接受IDX320每日一次治疗的慢性丙型肝炎患者病毒RNA迅速下降：一种新型大环丙型肝炎病毒蛋白酶抑制剂。

Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor.

作者信息

de Bruijne Joep, van Vliet Andre, Weegink Christine J, Mazur Włodzimierz, Wiercinska-Drapało Alicja, Simon Krzysztof, Cholewińska-Szymańska Grażyna, Kapocsi Judit, Várkonyi István, Zhou Xiao-Jian, Temam Marie-Francoise, Molles Jeffrey, Chen Jie, Pietropaolo Keith, McCarville Joseph F, Sullivan-Bólyai John Z, Mayers Douglas, Reesink Hendrik

机构信息

Academic Medical Center, Amsterdam, the Netherlands.

出版信息

Antivir Ther. 2012;17(4):633-42. doi: 10.3851/IMP2078. Epub 2012 Mar 16.

DOI:10.3851/IMP2078

PMID:22427481

Abstract

BACKGROUND

The addition of direct-acting antivirals to pegylated interferon-α plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease.

METHODS

This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection. HV (n=48) received single or multiple ascending doses of IDX320. Two HCV-infected patients received a single dose of 200 mg IDX320. Dosages for other HCV-infected patients were as follows: placebo, 50, 100, 200 or 400 mg of IDX320 orally once daily for 3 days (n=30) or placebo/200 mg of IDX320 twice-daily for 3 days (n=8).

RESULTS

In total, 48 HV and 40 HCV-infected patients were enrolled and all completed the study. There were no serious adverse events. The majority of adverse events were of mild or moderate intensity. Pharmacokinetics supported a once-daily dosing regimen. A rapid decline in plasma HCV RNA was observed in all patients. In the multiple-dose study, mean HCV RNA reductions were 2.6, 3.1, 3.1, 3.3 and 3.8 log(10) IU/ml after 3 days in the IDX320 50, 100, 200, 400 mg once-daily and 200 mg twice-daily treatment groups, respectively. This compared to a mean HCV RNA reduction of 0.04 log(10) in the placebo group.

CONCLUSIONS

Once-daily IDX320 dosing demonstrated potent dose-dependent antiviral activity in treatment-naive HCV genotype-1-infected patients.

摘要

背景

在聚乙二醇化干扰素-α加利巴韦林治疗慢性丙型肝炎病毒（HCV）感染中添加直接抗病毒药物可提高持续病毒学应答率，并可能缩短治疗疗程。IDX320是一种有效的HCV NS3/4A蛋白酶非共价大环抑制剂。

方法

这是一项随机双盲安慰剂对照的单剂量和多剂量研究，旨在评估IDX320在健康志愿者（HV）和慢性HCV 1型感染患者中的安全性、耐受性、抗病毒活性和药代动力学。HV（n = 48）接受单剂量或多剂量递增的IDX320。两名HCV感染患者接受了200 mg IDX320的单剂量治疗。其他HCV感染患者的剂量如下：安慰剂、50、100、200或400 mg IDX320，口服，每日一次，共3天（n = 30），或安慰剂/200 mg IDX320，每日两次，共3天（n = 8）。

结果

总共招募了48名HV和40名HCV感染患者，所有患者均完成了研究。没有严重不良事件。大多数不良事件为轻度或中度。药代动力学支持每日一次给药方案。所有患者均观察到血浆HCV RNA迅速下降。在多剂量研究中，IDX320 50、100、200、400 mg每日一次和200 mg每日两次治疗组在3天后的平均HCV RNA降低分别为2.6、3.1、3.1、3.3和3.8 log(10) IU/ml。相比之下，安慰剂组的平均HCV RNA降低为0.04 log(10)。