Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients
Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients
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DOI：
10.1053/j.gastro.2004.08.002
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发表时间：
2004-11-01
期刊：
影响因子：
29.4
通讯作者：
Steinmann, GG
中科院分区：
文献类型：
--
作者：
Hinrichsen, H;Benhamou, Y;Steinmann, GG
背景与目的：需要新的、有效的、耐受性良好的丙型肝炎病毒药物。BILN 2061是一种高效、特异的体外丙型肝炎病毒丝氨酸蛋白酶抑制剂。临床前毒理学数据和对健康志愿者的研究支持将BILN 2061用于丙型肝炎病毒感染患者。方法：在一项安慰剂对照的双盲先导研究中，对31例慢性1型丙型肝炎病毒感染者和轻度肝纤维化(Ishak评分0~2)的患者，每日两次单用25、200和500 mg BILN 2061进行抗病毒疗效、药代动力学和耐受性评估。在随后进行的两项类似设计的安慰剂对照研究中，10名晚期肝纤维化患者(Ishak评分为3或4)和10名代偿性肝硬变患者(Ishak评分为5或6)每日两次服用206 mg BILN 206：1，为期2天。结果：大多数患者的病毒RNA减少率为2~3log(10)拷贝/毫升。与接受25 mg BILN 2061的患者相比，接受500 mg BILN 2061的患者有更多的患者实现病毒RNA减少大于或等于3log(10)拷贝/毫升。晚期纤维化或代偿性肝硬变不影响BILN 2061的抗病毒效果。BILN 2061在所有研究中耐受性良好。结论：BILN 2061是一种耐受性很好的非常有效的化合物，可以在治疗2天后降低I型丙型肝炎患者的血清病毒RNA浓度，与纤维化程度无关。然而，进一步的临床试验被搁置，等待动物毒性问题的解决。
Background & Aims: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine protease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection. Methods: The antiviral efficacy, pharmacokinetic, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebocontrolled, double-blind pilot study. In 2 subsequent placebo-controlled studies, of similar design, 206 mg BILN 206:1 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6). Results: Viral RNA reductions of 2-3 log(10) copies/mL were achieved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction greater than or equal to3 log(10) copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or compensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies. Conclusions: BILN 2061 is a well-tolerated and very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype I HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity issues.