title: Evaluation of the absolute bioavailability of pegylated interferon alfa-2a after subcutaneous administration to healthy male volunteers: an open-label, randomized, parallel-group study.
abstract: 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 μg) 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 μg and 18 participants received PEG-IFN alfa-2a 180 μg 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 μg), 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 μg, 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.
authors.affiliation: Hoffmann-La Roche Inc, Nutley, New Jersey 07110, USA. barbara.brennan@roche.com
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brennan
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Xu
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grippo
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a