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Population pharmacokinetic modeling of plasma and intracellular ribavirin concentrations in patients with chronic hepatitis C virus infection.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2015 Apr; Vol. 59 (4), pp. 2179-88. Date of Electronic Publication: 2015 Feb 02. - Publication Year :
- 2015
-
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) infection 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 ribavirin monophosphate (RMP), ribavirin diphosphate (RDP), and ribavirin 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 (nonnucleated) and in peripheral blood mononuclear cells (nucleated). A time-independent two-compartment model with first-order absorption described the plasma data well. The cellular phosphorylation kinetics was described by a one-compartment model for RMP, with the formation rate driven by plasma concentrations and the first-order degradation rate. RDP and RTP rapidly reached 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 h. 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. (This study has been registered at ClinicalTrials.gov under registration no. NCT01097395.).<br /> (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- Adult
Antiviral Agents blood
Antiviral Agents therapeutic use
Body Weight
Erythrocytes metabolism
Female
Half-Life
Hepatitis C, Chronic drug therapy
Hepatitis C, Chronic genetics
Humans
Liver Function Tests
Male
Middle Aged
Models, Statistical
Oligopeptides therapeutic use
Phosphorylation
Population
Ribavirin blood
Ribavirin therapeutic use
Sex Characteristics
Antiviral Agents pharmacokinetics
Hepatitis C, Chronic blood
Ribavirin pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 59
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 25645847
- Full Text :
- https://doi.org/10.1128/AAC.04618-14