Skip to main content
SpringerLink
Log in

Pegylation

A Novel Process for Modifying Pharmacokinetics

  • Review Articles
  • Drug Delivery Systems
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

The use of liposomal carriers and the modification of therapeutic molecules through the attachment of poly(ethylene glycol) [PEG] moieties (‘pegylation’) are the most common approaches for enhancing the delivery of parenteral agents. Although ‘classical’ liposomes (i.e. phospholipid bilayer vehicles) have been effective in decreasing the clearance of encapsulated agents and in passively targeting specific tissues, they are associated with considerable limitations.

Pegylation may be an effective method of delivering therapeutic proteins and modifying their pharmacokinetic properties, in turn modifying pharmacodynamics, via a mechanism dependent on altered binding properties of the native protein. Pegylation reduces renal clearance and, for some products, results in a more sustained absorption after subcutaneous administration as well as restricted distribution. These pharmacokinetic changes may result in more constant and sustained plasma concentrations, which can lead to increases in clinical effectiveness when the desired effects are concentration-dependent.

Maintaining drug concentrations at or near a target concentration for an extended period of time is often clinically advantageous, and is particularly useful in antiviral therapy, since constant antiviral pressure should prevent replication and may thereby suppress the emergence of resistant variants. Additionally, PEG modification may decrease adverse effects caused by the large variations in peak-to-trough plasma drug concentrations associated with frequent administration and by the immunogenicity of unmodified proteins. Pegylated proteins may have reduced immunogenicity because PEG-induced steric hindrance can prevent immune recognition.

Two PEG-modified proteins are currently approved by the US Food and Drug Administration; several others, including cytokines such as interferon-α (IFNα), growth factors and free radical scavengers, are under development. Careful assessment of various pegylated IFNα products suggests that pegylated molecules can be differentiated on the basis of their pharmacokinetic properties and related changes in pharmacodynamics. Because the size, geometry and attachment site of the PEG moiety play a crucial role in determining these properties, therapeutically optimised agents must be designed on a protein-by-protein basis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Table II
Table III

Similar content being viewed by others

References

  1. Florence AT, Jani PU. Novel oral drug formulations: their potential in modulating adverse effects. Drug Saf 1994; 10: 233–66

    Article  PubMed  CAS  Google Scholar 

  2. Wills RJ, Ferraiolo BL. The role of pharmacokinetics in the development of biotechnologically derived agents. Clin Pharmacokinet 1992; 23: 406–14

    Article  PubMed  CAS  Google Scholar 

  3. Nucci ML, Shorr R, Abuchowski A. The therapeutic value of poly(ethylene glycol)-modified proteins. Adv Drug Deliv Rev 1991; 6: 133–51

    Article  CAS  Google Scholar 

  4. Burnham NL. Polymers for delivering peptides and proteins. Am J Hosp Pharm 1994; 51: 210–8

    PubMed  CAS  Google Scholar 

  5. Allen TM. Liposomes: opportunities in drug development. Drugs 1997; 54 Suppl. 4: 8–14

    Article  PubMed  CAS  Google Scholar 

  6. Gobburu JV, Tenhoor C, Rogge MC, et al. Pharmacokinetics/dynamics of 5c8, a monoclonal antibody to CD154 (CD40 ligand) suppression of an immune response in monkeys. J Pharmacol Exp Ther 1998 Aug; 286(2): 925–30

    PubMed  CAS  Google Scholar 

  7. Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Drugs 1997; 54 Suppl. 4: 15–21

    Article  PubMed  CAS  Google Scholar 

  8. Szebeni J. The interaction of liposomes with the complement system. Crit Rev Ther Drug Carrier Syst 1998; 15: 57–88

    Article  PubMed  CAS  Google Scholar 

  9. Davis FF, Abuchowski A, Van Es T, et al. Enzyme-polyethylene glycol adducts: modified enzymes with unique properties. Enzyme Eng 1978; 4: 169–73

    Article  CAS  Google Scholar 

  10. Zalipsky S, Harris JM. Introduction to chemistry and biological applications of poly(ethylene glycol). In: Harris JM, Zalipsky S, editors. Poly(ethylene glycol): chemistry and biological applications. San Francisco (CA): American Chemical Society, 1997: 1–15

    Chapter  Google Scholar 

  11. Bailon P, Berthold W. Polyethylene glycol-conjugated pharmaceutical proteins. Pharm Sci Technol Today 1998; 1: 352–6

    Article  CAS  Google Scholar 

  12. Delgado C, Francis GE, Fisher D. The uses and properties of PEG-linked proteins. Crit Rev Ther Drug Carrier Syst 1992; 9: 249–304

    PubMed  CAS  Google Scholar 

  13. Monfardini C, Schiavon O, Caliceti P, et al. A branched monomethoxypoly(ethylene glycol) for protein modification. Bioconjugate Chem 1995; 6: 62–9

    Article  CAS  Google Scholar 

  14. Zhao X, Harris JM. Novel degradable poly(ethylene glycol) esters for drug delivery. In: Harris JM, Zalipsky S, editors. Poly(ethylene glycol): chemistry and biological applications. San Francisco (CA): American Chemical Society, 1997: 458–72

