Asahina Y, Izumi N, Umeda N, Hosokawa T, Ueda K, Doi F, Tsuchiya K, Nakanishi H, Matsunaga K, Kitamura T, Kurosaki M, Uchihara M, Higaki M, Miyake S
Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
J Viral Hepat. 2007 Jun;14(6):396-403. doi: 10.1111/j.1365-2893.2006.00803.x.
This study investigated the molecular and pharmacokinetic mechanisms of the enhanced antiviral efficacy associated with pegylated interferon (PEG-IFN) alpha-2b and ribavirin. The study involved comparing the expression of serial double-stranded RNA-activated protein kinase (PKR) before and during treatment in 26 PEG-IFN alpha-2b and 26 conventional IFN alpha-2b recipients matched for age, body weight and dose of ribavirin. The pharmacokinetics of PEG-IFN alpha-2b and ribavirin was analysed in 15 of the 26 PEG-IFN recipients. There was a rapid increase in PKR expression in both treatment groups, although expression from day 2 onwards was maintained at a significantly higher level in the PEG-IFN recipients (P < 0.05). C(max) of PEG-IFN occurred 12-48 h after the initial administration, with t(1/2) and C(min) being 49 h and 190 pg/mL, respectively. In contrast to ribavirin, accumulation of PEG-IFN was minimal. There was no association between serum PEG-IFN and ribavirin levels and virological response. Although baseline expression of PKR before treatment was marginally higher in nonresponders (NRs), from day 2 onwards, sequential PKR expression in response to PEG-IFN was higher in sustained viral responders compared with the NRs (P < 0.05). Significant correlations were found between kinetics of PKR expression and viral decline rates in each phase of hepatitis C virus dynamics (first phase, r = 0.67, P = 0.0006; second phase, r = 0.67, P = 0.001). In conclusion, improvement in pharmacokinetics following pegylation led to higher intracellular PKR expression, which was associated with enhanced virological efficacy of PEG-IFN-based combination therapy. The concentrations of both ribavirin and PEG-IFN alpha-2b were not associated with viral response and PKR expression.
本研究调查了聚乙二醇化干扰素（PEG-IFN）α-2b与利巴韦林联合使用时抗病毒疗效增强的分子机制和药代动力学机制。该研究比较了26例接受PEG-IFNα-2b治疗和26例接受常规IFNα-2b治疗的患者（年龄、体重和利巴韦林剂量相匹配）在治疗前及治疗期间双链RNA激活蛋白激酶（PKR）的表达情况。对26例接受PEG-IFN治疗的患者中的15例分析了PEG-IFNα-2b和利巴韦林的药代动力学。两个治疗组的PKR表达均迅速增加，不过从第2天起，PEG-IFN治疗组的表达维持在显著更高的水平（P<0.05）。PEG-IFN的C(max)在首次给药后12 - 48小时出现，t(1/2)和C(min)分别为49小时和190 pg/mL。与利巴韦林不同，PEG-IFN的蓄积极少。血清PEG-IFN和利巴韦林水平与病毒学应答之间无关联。虽然治疗前无应答者（NRs）的PKR基线表达略高，但从第2天起，持续病毒应答者对PEG-IFN的序贯PKR表达高于NRs（P<0.05）。在丙型肝炎病毒动态变化的各个阶段，PKR表达动力学与病毒下降率之间均发现显著相关性（第一阶段，r = 0.67，P = 0.0006；第二阶段，r = 0.67，P = 0.001）。总之，聚乙二醇化后药代动力学的改善导致细胞内PKR表达升高，这与基于PEG-IFN的联合治疗增强的病毒学疗效相关。利巴韦林和PEG-IFNα-2b的浓度均与病毒应答和PKR表达无关。
