Population Pharmacokinetic Modeling of Plasma and Intracellular Ribavirin Concentrations in Patients with Chronic Hepatitis C Virus Infection

Abstract

e 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.) R ibavirin (1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a nucleoside analog first synthesized in 1972, exhibits broad-spectrum antiviral activity against several RNA and DNA viruses in vitro (1, 2). For several decades, ribavirin was combined with pegylated interferon alpha (Peg-IFN-␣) as the standard of care for treating chronic hepatitis C virus (HCV) infections. Though several directacting antiviral agents have recently been approved for the treatment of HCV and dozens more are in various stages of clinical development, ribavirin remains an important component of several HCV treatment regimens (3-7).Ribavirin's mechanism of antiviral action is not completely understood. In vitro, ribavirin has been shown to mimic the endogenous nucleoside guanosine, and its triphosphate anabolite (ribavirin triphosphate [RTP]) may be incorporated into replicating RNA strands by viral RNA polymerases. This erroneous incorporation inhibits chain elongation and viral replication. Other antiviral effects observed in vitro include immunologic modulation through switching the T-cell phenotype from phenotype 2 to phenotype 1, inhibition of host IMP dehydrogenase leading to depletion of intracellular GTP pools, induction o...

Population pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin in hepatitis C virus genotype 1 infection: analysis of six phase III trials

“…This analysis showed that ribavirin coadministration did not affect the pharmacokinetics of any of the DAAs in HCV genotype 1‐infected subjects, as ribavirin was not identified as a covariate in any of the analyses. Ribavirin values of clearance and volume parameters estimated from the population pharmacokinetic analysis were in close agreement with those reported in the population pharmacokinetic analysis of phase Ib and II studies of the 3D regimen and in the literature , suggesting that the pharmacokinetics of ribavirin were not altered when coadministered with the 3D regimen. The weight‐based ribavirin dosing used in the clinical trials that contributed to the present analysis provided consistent exposures across the various covariates.…”

A LC-MS/MS Method for Quantifying Adenosine, Guanosine and Inosine Nucleotides in Human Cells

“…As such, there is less need for high concentrations of these molecules and so the quantities are lower compared to PBMCs. Additionally, the MP is the rate limiting step to become the TP, and higher TP is favored when nucleotide pools are at equilibrium (23, 30). The exception to this would be IMP in PBMCs since it is an important molecule for the production of other nucleotides via the de novo synthesis pathway in nucleated cells.…”

“…Clinical samples (PBMCs, RBCs and DBS) were obtained from 36 hepatitis C-infected individuals participating in an IRB-approved study of ribavirin (RBV) pharmacokinetics (23). All patients provided written informed consent.…”

Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels

“…We had previously identified higher RBV‐TP concentrations in individuals with variant ITPA phenotypes in 2 smaller studies but wished to confirm this association in a larger cohort of patients with a greater number of individuals with variant ITPA phenotypes. Studying a larger population allowed for an analysis of 4 different ITPA activity phenotype groups (ie, 100%, 60%, 30%, and ≤10%) rather than simply 100% activity vs less than 100% activity.…”

“…However, ITPA‐deficient individuals appear to have a similar rate of SVR as nondeficient individuals despite this potential decrease in RBV‐TP . There are limited data on the association between ITPA genetics and RBV pharmacokinetics – . Because RBV is an analogue for adenosine and guanosine and is phosphorylated to active RBV‐TP in the cell, it is likely that ITPA activity will have an effect on its intracellular pharmacology.…”