Improved pharmacodynamics and pharmacokinetics after i.v. application of peginterferon alfa-2a in hepatitis C null responders.

Abstract

BACKGROUND & AIM:

Mechanisms of non-responsiveness to peginterferon alfa-2a are not completely understood. Inadequate plasma levels may contribute to reduced response. The aim of this prospective, multicentre, crossover, Phase 1 study was to evaluate the pharmacokinetics and viral kinetics of intravenous vs. subcutaneous peginterferon alfa-2a in patients with genotype 1 chronic hepatitis C infection who showed null response to previous peginterferon/ribavirin.

METHODS:

Patients were randomized in four treatment arms to subcutaneous or intravenous peginterferon alfa-2a 180 μg, once or twice weekly for 2 weeks. After a washout phase of 6 weeks, patients first receiving intravenous administration switched to subcutaneous or vice versa for additional 2 weeks.

RESULTS:

Intravenous administration of pegylated interferon resulted in a stronger and faster decline in HCV RNA than subcutaneous administration with a maximum decline of 1.17 log10 vs. 0.41 log10 or 1.32 log10 vs. 0.54 log10 after a once or twice weekly application, respectively. Pharmacokinetic studies revealed significantly higher maximum concentration (C(max))(0-12) h and C(max 0-7) d following intravenous administration, irrespective of dosing frequency A rapid rebound in HCV RNA was observed in all treatment arms. Adverse events occurred more frequently following intravenous administration.

CONCLUSION:

Intravenous administration of peginterferon alfa-2a results in considerably higher plasma concentration and a stronger decline in HCV RNA and offers an interesting approach in order to overcome interferon non-responsive state in patients with full null response to previous peginterferon/ribavirin combination therapy.

• Authors: Balazs Fülöp, Michael Biermer, Markus Cornberg, Heiner Wedemeyer, Kerstin Port, Renate Heyne, Stefan Zeuzem, Kai-Henrik Peiffer, Tania Welzel, Adam Herber, Peter Buggisch, Christoph Moser, Sabine Stoll, Ulrich Alshuth, Thomas Berg
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 35 Issue 10 Pg. 2275-84 (Oct 2015) ISSN: 1478-3231 [Electronic] United States
• PMID: 25801095 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Antiviral Agents
• Interferon-alpha
• RNA, Viral
• Recombinant Proteins
• Polyethylene Glycols
• peginterferon alfa-2a

Topics

• Aged
• Antiviral Agents (adverse effects, pharmacokinetics)
• Cross-Over Studies
• Drug Administration Schedule
• Female
• Genotype
• Hepacivirus (genetics)
• Hepatitis C, Chronic (drug therapy)
• Humans
• Injections, Intravenous
• Interferon-alpha (adverse effects, pharmacokinetics)
• Male
• Middle Aged
• Polyethylene Glycols (adverse effects, pharmacokinetics)
• Prospective Studies
• RNA, Viral (blood)
• Recombinant Proteins (adverse effects, pharmacokinetics)
• Treatment Outcome
• Viral Load (drug effects)