RIBAVIRIN PHARMACOKINETICS, RACE AND OUTCOME OF HEPATITIS C TREATMENT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在美国，慢性丙型肝炎病毒是导致肝硬变的最常见原因，也是导致原发性肝细胞癌的主要病因。丙型肝炎病毒在非裔美国人(AA)中的流行率是在高加索美国人(CA)中的2倍，这似乎是AA中肝癌发病率较高的重要原因。聚乙二醇化干扰素联合利巴韦林治疗慢性丙型肝炎病毒感染是最有效的治疗方法。在55%的接受治疗的患者中，丙型肝炎病毒被根除。由于不明原因，在治疗期间，AA患者清除丙型肝炎病毒的几率低于CA患者。在Virahep-C研究中，AA和CA的聚乙二醇化干扰素的药代动力学没有显著差异。其他人发现，在接受聚乙二醇干扰素联合治疗的患者中，利巴韦林血清浓度与病毒学反应和利巴韦林毒性之间存在显著的相关性。关于利巴韦林的药代动力学，一项初步研究发现，与CA相比，AA第一剂后的最大利巴韦林浓度(Cmax)显著降低。在AA患者中，通过时间浓度曲线(AUC)下的面积来衡量利巴韦林暴露有降低的趋势和较高的表观利巴韦林清除量。因此，我们假设再生障碍性贫血和丙型肝炎病毒1型患者的利巴韦林药代动力学不同，这种差异是佩格干扰素和利巴韦林治疗再生障碍性贫血疗效较低的原因之一。该项目包括两个部分：1)一项回顾研究，比较参加NIDDK VIRAHEP-C研究(2001-2006年)的75名AA和75名CA患者的利巴韦林药代动力学(PK)(利巴韦林血浆浓度、浓度-时间曲线下面积和清除量)和根除丙型肝炎的情况；以及2)聚乙二醇化干扰素和利巴韦林治疗慢性丙型肝炎期间，70名AA和70名CA患者第一剂利巴韦林药代动力学和稳定状态(6周)的前瞻性比较。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chronic hepatitis C virus (HCV) is the most common cause for liver cirrhosis and a major etiology for primary hepatocellular carcinoma (HCC) in the United States. HCV is 2 times more prevalent in African Americans (AA) than in Caucasian Americans (CA), and appear to be an important cause for the higher incidence of HCC among AA. Pegylated interferon (PEGIFN) plus ribavirin treatments is the most effective treatment for chronic hepatitis C virus (HCV) infections. HCV is eradicated in 55% of treated patients. For unclear reasons, AA have a lower probability of clearing HCV than CA during treatment. There were no major differences in the pharmacokinetics of PEGIFN between AA and CA in Virahep-C study. Others have found a significant correlation between ribavirin serum concentrations and both virologic responses and ribavirin toxicity in patients receiving PEGIFN combination therapy. Concerning ribavirin pharmacokinetics, a pilot study found a significantly lower maximum ribavirin concentrations (Cmax) after the first-dose in AA compared to CA. There was trend toward lower ribavirin exposure measured by the area-under-the concentration by time curve (AUC) and higher apparent ribavirin clearance in AA. Thus, we hypothesize that ribavirin pharmacokinetics differ between AA and CA HCV genotype 1 patients and that this difference contributes to the lower efficacy of PEGIFN and ribavirin in AA. This project has two components: 1) a retrospective study to compare ribavirin pharmacokinetic (PK) (ribavirin plasma concentrations, area under the concentration time curve, and clearance) and HCV eradication in 75 AA and 75 CA who participated in the NIDDK VIRAHEP-C study (2001-2006); and 2) a prospective comparison of ribavirin pharamcokinetics after the first dose and at steady state (6 weeks) in 70 AA and 70 CA patients during pegylated interferon and ribavirin treatment for chronic HCV.