Population pharmacokinetics and pharmacodynamics of ribavirin in patients with chronic hepatitis C genotype 1 infection.
ABSTRACT We 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 two-compartment 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), and Q/F (38.6). The Vp/F was approximately 50% greater in AA compared 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 (AUC(0-7)). 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.
Full-textDOI: · Available from: Michael J Fossler, May 29, 2015
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ABSTRACT: The application of pharmacometric principles to the treatment of infectious diseases must address important biological issues across the diversity of pathogenic organisms. Recent applications of pharmacometric tools in this therapeutic area have had important translational impact not only in drug development but on real-world clinical practice. The fruitful fusion of preclinical and population methodologies promises increasingly personalized and mechanistic approaches.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e70; doi:10.1038/psp.2013.46; published online 28 August 2013.08/2013; 2(8):e70. DOI:10.1038/psp.2013.46
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ABSTRACT: Ribavirin, a guanosine analog, is a broad spectrum antiviral agent. Ribavirin has been a fundamental component of the treatment of hepatitis C virus (HCV) for decades, but there is a very limited understanding of the clinical pharmacology of this drug. Furthermore, it is associated with a major dose-limiting toxicity, hemolytic anemia. Ribavirin undergoes intracellular phosphorylation by host enzymes to a mono- (RMP), di- (RDP), and triphosphate (RTP). The intracellular forms have been associated with antiviral and toxic effects in vitro, but the kinetics of these phosphorylated moieties have not been fully elucidated in vivo. We developed a model to characterize the plasma pharmacokinetics of ribavirin, and the difference between intracellular phosphorylation kinetics in red cells (anucleated) vs. peripheral blood mononuclear cells (nucleated). A time-independent 2-compartment model with first-order absorption described the plasma data well. Cellular phosphorylation kinetics was described by a 1-compartment model for RMP, with formation rate driven by plasma concentrations and first-order degradation rate. RDP and RTP were in rapid equilibrium with RMP. Concomitant telaprevir use, inosine triphosphatase genetics, creatinine clearance, weight and sex were significant covariates. The terminal ribavirin half-life in plasma and phosphorylated anabolites in cells was approximately 224 hours. We found no evidence of time-dependent kinetics. These data provide a foundation for uncovering concentration-effect associations for ribavirin and determining the optimal dose and duration of this drug for use in combination with newer direct-acting HCV agents. (NCT01097395). Copyright © 2015, American Society for Microbiology. All Rights Reserved.Antimicrobial Agents and Chemotherapy 02/2015; 59(4). DOI:10.1128/AAC.04618-14 · 4.45 Impact Factor
Journal of Hepatology 12/2012; DOI:10.1016/j.jhep.2012.12.004 · 10.40 Impact Factor