Pharmacokinetics of ribavirin in combined interferon-alpha 2b and ribavirin therapy for chronic hepatitis C virus infection.
OBJECTIVE
The aim of this study was to clarify the pharmacokinetics of ribavirin and interferon-alpha (IFN-alpha) 2b when administered in combination for 24 weeks and effects of pharmacokinetics of both on treatment outcome in chronic hepatitis C with genotype 1b and high viral load.


METHODS
In this multicentre open study, 27 patients received 2-week daily induction therapy followed by 22-week, three-times-a-week maintenance therapy of intramuscular IFN-alpha 2b at a dose of 6 million units and oral ribavirin at 400 mg twice daily for 24 weeks, and followed up for 24 weeks post-treatment. Single- and multiple-dose pharmacokinetic studies were assessed by serial measurements of serum concentrations of both compounds at weeks 1 and 24.


RESULTS
Five patients attained sustained virological response. Serum ribavirin concentrations asymptoted after 4-8 weeks of treatment in all patients. The steady-state concentration correlated significantly with serum ribavirin clearance after multiple dosing (r = -0.875; 95% CI -0.932, -0.721; P < 0.001). Serum concentrations at weeks 4 and 8, Cmax and AUC(0,12 h) after multiple dosing and AUC(0,28 weeks) of ribavirin were significantly higher in sustained virological responders than in virological responders or nonresponders (P < 0.05, each). Increased Cmax and accumulation index of AUC(0,12 h) (median 10.5; 95% CI 6.4, 12.4), and prolonged washout half-life after multiple dosing reflected accumulation and slow clearance of ribavirin from the tissue compartments.


CONCLUSIONS
Continuous exposure and accumulation of ribavirin may be necessary for sustained virological response to combination therapy in chronic hepatitis C with genotype 1b and high viral load.
Tsubota
Akihito
A
Department of Gastroenterology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan. zua05135@nifty.com
Hirose
Yuichi
Y
Izumi
Namiki
N
Kumada
Hiromitsu
H
D000328:Adult; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D012254:Ribavirin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin