The AAPS Journal

, Volume 14, Issue 3, pp 571–580

Population Pharmacokinetics and Pharmacodynamics of Ribavirin in Patients with Chronic Hepatitis C Genotype 1 Infection

  • Runyan Jin
  • Michael J. Fossler
  • John G. McHutchison
  • Charles D. Howell
  • Thomas C. Dowling
Research Article

DOI: 10.1208/s12248-012-9368-z

Cite this article as:
Jin, R., Fossler, M.J., McHutchison, J.G. et al. AAPS J (2012) 14: 571. doi:10.1208/s12248-012-9368-z

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 (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.

KEY WORDS

hepatitis C pharmacodynamics population pharmacokinetics ribavirin 

Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  • Runyan Jin
    • 1
  • Michael J. Fossler
    • 2
  • John G. McHutchison
    • 3
  • Charles D. Howell
    • 4
  • Thomas C. Dowling
    • 1
  1. 1.School of PharmacyUniversity of MarylandBaltimoreUSA
  2. 2.GlaxoSmithKlineKing of PrussiaUSA
  3. 3.Duke Clinical Research InstituteDuke UniversityDurhamUSA
  4. 4.School of MedicineUniversity of MarylandBaltimoreUSA