PMID- 21317794
OWN - NLM
STAT- MEDLINE
DCOM- 20110909
LR  - 20201209
IS  - 1944-7884 (Electronic)
IS  - 1525-4135 (Linking)
VI  - 57
IP  - 2
DP  - 2011 Jun 1
TI  - Safety, efficacy, and pharmacokinetics of TBR-652, a CCR5/CCR2 antagonist, in 
      HIV-1-infected, treatment-experienced, CCR5 antagonist-naive subjects.
PG  - 118-25
LID - 10.1097/QAI.0b013e318213c2c0 [doi]
AB  - OBJECTIVES: 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. DESIGN: 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.
FAU - Lalezari, Jacob
AU  - Lalezari J
AD  - Quest Clinical Research, San Francisco, CA, USA.
FAU - Gathe, Joseph
AU  - Gathe J
FAU - Brinson, Cynthia
AU  - Brinson C
FAU - Thompson, Melanie
AU  - Thompson M
FAU - Cohen, Calvin
AU  - Cohen C
FAU - Dejesus, Edwin
AU  - Dejesus E
FAU - Galindez, Jorge
AU  - Galindez J
FAU - Ernst, Jerome A
AU  - Ernst JA
FAU - Martin, David E
AU  - Martin DE
FAU - Palleja, Sandra M
AU  - Palleja SM
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Acquir Immune Defic Syndr
JT  - Journal of acquired immune deficiency syndromes (1999)
JID - 100892005
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Biomarkers)
RN  - 0 (CCR5 Receptor Antagonists)
RN  - 0 (Imidazoles)
RN  - 0 (RNA, Viral)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Sulfoxides)
RN  - 15C116UA4Y (cenicriviroc)
SB  - IM
MH  - Adult
MH  - Anti-HIV Agents/pharmacokinetics/*pharmacology/therapeutic use
MH  - Area Under Curve
MH  - Biomarkers
MH  - *CCR5 Receptor Antagonists
MH  - CD4 Lymphocyte Count
MH  - Double-Blind Method
MH  - Female
MH  - HIV Infections/*drug therapy
MH  - HIV-1/*drug effects
MH  - Half-Life
MH  - Humans
MH  - Imidazoles/pharmacokinetics/*pharmacology/therapeutic use
MH  - Inflammation/blood/metabolism
MH  - Male
MH  - Middle Aged
MH  - RNA, Viral/blood
MH  - Receptors, CCR2/*antagonists & inhibitors
MH  - Sulfoxides
MH  - Young Adult
EDAT- 2011/02/15 06:00
MHDA- 2011/09/10 06:00
CRDT- 2011/02/15 06:00
PHST- 2011/02/15 06:00 [entrez]
PHST- 2011/02/15 06:00 [pubmed]
PHST- 2011/09/10 06:00 [medline]
AID - 10.1097/QAI.0b013e318213c2c0 [doi]
PST - ppublish
SO  - J Acquir Immune Defic Syndr. 2011 Jun 1;57(2):118-25. doi: 
      10.1097/QAI.0b013e318213c2c0.