Population Pharmacokinetics and Pharmacodynamics of Ribavirin in Patients with Chronic Hepatitis C Genotype 1 Infection
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AbstractWe report a population pharmacokinetic (PK) and pharmacodynamic (PD) model of orally administered ribavirin in patients with chronic hepatitis C virus (HCV) infection enrolled in a multicenter clinical trial, including the estimation of covariate effects on ribavirin PK parameters and sustained viral response (SVR). Ribavirin concentrations obtained from 144 patients, consisting of n=71 African American (AA) and n=73 Caucasian Americans (CA), during 24 weeks of therapy were best described by a twocompartment model with first-order absorption and elimination parameterized in terms of apparent oral clearance (CL/F), apparent central volume (Vc/F), apparent peripheral volume (Vp/F), and apparent intercompartmental clearance (Q/F). The typical population parameters were CL/F (19.0 L/h), Vc/F (1,130 L), Vp/F (4,020 L), andQ/F (38.6). The Vp/F was approximately 50% greater inAAcompared to CA. Significant covariates in the SVR model included IL-28B genotype, homeostasis model assessment of insulin resistance, and ribavirin exposure during the first week (AUC0−7). The population PK and logistic regression models both described the observed ribavirin concentration data and SVR data well. These findings suggest that optimization of ribavirin plasma concentrations during the first week of ribavirin dosing is most critical in AA patients in order to increase the rate of SVR, especially those with the IL-28B TT genotype.
DescriptionThis work was presented at the 2010 American College of Clinical Pharmacology 39th Annual Meeting and received the 2010 Wayne A. Colburn Memorial Award (RJ). Author affiliations: 1 School of Pharmacy, University of Maryland, 20 N. Pine St, PH N413, Baltimore, Maryland 21201, USA. 2 GlaxoSmithKline, King of Prussia, Pennsylvania, USA. 3 Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA. 4 School of Medicine, University of Maryland, Baltimore, Maryland, USA. 5 To whom correspondence
CitationJin, R., Fossler, M. J., McHutchison, J. G., Howell, C. D., & Dowling, T. C. (2012). Population Pharmacokinetics and Pharmacodynamics of Ribavirin in Patients with Chronic Hepatitis C Genotype 1 Infection. AAPS Journal, 14(3), 571-580, DOI: 10.1208/s12248-012-9368-z.
Hepatitis C, Chronic--metabolism
Hepatitis C, Chronic--drug therapy
Hepatitis C, Chronic--virology
Area Under Curve
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/2336