Population pharmacokinetic analysis of pegylated interferon alfa-2b and interferon alfa-2b in patients with chronic hepatitis C

Background: This study quantified pharmacokinetic changes in pegylated and nonpegylated interferon alfa-2b during 48 weeks of treatment and the influe nces of covariate on the basis of sparsely sampled serum concentrations and activity values. Possible relationships between pharmacokinetic and pharma codynamic variables were investigated. Methods: Patients with chronic hepatitis C were enrolled in a clinical tria l that compared the efficacy of pegylated interferon alfa-2b with interfero n alfa-2b. Single blood samples were obtained from each patient at weeks 4, 12, 24, 36, and 48. Three pharmacostatisdcal models were developed for 2 i mmunoassays and 1 bioassay. Results: Apparent clearance values of pegylated interferon alfa-2b and inte rferon alfa-2b at the end of treatment declined 33.7% and 80.0%, respective ly, from their week 4 values. Bioactivity increased 41% to 58% at week 48 f or different treatment groups. Changes were greatest in the first weeks of administration and diminished during the subsequent months. Body weight had a modest positive effect on clearance values and activity. Within each dos e level, no significant associations were observed between pharmacokinetic variables and any pharmacodynamic variables (hepatitis C virus-RNA response s or changes in neutrophils and platelets). Conclusions: This analysis confirms earlier observations of progressive pha rmacokinetic changes in the patients with hepatitis C during 48 weeks of tr eatment. The absence of a relationship between toxicity or efficacy variabl es and interferon concentration or activity (within a dose level) suggests that clinical management of patients leg, for efficacy or to manage toxicit y) should be based on clinically derived dosing guidelines rather than on s erum concentration or activity criteria.