Evaluation of the Absolute Bioavailability of Pegylated Interferon Alfa-2a After Subcutaneous Administration to Healthy Male Volunteers: An Open-Label, Randomized, Parallel-Group Study

Background: Interferon (IFN)-based therapy is the recommended treatment for hepatitis C virus. Because pegylated IFN (PEG-IFN) alfa-2a is administered subcutaneously, it is of interest to determine the proportion of the dose that is absorbed from the subcutaneous (SC) tissue and ultimately reaches systemic circulation. Objective: The goal of this study was to characterize the absolute bioavailability of PEG-IFN alfa-2a (40 kDa) after SC dosing (180 mu g) and to evaluate the pharmacokinetics of PEG-IFN alfa-2a after intravenous (IV) and SC administration. Methods: In this parallel-group study, 18 participants were given a single IV dose of PEG-IFN alfa-2a 90 mu g and 18 participants received PEG-IFN alfa-2a 180 mu g SC. Serum concentrations of PEG-IFN alfa-2a were measured predose and serially until 312 hours after the first dose. Pharmacokinetic parameters (CL/F, volume of distribution, C-max, and T-max) were estimated using noncompartmental methods. Bioavailability was calculated by using the following formula: (AUC(SC)/AUC(IV)) . (dose(IV)/dose(SC)). Results: Eighteen healthy males received IV PEG-IFN alfa-2a, and an additional 18 healthy males received SC PEG-IFN alfa-2a. Subjects in each group had comparable mean weight, height, and body mass index. After IV administration of PEG-IFN alfa-2a (90 mu s), there was a slow decline in serum concentration, the mean rate of systemic clearance was low at 126 mL/h, and the estimated mean volume of distribution at steady state was 9 L. After SC administration of PEG-IFN alfa-2a 180 mu g, absorption was sustained, with mean T-max occurring 102 hours after administration. The mean absolute bioavailability was 84%. A higher rate of influenza-like symptoms was observed after IV administration, along with decreased neutrophil counts, compared with subjects who underwent SC dosing. Conclusions: Approximately 84% of a SC-administered dose of PEG-IFN alfa-2a reached the systemic circulation in these male healthy volunteers. The slow absorption, restricted distribution, and slow elimination of PEG-IFN alfa-2a resulted in sustained serum levels throughout the 7-day dosing interval. (Clin Ther. 2012;34:1883-1891) (C) 2012 Elsevier HS Journals, Inc. All rights reserved.