Abstract
Interferon-α (IFN-α) 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-α makes frequent dosing (daily or three times weekly) over an extended period (6–12 months or more) necessary. To improve the pharmacokinetics of IFN-α and decrease dosing frequency, IFN-α was fused to human serum albumin producing a new protein, Albuferon. In vitro comparisons of Albuferon and IFN-α showed similar antiviral and antiproliferative activities, although Albuferon was less potent on a molar basis than IFN-α. Pharmacokinetic and pharmacodynamic properties of the fusion protein were enhanced in monkeys. After a single intravenous injection (30 μg/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 μg/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-α given by the subcutaneous route in other monkey studies. Sera from Albuferon-treated monkeys demonstrated dose-related antiviral activity for ≥8 days based on an in vitro bioassay, whereas antiviral activity from IFN-α-treated animals was only slightly elevated relative to vehicle on day 0. Significant increases in 2′,5′-oligoadenylate synthetase mRNA relative to IFN-α- or vehicle-treated animals were maintained for ≥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-α.
Footnotes
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Financial support was provided by Human Genome Sciences, Inc., Rockville, MD.
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DOI: 10.1124/jpet.102.037002
- Abbreviations:
- IFN
- interferon
- PEG
- polyethylene glycol
- OAS
- oligoadenylate synthetase
- EMCV
- encephalomyocardititis virus
- VSV
- vesicular stomatitis virus
- ELISA
- enzyme-linked immunosorbent assay
- AUC
- area under the curve
- CL/F
- clearance adjusted for fraction (F) of drug absorbed (bioavailability)
- Cmax
- maximal plasma concentration
- EC50
- concentration to achieve 50% maximal effect
- (bioavailability)
- PBMC, peripheral blood mononuclear cell
- Tmax
- time to maximal plasma concentration
- Vz
- terminal volume of distribution
- Vz/F
- terminal volume of distribution adjusted for bioavailability
- Received May 6, 2002.
- Accepted July 12, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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