Format

Send to

Choose Destination
See comment in PubMed Commons below
J Pharmacol Exp Ther. 2002 Nov;303(2):540-8.

Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys.

Author information

1
Human Genome Sciences, Inc., 9410 Key West Avenue, Rockville, MD 20850, USA. blaire_osborn@hgsi.com

Abstract

Interferon-alpha (IFN-alpha) is indicated for the treatment of certain viral infections including hepatitis B and C, and cancers such as melanoma. The short circulating half-life of unmodified IFN-alpha makes frequent dosing (daily or three times weekly) over an extended period (6-12 months or more) necessary. To improve the pharmacokinetics of IFN-alpha and decrease dosing frequency, IFN-alpha was fused to human serum albumin producing a new protein, Albuferon. In vitro comparisons of Albuferon and IFN-alpha showed similar antiviral and antiproliferative activities, although Albuferon was less potent on a molar basis than IFN-alpha. Pharmacokinetic and pharmacodynamic properties of the fusion protein were enhanced in monkeys. After a single intravenous injection (30 microg/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 microg/kg subcutaneous injection, apparent clearance (clearance divided by bioavailability) was 1.4 ml/h/kg, the terminal half-life was 93 h, and bioavailability was 64%. The rate of clearance of Albuferon was approximately 140-fold slower, and the half-life 18-fold longer, than for IFN-alpha given by the subcutaneous route in other monkey studies. Sera from Albuferon-treated monkeys demonstrated dose-related antiviral activity for > or =8 days based on an in vitro bioassay, whereas antiviral activity from IFN-alpha-treated animals was only slightly elevated relative to vehicle on day 0. Significant increases in 2',5'-oligoadenylate synthetase mRNA relative to IFN-alpha- or vehicle-treated animals were maintained for > or =10 days after subcutaneous dosing. The improved pharmacokinetics of Albuferon are accompanied by an improved pharmacodynamic response suggesting that Albuferon may offer the benefits of less frequent dosing and a potentially improved efficacy profile compared with IFN-alpha.

PMID:
12388634
DOI:
10.1124/jpet.102.037002
[Indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Support Center