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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Blaire L. Osborn, Henrik S. Olsen, Bernardetta Nardelli, James H. Murray, Joe X. H. Zhou, Andrew Garcia, Gordon Moody, Liubov S. Zaritskaya and Cynthia Sung
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 540-548; DOI: https://doi.org/10.1124/jpet.102.037002
Blaire L. Osborn
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Henrik S. Olsen
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Bernardetta Nardelli
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James H. Murray
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Joe X. H. Zhou
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Andrew Garcia
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Gordon Moody
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Liubov S. Zaritskaya
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Cynthia Sung
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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

  • Financial support was provided by Human Genome Sciences, Inc., Rockville, MD.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Blaire L. Osborn, Henrik S. Olsen, Bernardetta Nardelli, James H. Murray, Joe X. H. Zhou, Andrew Garcia, Gordon Moody, Liubov S. Zaritskaya and Cynthia Sung
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 540-548; DOI: https://doi.org/10.1124/jpet.102.037002

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Blaire L. Osborn, Henrik S. Olsen, Bernardetta Nardelli, James H. Murray, Joe X. H. Zhou, Andrew Garcia, Gordon Moody, Liubov S. Zaritskaya and Cynthia Sung
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 540-548; DOI: https://doi.org/10.1124/jpet.102.037002
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