Safety, Efficacy, and Pharmacokinetics of TBR-652, a CCR5/CCR2 Antagonist, in HIV-1-Infected, Treatment-Experienced, CCR5 Antagonist-Naive Subjects

被引:55
作者
Lalezari, Jacob [1 ]
Gathe, Joseph
Brinson, Cynthia [2 ]
Thompson, Melanie [3 ]
Cohen, Calvin [4 ]
Dejesus, Edwin [5 ]
Galindez, Jorge [6 ]
Ernst, Jerome A. [7 ]
Martin, David E. [8 ]
Palleja, Sandra M. [8 ]
机构
[1] Quest Clin Res, San Francisco, CA USA
[2] Cent Texas Clin Res, Austin, TX USA
[3] AIDS Res Consortium Atlanta, Atlanta, GA USA
[4] Community Res Initiat New England, Boston, MA USA
[5] Orlando Immunol Ctr, Orlando, FL USA
[6] CIBIC, Rosario, Argentina
[7] AIDS Community Res Initiat Amer Inc, New York, NY USA
[8] Tobira Therapeut Inc, Princeton, NJ USA
关键词
TBR-652; receptors; CCR5/antagonists and inhibitors; antiretroviral therapy; clinical trial; phase II; CCR2/antagonists and inhibitors; MONOCYTE CHEMOATTRACTANT PROTEIN-1; HIV-INFECTION; MCP-1; INFLAMMATION; POPULATION; ACTIVATION; MARKERS;
D O I
10.1097/QAI.0b013e318213c2c0
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 log(10) 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.
引用
收藏
页码:118 / 125
页数:8
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