Ribavirin Pharmacokinetics, Race and HCV Treatment

利巴韦林药代动力学、种族和 HCV 治疗

• 批准号: 7440199
• 负责人: CHARLES D HOWELL
• 金额: $ 18.19万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7440199
• 关键词: Address; African American; Aftercare; American; Anemia; Area; Cessation of life; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical Research; Clinical Trials; Combined Modality Therapy; Dose; Drug Kinetics; Etiology; Exhibits; Future; Genotype; Hepatitis C virus; Hospital Mortality; Incidence; Infection; Interferon-alpha; Interferons; Kinetics; Lead; Liver Cirrhosis; Liver diseases; Maryland; Measures; Morbidity - disease rate; Numbers; Outcome; Patients; Pegylated Interferon Alfa; Pharmaceutical Preparations; Pilot Projects; Plasma; Polymerase; Population; Prevalence; Primary carcinoma of the liver cells; Probability; Prospective Studies; Protease Inhibitor; RNA Polymerase Inhibitor; Race; Rate; Relapse; Relative (related person); Relative Risks; Resistance; Ribavirin; Risk Factors; Serum; Testing; Time; Toxic effect; Treatment Efficacy; United States; Universities; Viral; Virus; Week; base; caucasian American; day; health disparity; hepatitis C virus NS3 protein; improved; mathematical model; mortality; novel; response; treatment duration; trend; viral RNA

DESCRIPTION (provided by applicant): Chronic hepatitis C virus (HCV) is the most common cause for liver cirrhosis and a major risk factor for primary hepatocellular carcinoma (HCC) in the United States. In the absence of highly effective treatment, the number of patients with decompensated liver cirrhosis and primary HCC related to HCV is projected to increase by 200% and the number of deaths by 300% by the year 2030. HCV is 2 times more prevalent and is associated with worse outcome in African Americans (AA) than in Caucasian Americans (CA). Ironically, AA infected with HCV genotype 1 exhibit significantly lower rates of HCV clearance following treatment pegylated interferon alfa (PEGIFNa) in combination with ribavirin. More effective treatments for HCV genotype 1 infections in AA are needed to reduce the future health disparity between AA and CA with HCV. When combined with IFN ribavirin decreases HCV relapse rate following treatment resulting in a 2-3 higher sustained virological rate by compared to IFN alone. Several recent studies lead us to hypothesize that ribavirin pharmacokinetics is different in AA and CA HCV genotype 1 patients and that this difference contributes to the lower efficacy of PEGIFN and ribavirin in AA: 1) there is a significant correlation between both the ribavirin dose and ribavirin serum concentration during treatment and virologic response rates in patients receiving PEGIFN combination therapy; 2) a recent mathematical model HCV RNA kinetics suggests ribavirin treatment is more important to HCV clearance in patients in whom IFN therapy is less effective such as AA infected with HCV genotype 1; 3) a pilot study by Brennan et al. found increased ribavirin clearance and lower ribavirin serum levels in AA compared to CA HCV patients. The long-term objective of this project is to reduce the disparity in the efficacy of treatment for HCV between AA and CA. The project has 2 specific aims: 1) to determine the relationship between ribavirin plasma levels and virologic response and anemia in AA and CA HCV genotype 1 patients during PEGIFN alfa-2a and ribavirin treatment in the Virahep-C study; and 2) to determine ribavirin pharmacokinetics in AA and CA infected with HCV genotype 1. In all probability, PEGIFN and ribavirin or a ribavirin-like drug will remain a component of future HCV treatments that include HCV polymerase and protease inhibitors. The results of this study will clarify the importance of ribavirin pharmacokinetics during PEGIFN and ribavirin treatment, help to optimize ribavirin dose, and ultimately improve the efficacy of HCV genotype 1 treatment in AA as well as in CA patients. This proposed study seeks to improve the efficacy of current therapy for chronic hepatitis C (HCV) in African Americans infected with genotype 1 of the virus, the most resistant to treatment. More effective treatments are necessary to reduce the disparities between African Americans and Caucasian Americans in sickness and deaths related to HCV liver disease.

描述（由申请人提供）：慢性丙型肝炎病毒（HCV）是美国肝硬化的最常见原因，也是美国原发性肝细胞癌（HCC）的主要危险因素。在没有高度有效治疗的情况下，肝硬化代表性肝硬化和与HCV相关的原发性HCC的患者数量预计将增加200％，到2030年，死亡人数增加了300％。HCV的流行程度高2倍，并且与非洲裔美国人（AA）的结果相关的是比起激素的美国人（AA）的差。具有讽刺意味的是，在处理Pegypy干扰素阿尔法（PEGIFNA）与Ribavirin结合使用后，感染HCV基因型1的AA显示出HCV清除率的明显降低。需要在AA中对HCV基因型1感染进行更有效的治疗方法，以减少AA和CA与HCV之间的未来健康差异。当与IFN相比，与单独的IFN相比，当与IFN的IFN结合使用时，可降低治疗后的HCV复发率，导致持续病毒率高2-3。最近的几项研究导致我们假设AA和CA HCV基因型1患者中的利巴韦林药代动力学有所不同，并且这种差异有助于AA中Pegifn和Ribavirin在AA中的疗效较低：1）在治疗和核能疗法中，PEG NE二维体剂量浓度之间存在显着的相关性。 2）最近的数学模型HCV RNA动力学表明，利巴韦林治疗对于IFN疗法较低的患者中的HCV清除率更为重要，例如感染了HCV基因型1的AA； 3）Brennan等人的试点研究。发现与CA HCV患者相比，AA中的利巴韦林清除率增加，可利巴韦林血清水平降低。该项目的长期目的是降低AA和CA之间HCV治疗功效的差异。该项目具有2个特定目的：1）在PEGIFN ALFA-2A期间AA和CA HCV基因型1患者与Virahep-C研究中的AA和CA HCV基因型1患者中的利巴韦林血浆水平与病毒学反应与贫血之间的关系； 2）为了确定AA中的利巴韦林药代动力学和Ca感染HCV基因型1。这项研究的结果将阐明PEGIFN和Ribavirin治疗过程中利巴韦林药代动力学的重要性，有助于优化利巴韦林剂量，并最终提高AA和CA患者中HCV基因型1治疗的功效。这项拟议的研究旨在提高当前疗法对慢性丙型肝炎（HCV）在感染该病毒基因型1的非洲裔美国人中，是对治疗的最耐药性。更有效的治疗方法是减少非洲裔美国人与疾病中的白人美国人之间的差异和与HCV肝病有关的差异。