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

描述(由申请人提供)： Kiser博士的整个职业目标是开发一个独立的研究计划，专门将临床药理学研究应用于病毒性肝炎的治疗。慢性丙型肝炎病毒(HCV)的药理学研究迫在眉睫，因为目前治疗的应答率很低，而且需要研究最佳剂量和药物与新化合物相互作用的可能性。通过拟议的研究，候选人将使用药代动力学(PK)来指导利巴韦林的剂量决定，产生关于细胞内利巴韦林浓度的初步数据，并准备将PK技术应用于新的丙型肝炎病毒制剂的研究。这项研究的具体目的是(1)证明与基于标准重量的利巴韦林剂量相比，浓度控制的利巴韦林剂量可以达到目标水平的血浆暴露，并且与基于标准重量的利巴韦林剂量相比，在稳态面积-浓度-时间曲线上的变异性减少，(2)评估浓度控制与基于标准重量的利巴韦林治疗的安全性和有效性，(3)定量外周血单核细胞(PBMC)和红细胞中的利巴韦林单(RBV-MP)、二(RBV-DP)和三磷酸(RBV-TP)的浓度，(4)建立群体PK-药效学模型，研究利巴韦林全身和细胞内暴露的反应和毒性关系。40名之前接受治疗的丙型肝炎病毒1型患者，开始使用聚乙二醇化干扰素α2a和利巴韦林，将根据体重、肝损害程度和种族进行分层，并随机分为两组：标准重量利巴韦林剂量或浓度引导利巴韦林剂量。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，并且看起来安全有效，那么这一策略可以在其他人群中探索，包括无应答者、肝移植后丙型肝炎复发的患者和/或艾滋病毒/丙型肝炎病毒合并感染的患者。我们也可以将这种“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丙型肝炎病毒蛋白水解酶和聚合酶抑制剂。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：全球数百万人将因慢性丙型肝炎病毒感染而出现肝脏并发症，我们目前的治疗方法不够充分，因为它们的不良反应发生率高，治疗成功的机会不佳。浓度控制利巴韦林剂量可能是一种新的治疗策略，可以帮助每个患者在最小化毒性和最大化病毒学反应之间找到平衡。

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.