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: 8465222
• 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/8465222
• 关键词: Adverse effects; Area; Chronic; Chronic Hepatitis C; Clinical Pharmacology; Data; Development; Disease; Dose; Drug Interactions; Drug Kinetics; Drug Targeting; Drug resistance; Effectiveness; Equilibrium; Erythrocytes; Genotype; Goals; HIV; Hemolytic Anemia; Hepatic; Hepatitis; Hepatitis C virus; Incidence; Justice; Lead; 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 injury; liver transplantation; novel strategies; novel therapeutics; nucleoside analog; peginterferon alfa-2a; pharmacodynamic model; programs; public health relevance; 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."

描述（由申请人提供）： Kiser 博士的总体职业目标是开发一个独立的研究项目，专门从事临床药理学研究在病毒性肝炎治疗中的应用。由于当前疗法的反应率较差，因此迫切需要对慢性丙型肝炎病毒 (HCV) 进行药理学研究。以及需要研究最佳剂量以及与新化合物的药物相互作用的潜力。通过提出的研究，候选人将使用药代动力学（PK）来指导利巴韦林的剂量决策，生成细胞内利巴韦林的初步数据。浓度，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) 证明浓度控制的利巴韦林剂量可以达到血浆暴露的目标水平，同时减少稳态的变异性。与基于标准体重的利巴韦林给药相比，浓度-时间曲线下面积，(2) 评估浓度控制的利巴韦林治疗与基于标准体重的利巴韦林治疗的安全性和有效性，(3) 量化细胞内利巴韦林单剂量外周血单核细胞 (PBMC) 和红细胞中的 (RBV-MP)、二磷酸 (RBV-DP) 和三磷酸 (RBV-TP) 浓度，以及 (4) 开发群体 PK 药效模型来研究与全身和细胞内利巴韦林暴露相关的反应和毒性关系。开始使用聚乙二醇干扰素 α 2a 和利巴韦林的 HCV 基因型 1 患者将根据体重、肝损伤程度和种族进行分层，并随机分为 2 组：基于体重的标准利巴韦林剂量或浓度指导的利巴韦林剂量。控制疗法可以将浓度维持在目标范围内，并且看起来安全有效，那么可以在其他人群中探索该策略，包括无反应者、肝病后 HCV 复发的人群我们还可以将这种“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以及 HCV 蛋白酶和聚合酶抑制剂。这项研究与长期研究目标一致。 NIDDK 的“评估所有形式病毒性肝炎的新治疗方法”。

项目成果

Intrahepatic antiviral quantification in a patient undergoing orthotopic cadaveric liver transplantation.

接受原位尸体肝移植的患者的肝内抗病毒定量。

• DOI: 10.1093/jac/dku334
• 发表时间: 2015
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Moorehead,KaitlynJ;BurtonJr,JamesR;Everson,GregoryT;Zheng,Jia-Hua;Kerr,BeckyJo;Bushman,LaneR;Wang,Meng;Ju,Cynthia;Nydam,Trevor;Kiser,JenniferJ
• 通讯作者: Kiser,JenniferJ

Review and management of drug interactions with boceprevir and telaprevir.

• DOI: 10.1002/hep.25653
• 发表时间: 2012-05
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Kiser, Jennifer J.;Burton, James R.;Anderson, Peter L.;Everson, Gregory T.
• 通讯作者: Everson, Gregory T.

Validation of a sensitive LC/MS/MS method for the determination of telaprevir and its R-isomer in human plasma.

验证用于测定人血浆中特拉匹韦及其 R 异构体的灵敏 LC/MS/MS 方法。

• DOI: 10.1002/bmc.3211
• 发表时间: 2014
• 期刊: Biomedical chromatography : BMC
• 作者: Chen,Xinhui;Bushman,LaneR;McAllister,KevinJ;Anderson,PeterL;Kiser,JenniferJ
• 通讯作者: Kiser,JenniferJ

Development and validation of a dried blood spot assay for the quantification of ribavirin using liquid chromatography coupled to mass spectrometry.

• DOI: 10.1016/j.jchromb.2013.10.035
• 发表时间: 2014-01-01
• 期刊: JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
• 影响因子: 3
• 作者: Jimmerson, Leah C.;Zheng, Jia-Hua;Bushman, Lane R.;MacBrayne, Christine E.;Anderson, Peter L.;Kiser, Jennifer J.
• 通讯作者: Kiser, Jennifer J.