Population pharmacokinetic modeling of plasma and intracellular ribavirin concentrations in patients with chronic hepatitis C virus infection

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.).

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Composite model describing the plasma PK of ribavirin as well as its intracellular kinetics in both RBCs and PBMCs. CLt: total clearance. Vc: central compartment volume of distribution. CLd: distributional clearance. Vp: peripheral compartment volume of distribution. ka: absorption rate constant. kmp: transport/formation rate constant for ribavirin monophosphate (RMP). kmpout: rate constant for the disappearance of phosphorylated ribavirin. Rdpmp: rapid equilibrium partition coefficient between ribavirin diphosphate (RDP) and RMP. Rtpdp: rapid equilibrium partition coefficient between ribavirin triphosphate (RTP) and RDP.

FIG 2

(a) Means and standard errors of ribavirin concentration-time profiles at day 1 and the steady state with and without telaprevir coadministration, overlaid with the mean of the model predictions. Black circles: dual therapy (Peg–IFN-α–2a and ribavirin). Black triangles: triple therapy (Peg–IFN-α–2a, ribavirin, and telaprevir). Solid and dashed lines: mean individual predictions for dual therapy and triple therapy, respectively. (b) Goodness-of-fit plots of the final plasma PK model. Top left: observed plasma ribavirin versus population prediction. Top right: observed plasma ribavirin versus individual prediction. Bottom left: standardized residuals versus individual prediction. Bottom right: standardized residuals versus time. (c) Visual predictive check overlaying plasma ribavirin concentration-time profiles at day 1 and the steady state (weeks 9 to 13) with simulation. Left: day 1. Right: steady state (weeks 9 to 13). Gray shaded areas and dashed lines: median and 90% prediction intervals of the median, 5th and 95th percentiles of the simulated profiles. Solid lines: median and 5th and 95th percentiles of the observed concentrations. Open circles: observed data points.

FIG 3

(a) Observed intracellular data overlaid with the medians (solid lines) and 90% prediction intervals (gray-shaded area) for RMP (left), RDP (middle), and RTP (right) concentration-time profiles in PBMCs (top panels) and RBCs (bottom panels). Gray circles represent the data observed within 12 h postdose at different visits. D1: day 1. W1: week 1. W2: week 2. W4: week 4. SS: steady state (weeks 9 to 13). W16: week 16. W24: week 24. W48: week 48. (b) Simulation of ribavirin plasma and intracellular concentrations after a single dose, at the steady state, and during washout, based on the typical population parameter values. Data points represent the concentrations observed after the last administered ribavirin dose (solid circles = RMP, open triangles = RDP, solid squares = RTP).