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）：

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.