Concentration-Controlled Ribavirin for the Treatment of Patients with Chronic HVC

浓度控制的利巴韦林用于治疗慢性 HVC 患者

• 批准号: 8261960
• 负责人: JENNIFER JUSTICE KISER
• 金额: $ 16.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261960
• 关键词: Adverse effects; Area; Chronic; Chronic Hepatitis C; Clinical Pharmacology; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Drug resistance; Effectiveness; Equilibrium; Erythrocytes; Genotype; Goals; HIV; Health; Hemolytic Anemia; Hepatic; Hepatitis; Hepatitis C virus; Incidence; Justice; Lead; Liver; Mono-S; National Institute of Diabetes and Digestive and Kidney Diseases; Patients; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Plasma; Polymerase; Population; Race; Randomized; Recurrence; Regimen; Relative (related person); Research; Research Personnel; Resistance development; Ribavirin; Safety; Serum; Specific qualifier value; Techniques; Therapeutic; Therapeutic Index; Time; Toxic effect; Variant; Viral; Viral hepatitis; Weight; base; career; improved; in vivo; inhibitor/antagonist; inorganic phosphate; insight; liver transplantation; novel strategies; novel therapeutics; nucleoside analog; peginterferon alfa-2a; pharmacodynamic model; programs; research study; response; standard of care; success; treatment duration; treatment strategy

DESCRIPTION (provided by applicant): Dr. Kiser's overall career goal is to develop an independent research program specializing in the application of clinical pharmacology research to the treatment of viral hepatitis. Pharmacology research in chronic Hepatitis C virus (HCV) is urgently needed because of the poor response rates with current therapies and the need to investigate the optimal dose and the potential for drug interactions with newer compounds. Through the study proposed, the candidate will use pharmacokinetics (PK) to guide dosing decisions with ribavirin, generate preliminary data on intracellular ribavirin concentrations, and become poised to apply PK techniques to studies with new HCV agents. The specific aims for the study are to (1) demonstrate that concentration-controlled ribavirin dosing can achieve a targeted level of plasma exposure with reduced variability in the steady-state area-under-the-concentration-time curve compared with standard weight-based ribavirin dosing, (2) evaluate the safety and efficacy of concentration-controlled versus standard weight- based ribavirin therapy, (3) quantify the intracellular ribavirin mono- (RBV-MP), di- (RBV-DP), and tri- phosphate (RBV-TP) concentrations in peripheral blood mononuclear cells (PBMCs) and red blood cells, and (4) develop a population PK-pharmacodynamic model to investigate the response and toxicity relationships relative to systemic and intracellular ribavirin exposures. Forty, previously treatment-na¿ve HCV genotype 1 patients, initiating peginterferon alfa 2a and ribavirin will be stratified on weight, degree of liver damage, and race and randomized to 2 groups: standard weight-based ribavirin dosing or concentration-guided ribavirin dosing. If we find that concentration-controlled therapy can maintain concentrations within a target range and that it appears safe and effective, then this strategy can be explored in other populations including non- responders, those with HCV recurrence following liver transplantation, and/or patients with HIV/HCV coinfection. We can also apply this "proof of concept" concentration-controlled strategy to other compounds including peginterferon and the HCV protease and polymerase inhibitors. This study is consistent with a long-term research goal of NIDDK to "evaluate new approaches to therapy for all forms of viral hepatitis." PUBLIC HEALTH RELEVANCE: Millions of people around the world will develop hepatic complications from chronic HCV infection and our current therapies are inadequate because of their high incidence of adverse effects and suboptimal chances for therapeutic success. Concentration-controlled ribavirin dosing may be the novel therapeutic strategy that helps each patient find the balance between minimizing toxicities and maximizing virologic response.

描述（由申请人提供）： Kiser博士的整体职业目标是制定一项独立的研究计划，专门研究临床药理学研究以治疗病毒肝炎。由于当前疗法的反应率较差，并且需要研究最佳剂量以及药物与新化合物相互作用的潜力，因此迫切需要慢性丙型肝炎病毒（HCV）的药理学研究。通过提出的研究，候选人将使用药代动力学（PK）指导利巴韦林的剂量决策，生成有关细胞内利巴韦林浓度的初步数据，并在使用新的HCV剂的研究中毒化以将PK技术应用于研究。 The specific aims for the study are to (1) demonstrate that concentration-controlled ribavirin dose can achieve a targeted level of plasma exposure with reduced variability in the steady-state area-under-the-concentration-time curve compared with standard weight-based ribavirin dosing, (2) evaluate the safety and efficiency of concentration-controlled versus standard weight-based ribavirin therapy, (3) quantify the intracellular ribavirin单（RBV-MP），DI-（RBV-DP）和三磷酸（RBV-TP）浓度在外周血单核细胞（PBMC）和红细胞中的浓度，以及（4）开发群体PK-PHARMACINAGINAL模型，以研究相对于系统性和内部依然依然依然依然依次的响应和毒性关系。 40例先前治疗的人 - VE HCV基因型1患者，启动Peginterferon alfa 2a和利巴韦林将根据体重，肝脏损伤程度和种族分层，并随机分为2组：基于标准的基于体重的利巴韦林给药或浓度引导的利巴韦林剂量。如果我们发现浓度控制的治疗可以在目标范围内保持浓度，并且看起来安全有效，那么可以在包括非反应器（包括非反应者）的其他人群中探索该策略，肝移植后具有HCV复发的患者和/或HIV/HCV共感染患者。我们还可以将此“概念证明”浓度控制的策略应用于其他化合物，包括Peginterferon和HCV蛋白酶和聚合酶抑制剂。这项研究与NIDDK的长期研究目标一致，即“评估各种形式的病毒肝炎的新方法”。 公共卫生相关性：世界各地数以百万计的人会从慢性HCV感染中发展出肝病并发症，并且我们当前的疗法不足，因为他们对治疗成功的不良反应和次优的机会。浓度控制的利巴韦林给药可能是一种新型的治疗策略，可以帮助每个患者找到最小化毒性和最大化病毒学反应之间的平衡。