RIBAVIRIN PHARMACOKINETICS, RACE AND OUTCOME OF HEPATITIS C TREATMENT

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在美国，慢性丙型肝炎病毒（HCV）是肝硬化的最常见原因，也是原发性肝细胞癌（HCC）的主要病因。HCV在非裔美国人（AA）中的流行率是白人美国人（CA）的2倍，并且似乎是AA中HCC发病率较高的重要原因。聚乙二醇干扰素（PEGIFN）加利巴韦林治疗是最有效的治疗慢性丙型肝炎病毒（HCV）感染。HCV在55%的治疗患者中被根除。由于不清楚的原因，AA在治疗期间清除HCV的可能性低于CA。在Virahep-C研究中，AA和CA之间的PEGIFN药代动力学无重大差异。其他人已经发现在接受PEGIFN联合治疗的患者中利巴韦林血清浓度与病毒学应答和利巴韦林毒性之间存在显著相关性。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患者首次给药后的利巴韦林最大浓度（Cmax）显著较低。在AA患者中，通过浓度-时间曲线下面积（AUC）测量的利巴韦林暴露量有降低的趋势，而利巴韦林的表观清除率有升高的趋势。因此，我们假设利巴韦林的药代动力学AA和CA HCV基因型1患者之间的差异，这种差异有助于降低疗效的聚乙二醇干扰素和利巴韦林在AA。本项目有两个组成部分：1）回顾性研究，比较利巴韦林的药代动力学（PK）在参与NIDDK VIRAHEP-C研究的75例AA和75例CA中观察（利巴韦林血浆浓度、浓度-时间曲线下面积和清除率）和HCV根除情况（2001-2006年）;和2）首次给药后和稳态（6周）时利巴韦林药代动力学的前瞻性比较70例AA和70例CA患者在聚乙二醇干扰素和利巴韦林治疗慢性HCV期间。

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.