Download PDF
Semin Liver Dis 2003; 23: 013-018
DOI: 10.1055/s-2003-41630
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Modeling Viral and Drug Kinetics: Hepatitis C Virus Treatment with Pegylated Interferon Alfa-2b

Kimberly A. Powers1 , Narendra M. Dixit1 , Ruy M. Ribeiro1,2 , Preeti Golia3 , Andrew H. Talal3 , Alan S. Perelson1
  • 1Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico
  • 2Current address: Department of Zoology, University of Oxford, Oxford, United Kingdom
  • 3Department of Medicine and Center for the Study of Hepatitis C, Weill Medical College of Cornell University, New York, New York
Further Information

Publication History

Publication Date:
21 August 2003 (online)

    Permissions and Reprints

ABSTRACT

Administration of peginterferon alfa-2b plus ribavirin results in an early hepatitis C virus (HCV) RNA decay followed by an increase as the drug concentration declines between doses. Upon administration of the next dose 1 week later, the same pattern is observed. We have incorporated pharmacokinetic/pharmacodynamic analysis into a model of viral dynamics to describe the effect that changes in drug concentration and effectiveness can have on viral levels. To illustrate the relationship between pharmacokinetics and viral dynamics, we fit the model to data from four HCV/human immunodeficiency virus co-infected patients, and obtained good agreement with the measured serum HCV RNA levels. We were able to account for the observed increases in HCV RNA, and estimate virion and drug half-lives that are in agreement with previous reports. Models incorporating pharmacokinetics are needed to correctly interpret viral load changes and estimate drug effectiveness in treatment protocols using peginterferon alfa-2b.

KEYWORDS

PEG-IFN - pharmacokinetics - modeling - HCV - viral dynamics

REFERENCES

  • 1 Glue P, Fang J W, Rouzier-Panis R. et al . Pegylated interferon-alpha 2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group.  Clin Pharmacol Ther . 2000;  68 556-567
    PubMedGoogle Scholar
  • 2 Lindsay K L, Trepo C, Heintges T. et al . A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C.  Hepatology . 2001;  34 395-403
    CrossrefPubMedGoogle Scholar
  • 3 Formann E, Jessner W, Bennett L, Ferenci P. Twice-weekly administration of peginterferon alfa-2b PEG-Intron (12kD) improves viral kinetics in patients with HCV genotype 1 (Abstract 502).  Hepatology . 2002;  36 288A
    PubMedGoogle Scholar
  • 4 Neumann A U, Lam N P, Dahari H. et al . Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy.  Science . 1998;  282 103-107
    CrossrefPubMedGoogle Scholar
  • 5 Neumann A U, Lam N P, Dahari H. et al . Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus.  J Infect Dis . 2000;  182 28-35
    CrossrefPubMedGoogle Scholar
  • 6 Rosen H R, Ribeiro R R, Weinberger L. et al . Early hepatitis C viral kinetics correlate with long-term outcome in patients receiving high dose induction followed by combination interferon and ribavirin therapy.  J Hepatol . 2002;  37 124-130
    CrossrefPubMedGoogle Scholar
  • 7 Zeuzem S, Schmidt J M, Lee J H, Ruster B, Roth W K. Effect of interferon alfa on the dynamics of hepatitis C virus turnover in vivo.  Hepatology . 1996;  23 366-371
    PubMedGoogle Scholar
  • 8 Zeuzem S, Herrmann E, Lee J H. et al . Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha-2a.  Gastroenterology . 2001;  120 1438-1447
    PubMedGoogle Scholar
  • 9 Gabrielsson J, Weiner D. Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts & Application. Stockholm: Swedish Pharmaceutical Press 2000
    Google Scholar
      >