Department of Clinical Medicine and Surgery (Ed. 18) - University of Naples "Federico II", via S. Pansini 5, I-80131 Naples, Italy.
Curr Med Chem. 2014;21(28):3261-70. doi: 10.2174/0929867321666140706125950.
About 2.3% of the world's population is infected with hepatitis C virus (HCV) and patients have a high risk of developing liver cirrhosis and its complications. Current therapeutic strategies are based on a combination of pegylatedinterferon, ribavirin and (only for patients with genotype 1 infection) a protease inhibitor (boceprevir or telaprevir). Consequently, all these combinations have the limitations of interferon. In fact, they are contraindicated in decompensated disease and in subjects with severe comorbidities, and are associated with a high rate of side effects. Moreover, they are poorly effective in advanced disease. As complete viral eradication is associated with improved disease-free survival, several molecules are under clinical development for their potential to overcome the drawbacks of currently available treatments. This review focuses on the pharmacodynamics, pharmacokinetics, safety and tolerability of ABT-450, a potent inhibitor of non-structural 3 protease. ABT-450 is a substrate of cytochrome P450; hence its co-administration with ritonavir, a cytochrome P450 inhibitor, dramatically increases the plasma concentration and half-life of ABT-450 and allows once-daily administration. Given in monotherapy for 3 days at different doses, ABT-450 causes a mean maximum viral decline of about 4 logs. Interestingly, high doses of ABT-450 are associated with a reduced and delayed development of resistance-conferring mutations. Given in combination with other direct antiviral drugs, the sustained response rate reaches 90-95% in both naïve and treatment-experienced genotype 1 patients, and tolerability is good. In conclusion, ABT-450 is an excellent component of interferon-free combinations for the treatment of chronic HCV infection.
全球约有 2.3%的人口感染丙型肝炎病毒（HCV），患者发生肝硬化及其并发症的风险很高。目前的治疗策略基于聚乙二醇干扰素、利巴韦林和（仅用于基因型 1 感染的患者）蛋白酶抑制剂（博赛泼维或特拉泼维）的联合应用。因此，所有这些联合应用都有干扰素的局限性。事实上，它们在失代偿性疾病和严重合并症患者中是禁忌的，并且与高不良反应率相关。此外，它们在晚期疾病中的疗效较差。由于完全清除病毒与改善无病生存相关，因此有几种分子正在临床开发中，以潜在地克服现有治疗方法的缺点。本文重点介绍了 ABV-450 的药效学、药代动力学、安全性和耐受性，ABV-450 是一种非结构 3 蛋白酶的强效抑制剂。ABV-450 是细胞色素 P450 的底物；因此，与细胞色素 P450 抑制剂利托那韦联合应用可显著增加 ABV-450 的血浆浓度和半衰期，并允许每日一次给药。以不同剂量单药治疗 3 天，ABV-450 可使平均最大病毒下降约 4 个对数。有趣的是，高剂量 ABV-450 与耐药相关突变的减少和延迟出现相关。与其他直接抗病毒药物联合使用时，在初治和治疗经验丰富的基因型 1 患者中，持续应答率达到 90-95%，且耐受性良好。总之，ABV-450 是治疗慢性 HCV 感染的无干扰素联合治疗的理想药物。
