Safety, Efficacy, and Pharmacokinetics of TBR-652, a CCR5/CCR2 Antagonist, in HIV-1-Infected, Treatment-Experienced, CCR5 Antagonist-Naive Subjects
Safety, Efficacy, and Pharmacokinetics of TBR-652, a CCR5/CCR2 Antagonist, in HIV-1-Infected, Treatment-Experienced, CCR5 Antagonist-Naive Subjects
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DOI：
10.1097/qai.0b013e318213c2c0
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发表时间：
2011-06-01
影响因子：
3.6
通讯作者：
Palleja, Sandra M.
中科院分区：
文献类型：
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作者：
Lalezari, Jacob;Gathe, Joseph;Palleja, Sandra M.
目的：在HIV-1感染、有抗逆转录病毒经验、CCR5受体拮抗剂未使用的受试者中，确定几种剂量水平的口服TBR-652单一疗法的抗病毒活性、药代动力学、安全性和耐受性。设计：在美国和阿根廷进行的双盲安慰剂对照研究。方法：受试者按4：1的剂量水平随机加入TBR-652(25、50、75、100或150 mg)或安慰剂，每天服用一次，共10天。在第40天测量HIV-1RNA和CD4(+)细胞计数的变化，在第10天测量单核细胞趋化蛋白-1(MCP-1)、高敏C-反应蛋白(hs-CRP)和IL-6的变化。药代动力学数据用非区室统计进行分析。结果：25、50、75和150 mg剂量的HIV-1RNA最大下降中位数分别为-0.7、-1.6、-1.8和-1.7log(10)拷贝/毫升。所有的变化都是显著的。中位到达最低点的时间为10-11天。抑制作用一直持续到治疗后阶段。在50 mg和150 mg剂量组中，平均MCP-1在第10天时显著增加。对CD4(+)细胞计数、hs-CRP和IL-6水平的影响可以忽略不计。TBR-652总体上是安全的，耐受性良好，没有因不良反应而停药。结论：TBR-652在所有剂量下都能显著降低HIV-1RNA。单核细胞趋化蛋白-1水平的显著升高表明CCR2被强烈阻断。TBR-652一般耐受性良好，没有剂量限制的不良反应。药效学表明，TBR-652作为一种非增强的每日一次口服CCR5拮抗剂，具有潜在的重要的CCR2介导的抗炎作用，值得进一步研究。
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.