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

描述（由申请人提供）： 博士Kiser的总体职业目标是开发一个独立的研究项目，专门研究临床药理学研究在病毒性肝炎治疗中的应用。慢性丙型肝炎病毒（HCV）的药理学研究是迫切需要的，因为目前的治疗反应率低，需要研究最佳剂量和与新化合物的药物相互作用的潜力。通过拟议的研究，候选人将使用药代动力学（PK）来指导利巴韦林的给药决策，生成细胞内利巴韦林浓度的初步数据，并准备将PK技术应用于新HCV药物的研究。该研究的具体目的是（1）证明与基于标准体重的利巴韦林给药相比，浓度控制的利巴韦林给药可以实现血浆暴露的目标水平，同时稳态浓度-时间曲线下面积的变异性降低，（2）评价浓度控制的利巴韦林治疗相对于基于标准体重的利巴韦林治疗的安全性和功效，（3）定量外周血单核细胞（PBMC）和红细胞中的细胞内利巴韦林单磷酸（RBV-MP）、二磷酸（RBV-DP）和三磷酸（RBV-TP）浓度，（4）建立群体PK-药效学模型，以研究相对于全身和细胞内利巴韦林暴露的反应和毒性关系。40例既往未接受过治疗的HCV基因型1患者，开始使用聚乙二醇干扰素α 2a和利巴韦林，将根据体重、肝损伤程度和种族进行分层，并随机分为2组：标准体重利巴韦林给药或浓度指导的利巴韦林给药。如果我们发现浓度控制治疗可以将浓度维持在目标范围内，并且似乎安全有效，则可以在其他人群中探索该策略，包括无应答者、肝移植后HCV复发患者和/或HIV/HCV合并感染患者。我们还可以将这种“概念验证”浓度控制策略应用于其他化合物，包括聚乙二醇干扰素和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“评估治疗所有形式病毒性肝炎的新方法”。" 公共卫生相关性：全世界有数百万人将因慢性HCV感染而发生肝脏并发症，而我们目前的治疗方法是不充分的，因为它们的不良反应发生率高，治疗成功的机会不佳。浓度控制的利巴韦林给药可能是一种新的治疗策略，可以帮助每个患者找到最小化毒性和最大化病毒学应答之间的平衡。

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.