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."
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.
|Wu, L S; Jimmerson, L C; MacBrayne, C E et al. (2016) Modeling Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C Virus. CPT Pharmacometrics Syst Pharmacol 5:65-73|
|Wu, Liviawati S; Rower, Joseph E; Burton Jr, James R et al. (2015) Population pharmacokinetic modeling of plasma and intracellular ribavirin concentrations in patients with chronic hepatitis C virus infection. Antimicrob Agents Chemother 59:2179-88|
|Jimmerson, Leah C; Ray, Michelle L; Bushman, Lane R et al. (2015) Measurement of intracellular ribavirin mono-, di- and triphosphate using solid phase extraction and LC-MS/MS quantification. J Chromatogr B Analyt Technol Biomed Life Sci 978-979:163-72|
|Moorehead, Kaitlyn J; Burton Jr, James R; Everson, Gregory T et al. (2015) Intrahepatic antiviral quantification in a patient undergoing orthotopic cadaveric liver transplantation. J Antimicrob Chemother 70:315-7|
|Jimmerson, Leah C; Zheng, Jia-Hua; Bushman, Lane R et al. (2014) Development and validation of a dried blood spot assay for the quantification of ribavirin using liquid chromatography coupled to mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 944:18-24|
|Chen, Xinhui; Bushman, Lane R; McAllister, Kevin J et al. (2014) Validation of a sensitive LC/MS/MS method for the determination of telaprevir and its R-isomer in human plasma. Biomed Chromatogr 28:1714-21|
|Kiser, Jennifer J; Flexner, Charles (2013) Direct-acting antiviral agents for hepatitis C virus infection. Annu Rev Pharmacol Toxicol 53:427-49|
|Kiser, Jennifer J; Burton, James R; Anderson, Peter L et al. (2012) Review and management of drug interactions with boceprevir and telaprevir. Hepatology 55:1620-8|