title: Safety, efficacy, and pharmacokinetics of TBR-652, a CCR5/CCR2 antagonist, in HIV-1-infected, treatment-experienced, CCR5 antagonist-naive subjects.
abstract: OBJECTIVE
  To determine the antiviral activity, pharmacokinetics, pharmacodynamics, safety, and tolerability of several dose levels of oral TBR-652 monotherapy in HIV-1-infected, antiretroviral experienced, CCR5 antagonist-naive subjects.
  
  
  METHODS
  Double-blind placebo-controlled study in the United States and Argentina.
  
  
  METHODS
  Subjects were randomized in a ratio of 4:1 per dose level to TBR-652 (25, 50, 75, 100, or 150 mg) or placebo, taken once daily for 10 days. Changes from baseline in HIV-1 RNA and CD4 cell counts were measured through day 40 and for monocyte chemotactic protein-1 (MCP-1), high-sensitivity C-reactive protein (hs-CRP), and IL-6 at day 10. Pharmacokinetic data were analyzed using noncompartmental statistics. Laboratory and clinical adverse events (AEs) and electrocardiogram changes were recorded.
  
  
  RESULTS
  Maximum median reductions in HIV-1 RNA values for the 25, 50, 75, and 150 mg doses were -0.7, -1.6, -1.8, and -1.7 log10 copies per milliliter, respectively. All changes were significant. Median time to nadir was 10-11 days. Suppression persisted well into the posttreatment period. Mean MCP-1 increased significantly by day 10 in the 50-mg and 150-mg dose groups. Effects on CD4 cell counts, hs-CRP, and IL-6 levels were negligible. TBR-652 was generally safe and well tolerated, with no withdrawals due to AEs.
  
  
  CONCLUSIONS
  TBR-652 caused significant reductions in HIV-1 RNA at all doses. Significant increases in MCP-1 levels suggested a strong CCR2 blockade. TBR-652 was generally well tolerated with no dose-limiting AEs. Pharmacodynamics indicate that TBR-652 warrants further investigation as an unboosted once-daily oral CCR5 antagonist with potentially important CCR2-mediated anti-inflammatory effects.
authors.affiliation: Quest Clinical Research, San Francisco, CA, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Lalezari
authors.forename: Joseph
authors.initials: J
authors.lastname: Gathe
authors.forename: Cynthia
authors.initials: C
authors.lastname: Brinson
authors.forename: Melanie
authors.initials: M
authors.lastname: Thompson
authors.forename: Calvin
authors.initials: C
authors.lastname: Cohen
authors.forename: Edwin
authors.initials: E
authors.lastname: Dejesus
authors.forename: Jorge
authors.initials: J
authors.lastname: Galindez
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Ernst
authors.forename: David E
authors.initials: DE
authors.lastname: Martin
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Palleja
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D015415:Biomarkers; D065100:CCR5 Receptor Antagonists; D018791:CD4 Lymphocyte Count; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D013454:Sulfoxides; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D065100:CCR5 Receptor Antagonists; D007093:Imidazoles; D012367:RNA, Viral; D054390:Receptors, CCR2; D013454:Sulfoxides; C506967:cenicriviroc