Pharmacokinetics of ribavirin in combined interferon-alpha 2b and ribavirin therapy for chronic hepatitis C virus infection

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.

Figures

Figure 1

Mean ribavirin concentration–time profiles in the initial single-dose (a) and final multiple-dose (b) studies and steady-state phase (c) in patients treated with interferon-alpha 2b plus ribavirin combination therapy. —, Patients with sustained virological response; —, those with virological response during treatment, but without sustained virological response after cessation of treatment; ·····, patients without virological response throughout the study period.

Figure 2

Correlation between apparent serum clearance of ribavirin following multiple dosing (CLss/F) and serum ribavirin concentration at steady-state phase. ○, Patients with sustained virological response; Δ, those with virological response during treatment, but without sustained virological response after cessation of treatment; patients without virological response throughout the study period.

Figure 3

Interferon-alpha (IFN-α) 2b concentration–time profiles in the initial single-dose (a) and final multiple-dose (b) studies in patients treated with IFN-α 2b plus ribavirin combination therapy. —, Patients with sustained virological response; —, those with virological response during treatment, but without sustained virological response after cessation of treatment; ·····, patients without virological response throughout the study period.