Pharmacokinetics of ribavirin in combined interferon-alpha 2b and ribavirin therapy for chronic hepatitis C virus infection |
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| Authors: | Tsubota Akihito Hirose Yuichi Izumi Namiki Kumada Hiromitsu |
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| Affiliation: | 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 |
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| Abstract: | AIMS: 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. |
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| Keywords: | chronic hepatitis C genotype 1b high viral load interferon alpha 2b pharmacokinetics ribavirin |
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