A Dose-Ranging Study of Pegylated Interferon Alfa-2b and... : Hepatology (original) (raw)

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A Dose-Ranging Study of Pegylated Interferon Alfa-2b and Ribavirin in Chronic Hepatitis C

Glue, Paul M.D., Ph.D.*,1; Rouzier-Panis, Regine2; Raffanel, Claude3; Sabo, Ron1; Gupta, Samir K.1; Salfi, Margaret1; Jacobs, Shiela1; Clement, Robert P.1

1Schering-Plough Research Institute, Kenilworth, NJ

2Centre CAP, Montpellier, France

3Hopital Caremeau, Nimes, France

E-mail:[email protected]

*Address reprint requests to: Schering-Plough Research Institute, K-15-4455, 2015 Galloping Hill Rd, Kenilworth, NJ 07033. fax: 908-740-2169.

Received April 26, 2000; Accepted June 29, 2000; previously published online December 30, 2003

Abstract

The objectives of this study were to assess the safety, pharmacokinetics, and efficacy of pegylated interferon alfa-2b (PEG-Intron) plus ribavirin in patients with chronic hepatitis C. A total of 72 patients (35 men/37 women, age range 20-68 years) with clinically compensated chronic hepatitis C virus (HCV) were enrolled into this open-label, randomized, active controlled study. Patients received either PEG-Intron 0.35, 0.7, or 1.4 μg/kg subcutaneously weekly for 24 weeks alone, or in combination with ribavirin 600, 800, or 1,000 to 1,200 mg orally daily. Patients were evaluated during treatment and after a 24-week follow-up period for safety and efficacy. Detailed pharmacokinetic assessments were performed at weeks 1 and 4. PEG-Intron alone produced expected dose-related reductions in white cells, neutrophils and platelets. Addition of ribavirin reduced hemoglobin levels in a dose-related manner, did not further reduce PEG-Intron-induced decreases in neutrophil or white cell count, and increased platelet counts. Neutrophil function tests (C5a and FMLP migration, killing curves) were unaltered. Reported adverse events (flu-like symptoms, asthenia) were qualitatively similar in all dose groups. Anti-HCV activity, as measured by loss of detectable serum HCV RNA (i.e. <100 copies/mL) at the end of treatment (week 24) and after 24 weeks of follow-up (week 48) showed dose-response trends for PEG-Intron. At each PEG-Intron dose level, anti-HCV activity was higher in patients coadministered ribavirin than in patients treated with PEG-Intron monotherapy. There was no evidence of pharmacokinetic interactions with either drug. We conclude that the safety and tolerability of combined PEG-Intron/ribavirin and PEG-Intron alone were comparable. Combined PEG-Intron/ribavirin showed dose-related synergistic anti-HCV effects, which were numerically superior to those obtained with PEG-Intron monotherapy.

(Hepatology 2000;32:647-653.)