J.W. Goethe Universität, Frankfurt, Germany.
J Hepatol. 2011 Jun;54(6):1130-6. doi: 10.1016/j.jhep.2010.11.001. Epub 2011 Feb 24.
BACKGROUND & AIMS: Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics, and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection.
Four cohorts of treatment-naïve (TN) patients (100 mg q12 h, 100 mg q8 h, 200 mg q12 h, 200 mg q8 h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12 h) were investigated.
Danoprevir was safe and well tolerated; adverse events were generally mild, transient and were not associated with treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were: -3.9 log(10)IU/ml and -3.2 log(10)IU/ml in TN receiving 200 mg q8 h and 200 mg q12 h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10)IU/ml of the viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with the R155K substitution in NS3 regardless of the HCV subtype.
Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/ml reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.
达诺瑞韦是一种强效、选择性的丙型肝炎病毒（HCV）NS3/4A 丝氨酸蛋白酶抑制剂。本研究在一项随机、安慰剂对照、14 天多次递增剂量的研究中，评估了达诺瑞韦在慢性 HCV 基因 1 型感染患者中的安全性、药代动力学和抗病毒活性。
共纳入 4 个治疗初治（TN）患者队列（100mg q12h、100mg q8h、200mg q12h、200mg q8h）和一个既往聚乙二醇干扰素联合利巴韦林治疗无应答（NR）患者队列（300mg q12h）。
达诺瑞韦安全且耐受良好；不良事件通常为轻度、短暂，与治疗组或剂量水平无关。达诺瑞韦的暴露量随每日剂量的增加而略有超过比例增加，并迅速从血浆中清除。200mg q8h 和 200mg q12h 治疗的 TN 患者 HCV RNA 最大下降分别为-3.9log10IU/ml 和-3.2log10IU/ml。这两个队列的治疗结束时病毒下降幅度与病毒载量最低值相差 0.1log10IU/ml。NR 患者的 HCV RNA 下降幅度小于上剂量 TN 队列观察到的下降幅度。总的病毒反弹发生率较低（10/37），且与 HCV 亚型无关，与 NS3 中的 R155K 取代有关。
在慢性 HCV 基因 1 型感染患者中，达诺瑞韦连续治疗 14 天是安全且耐受良好的。治疗导致 HCV RNA 持续、多对数（10）IU/ml 的降低，在上剂量组中。这些结果支持进一步在慢性 HCV 患者中评估达诺瑞韦。
