Introduction
Chronic hepatitis C (CHC) is one of the most common causes of chronic liver disease, with as many as 170 million people infected worldwide.1 Interferon-alfa (IFN-a)–based regimens have remained the cornerstone for treating CHC,2–4 and modeling of hepatitis C virus (HCV) RNA and its association with IFN-a concentrations has provided several insights into the antiviral mechanisms of both standard and pegylated interferons.5–7 The biphasic pattern of HCV-RNA reduction is characterized by the major initial effect of blocking virion production or release (first-phase decline), followed by loss of infected cells (second-phase slope). The magnitude of this biphasic response defines the kinetics of early virologic response, which in turn has a high predictive value for sustained virologic response.6,8
Albinterferon alfa-2b (alb-IFN) is an 85.7-kD protein consisting of IFNa-2b genetically fused to human albumin.9 The pharmacokinetic parameters and early virologic response profile of this agent have been demonstrated in a dose-ranging phase 2a study in patients with genotype 1 CHC.10 At doses up to 1200 µg, alb-IFN demonstrated an extended half-life (t½) of ~ 6 days, with evidence of dose-dependent antiviral activity. High drug levels were maintained during the entire dosing interval following the administration of 2 injections 14 days apart, and the majority of patients showed continued viral decline over a 14-day to 28-day interval after the second dose. Based on these results and other phase 2 studies, the 900 µg and 1200 µg doses are currently being evaluated in phase 3 trials.9
Neumann et al5 developed a widely used model for the analysis of HCV dynamics after the initiation of unmodified IFNa that assumes the effectiveness of therapy in blocking virion production (e) is constant. The biweekly administration of alb-IFN is characterized by changes in drug concentration.11,12 Thus, it is important to measure whether these changes will lead to changes in drug effectiveness over the dosing interval. Advanced models allow for changes in drug effectiveness as drug concentrations vary between dosing intervals and incorporate estimation of pharmacodynamic parameters based on concomitant measurements of serum viral load and drug concentration.13,14 In the present report, the activity of alb-IFN 900 µg and 1200 µg is further characterized using a mathematical model integrating pharmacokinetics, viral kinetics, and pharmacodynamics based on data derived from the aforementioned phase 2a dose-ranging study.10
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