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Semin Liver Dis 2003; 23: 019-022
DOI: 10.1055/s-2003-41635
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Pegylation of Interferon Alfa: Structural and Pharmacokinetic Properties

Simon C. J. Pedder
  • Shearwater Corporation, a Division of Inhale Therapeutics, Charlotte, North Carolina
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Publication History

Publication Date:
21 August 2003 (online)

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ABSTRACT

The attachment of a polyethylene glycol (PEG) polymer to a protein or peptide is becoming increasingly common within the pharmaceutical industry as a way of altering the activity of the parent molecule. Significant improvements in biological activity with PEG molecules have been seen with several licensed drugs, allowing for product life cycle management, as well as with experimental compounds in development that have pharmaceutical properties making them suitable candidates for pegylation. Among the various disease states that have been targeted for the study of drugs incorporating pegylation technology, the treatment of chronic hepatitis C with interferon-based compounds offers significant potential for clinical impact. Two separate compounds, peginterferon alfa-2a (PEGASYS(r)) and peginterferon alfa-2b (PEG-Intron(r)) are now both approved for use alone and in combination with ribavirin for the treatment of chronic hepatitis C. However, the different PEG moieties attached to the native protein, the site of attachment and the type of bond involved lead to vast differences with respect to the pharmacokinetics (including absorption, biodistribution, metabolism and elimination) and pharmacodynamics of these two compounds. This article discusses the differences that exist between these compounds, which may lead to different clinical profiles for their use in the treatment of patients with hepatitis C.

KEYWORDS

Pegylation - interferons - PEGASYS(r) - PEG-Intron(r) - pharmacokinetics

REFERENCES

  • 1 Clark R, Olson K, Fuh G. et al . Long-acting growth hormones produced by conjugation with polyethylene glycol.  J Biol Chem . 1996;  271 21969-21977
    CrossrefPubMedGoogle Scholar
  • 2 Satake-Ishikawa R, Ishikawa M, OkadaY, et al. Chemical modification of granulocyte colony stimulating factor by poly(ethylene glycol) increases its biological activity in vivo.  Cell Struct Funct . 1992;  17 157-160
    PubMedGoogle Scholar
  • 3 Katre N V, Knauf M J, Laird W J. Chemical modification of interleukin-2 by poly(ethylene glycol) increases its potency in the murine meth A sarcoma model.  Proc Natl Acad Sci USA . 1987;  84 1487-1491
    PubMedGoogle Scholar
  • 4 Fuerteges F, Abuchowski A. The clinical efficacy of poly(ethylene glycol)-modified proteins.  J Controlled Release . 1990;  11 139-148
    CrossrefPubMedGoogle Scholar
  • 5 Caliceti P, Schiavon O, Veronese F M. Bipharmaceutical properties of uricase conjugated to neutral and amphiphilic polymers.  Bioconjugate Chem . 1999;  10 638-646
    CrossrefPubMedGoogle Scholar
  • 6 Katre N V. The conjugation of proteins with poly-(ethylene glycol) and other polymers; altering properties to enhance their therapeutic potential.  Adv Drug Deliv Sys . 1993;  10 91-114
    PubMedGoogle Scholar
  • 7 Abuchowski A, McCoy J R, Palczuk N C. et al . Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase.  J Biol Chem . 1977;  252 3582-3586
    PubMedGoogle Scholar
  • 8 Monfardini C, Schiavon O, Caliceti P. et al . A branched monomethoxypoly(ethylene glycol) for protein modification.  Bioconjug Chem . 1995;  6 62-69
    CrossrefPubMedGoogle Scholar
  • 9 Roberts M J, Bentley M D, Harris J M. Chemistry for peptide and protein PEGylation.  Adv Drug Deliv Rev . 2002;  54 459-476
    CrossrefPubMedGoogle Scholar
  • 10 Pestka S. The human interferons-from protein purification and sequence to cloning and expression in bacteria: before, between and beyond.  Arch Biochem Biophys . 1983;  21 1-37
    PubMedGoogle Scholar
  • 11 Wills R J. Clinical pharmacokinetics of the interferons.  Clin Pharmacokinetics . 1990;  19 390-339
    CrossrefPubMedGoogle Scholar
  • 12 Perry C M, Jarvis B. Peginterferon alfa-2a (40KD); a review of its use in the treatment of chronic hepatitis C.  Drugs . 2001;  61 2263-2288
    PubMedGoogle Scholar
  • 13 Lam N P, Neumann A U, Gretch D R. et al . Dose dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa.  Hepatology . 1997;  26 226-231
    PubMedGoogle Scholar
  • 14 Monkarsh S P, Ma Y, Aglione A. et al . Positional isomers of mono-pegylated interferon alfa-2a: isolation, characterization, and biological activity.  Anal Biochem . 1997;  247 434-440
    CrossrefPubMedGoogle Scholar
  • 15 Harris J M, Kozlowski A. Improvements in protein PEGylation: pegylated interferons for treatment of hepatitis C.  J Controlled Release . 2001;  72 217-224
    CrossrefPubMedGoogle Scholar
  • 16 Glue P, Fang J WS, Rouzier-Panis R. Pegylated interferon alpha-2b: pharmacokinetics, pharmacodynamics, safety and preliminary efficacy data.  Clin Pharmacol Ther . 2000;  68 556-567
    PubMedGoogle Scholar
  • 17 Lindsay K L, Trepo C, Heintges T. et al . A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C.  Hepatology . 2001;  34 395-403
    CrossrefPubMedGoogle Scholar
  • 18 Bailon P, Palleroni A, Schaffer C A. et al . Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene gylcol-conjugated interferon alfa-2a for the treatment of hepatitis C.  Bioconjug Chem . 2001;  12 195-202
    CrossrefPubMedGoogle Scholar
  • 19 Algranati N E, Sy S, Modi M. A branched methoxy 40 kDa polyethylene glycol (PEG) moiety optimizes the pharmacokinetics of pegIFN alfa-2a (PEG-IFN) and may explain its enhanced efficacy in chronic hepatitis C (CHC) (Abst).  Hepatology . 1999;  30 190
    PubMedGoogle Scholar
  • 20 Neiforth K, Nadeau R, Patel I H. et al . Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa-2a and a polyethylene glycol-modified derivative in healthy subjects.  Clin Pharmacol Ther . 1996;  59 636-646
    CrossrefPubMedGoogle Scholar
  • 21 Modi M W, Fried M, Reindollar R W, et e l. The pharmacokinetic behavior of pegylated (40kDa) interferon alfa-2a (PEGASYSTM) in chronic hepatitis C patients after multiple dosing (Abst).  Hepatology . 2000;  32 394
    CrossrefPubMedGoogle Scholar
  • 22 Lamb M W, Martin N E. Weight-based dosing versus fixed dosing of peginterferon (40kDa) alfa-2a.  Ann Pharmacother . 2002;  36 933-935
    CrossrefPubMedGoogle Scholar
  • 23 Modi M W, Fulton J S, Buckmann D K. et al . Clearance of pegylated (40kDa) interferon alfa-2a (PEGASYSTM) is primarily hepatic.  Hepatology . 2000;  32 371A
    PubMedGoogle Scholar
  • 24 Alter H J, Seeff L B. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome.  Semin Liver Dis . 2000;  20 17-35
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Buti M, Sanchez-Avila F, Lurie Y. et al . Viral kinetics in genotype 1 chronic hepatitis C patients during therapy with 2 different doses of peginterferon alfa-2b plus ribavirin.  Hepatology . 2002;  35 930-936
    CrossrefPubMedGoogle Scholar
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