg BID, respectively. Food increased the AUC and C_max by a mean of 1.7- and 2.2-fold, respectively. In vivo CCR5 binding analyses showed 0% receptor occupancy at baseline for all subjects and at all time points for subjects receiving placebo. Median receptor occupancy at 24 hours post single doses ranged from 68% to 88% despite GW873140 plasma concentrations being below or near assay limits (1 ng/ml). CCR5 occupancy was >97% at 2 and 12 hours after multiple dosing with GW873140.

Conclusions:  GW873140 was safe and well-tolerated following single doses and multiple doses administered twice daily. The prolonged CCR5 occupancy in vivo suggests a long half-life for GW873140 binding to the receptor. These data support further evaluation of GW873140 in HIV-infected individuals.

Keywords: CCR5; GW873140; pharmacokinetics