Rapid decline of viral RNA in hepatitis C patients treated with VX-950: A phase Ib, placebo-controlled, randomized study
Rapid decline of viral RNA in hepatitis C patients treated with VX-950: A phase Ib, placebo-controlled, randomized study
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DOI：
10.1053/j.gastro.2006.07.013
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发表时间：
2006-10-01
期刊：
影响因子：
29.4
通讯作者：
Jansen, Peter L. M.
中科院分区：
文献类型：
--
作者：
Reesink, Hendrik W.;Zeuzem, Stefan;Jansen, Peter L. M.
VX-950特异性抑制NS 3（.）4A蛋白酶，体外抗病毒活性。这项I期、安慰剂对照、双盲研究评价了VX-950在慢性丙型肝炎（CHC）患者中的抗病毒活性、药代动力学和安全性。研究方法：34例基因型1型CHC患者随机接受安慰剂或VX-950，剂量为450 mg或750 mg，每8小时一次或1250 mg，每12小时一次，持续14天。在34名参与者中，27名（79%）既往治疗失败。监测患者VX-950的安全性和耐受性。测定血浆VX-950浓度和HCV RNA水平。结果VX-950耐受性良好，具有显著的抗病毒作用：所有28名接受VX-950治疗的患者的病毒载量下降>= 2 log（10），26名（93%）患者的病毒载量下降>= 3 log（10）。在750 mg剂量组中，具有最高的血浆药物谷浓度，14天后HCV RNA的中位数降低为4.4 log（10）。在450 mg和1250 mg组中，在给药的第3天和第7天之间观察到最大效应，第7天和第14天之间的中位HCV RNA增加，第14天的中位降低分别为2.4 log（10）和2.2 log（10）。在所有VX-950组中，中位丙氨酸氨基转移酶水平在给药期间降低。结论：VX-950具有良好的耐受性和显著的抗病毒活性。一些患者在给药期间出现病毒突破，这与选择对VX-950敏感性降低的变体有关。结果支持VX-950在CHC患者中的进一步研究。
Background & Aims: VX-950 specifically inhibits the NS3(.)4A protease of hepatitis C and has antiviral activity in vitro. This phase 1, placebo-controlled, double-blind study evaluated the antiviral activity, pharmacokinetics, and safety of VX-950 in patients with chronic hepatitis C (CHC). Methods: Thirty-four patients with genotype 1 CHC were randomized to receive placebo or VX-950 at doses of 450 mg or 750 mg every 8 hours or 1250 mg every 12 hours for 14 days. Of the 34 participants, 27 (79%) had failed prior treatment. Patients were monitored for safety and tolerability of VX-950. Plasma VX-950 concentrations and HCV RNA levels were measured. Results. VX-950 was well tolerated and had substantial antiviral effects: viral loads dropped >= 2 log(10) in all 28 patients treated with VX-950 and >= 3 log(10) in 26 (93%) of the 28 patients. In the 750-mg-dose group, which had the highest trough plasma drug concentrations, the median reduction of HCV RNA was 4.4 log(10) after 14 days. In the 450-mg and 1250-mg groups, the maximal effect was seen between days 3 and 7 of dosing, and median HCV RNA increased between days 7 and 14, median reductions at day 14 were 2.4 log(10) and 2.2 log(10), respectively. Median alanine aminotransferase levels decreased during dosing in all VX-950 groups. Conclusions: VX-950 was well tolerated and demonstrated substantial antiviral activity. Some patients had viral breakthrough during dosing, related to selection of variants with decreased sensitivity to VX-950. The results support further studies of VX-950 in patients with CHC.