    Chapter  Google Scholar 

  15. Zalipsky S, Lee C. Use offunctionalized poly(ethylene glycol)s for modification of polypeptides. In Harris JM, editors. Poly(ethylene glycol) chemistry: biotechnical and biomedical applications. New York: Plenum Press, 1992: 347–370

    Google Scholar 

  16. Katre NV. The conjugation ofproteins with polyethylene glycol and other polymers: altering properties of proteins to enhancing their therapeutic potential. Adv Drug Del Rev 1993; 10: 91–114

    Article  CAS  Google Scholar 

  17. Fung W-J, Porter JE, Bailon P. Strategies for the preparation and characterization of polyethylene glycol (PEG) conjugated pharmaceutical proteins. Polymers Preprint 1997; 38: 565–6

    CAS  Google Scholar 

  18. Morpurgo M, Veronese FM, Kachensky D, et al. Preparation of characterization of poly(ethylene glycol) vinyl sulfone. Bioconjug Chem 1996; 7: 363–8

    Article  PubMed  CAS  Google Scholar 

  19. Kinstler OB, Brems DN, Lauren SL, et al. Characterization and stability of N-terminally PEGylated rhG-CSF. Pharm Res 1996; 13: 996–1002

    Article  PubMed  CAS  Google Scholar 

  20. Brenner B, Rector Jr F. Brenner and Rector’s: the kidney. 5th ed. Philadelphia (PA): W.B. Saunders Company, 1996

    Google Scholar 

  21. Nieforth KA, Nadeau R, Patel IH, 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: 636–46

    Article  PubMed  CAS  Google Scholar 

  22. Pardridge WM, Wu D, Sakane T. Combined use ofcarboxyl-directed protein pegylation and vector-mediated blood-brain barrier drug delivery system optimized brain uptake of brain-derived neurotrophic factor following intravenous administration. Pharm Res 1998; 15: 576–82

    Article  PubMed  CAS  Google Scholar 

  23. Yamaoka T, Tabata Y, Ikada Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci 1994 Apr; 83(4): 601–6

    Article  PubMed  CAS  Google Scholar 

  24. Olson K, Gehant R, Mukku V, et al. Preparation and characterization of poly(ethylene glycol)ylated human growth hormone antagonist. In: Harris JM, Zalipsky S, editors. Poly(ethylene glycol): chemistry and biological applications. San Francisco (CA): American Chemical Society, 1997: 170–81

    Chapter  Google Scholar 

  25. Gaertner HF, Offord RE. Site-specific attachment of functionalized poly(ethylene glycol) to the amino terminus of proteins. Bioconjug Chem 1996; 7: 38–44

    Article  PubMed  CAS  Google Scholar 

  26. Wills RJ, Dennis S, Speigel HE, et al. Interferon kinetics and adverse reactions after intravenous, intramuscular, and subcutaneous injection. Clin Pharmacol Ther 1984; 35: 722–7

    Article  PubMed  CAS  Google Scholar 

  27. Chatelut E, Rostaing L, Gregoire N, et al. A pharmacokinetic model for alpha interferon administered subcutaneously. Br J Clin Pharmacol 1999; 47: 365–71

    Article  PubMed  CAS  Google Scholar 

  28. Xu Z-X, Patel I, Joubert P. Single-dose safety/tolerability and pharmacokinetic/pharmacodynamics (PK/PD) following administration of ascending subcutaneous doses of pegylated-interferon (PEG-IFN) and interferon α-2a (IFN α-2a) to healthy subjects [abstract]. Hepatology 1998; 28 Suppl.: 702

    Article  Google Scholar 

  29. Algranati NE, Sy S, Modi M. A branched methoxy 40 kDa polyethylene glycol (PEG) moiety optimizes the pharmacokinet-ics (PK) of peginterferon α-2a (PEG-IFN) and may explain its enhanced efficacy in chronic hepatitis C (CHC) [abstract]. Hepatology 1999; 30 (4 Pt 2): 190A

    Google Scholar 

  30. F. Hoffmann-La Roche, Ltd., data on file

  31. Tsutsumi Y, Tsunoda S, Kamada H, et al. PEGylation of interleukin-6 effectively increases its thrombopoietic potency. Thromb Haemost 1997; 77: 168–73

    PubMed  CAS  Google Scholar 

  32. Tsutsumi Y, Kihira T, Tsunoda S, et al. Molecular design of hybrid tumour necrosis factor alfa with polyethylene glycol increases its anti-tumour potency. Br J Cancer 1995; 71: 963–8

    Article  PubMed  CAS  Google Scholar 

  33. Campbell RM, Heimer EP, Ahmad M, et al. Pegylated peptides: V. Carboxy-terminal PEGylated analogs of growth hormone-releasing factor (GRF) display enhanced duration of biological activity in vivo. J Pept Res 1997; 49: 527–37

    Article  PubMed  CAS  Google Scholar 

  34. Hokom MM, Lacey D, Kinsler O, et al. Megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice. Blood 1995; 86: 4486–92

    PubMed  CAS  Google Scholar 

  35. Holle LM. Pegaspargase: an alternative. Ann Pharmacother 1997; 3: 616–24

    Google Scholar 

  36. Beauchamp CO, Gonias SL, Menapace DP, et al. Anew procedure for the synthesis of polyethylene glycol-protein adducts; effects on function, receptor recognition, and clearance of superoxide dismutase, lactoferrin, and alfa 2-macroglobulin. Anal Biochem 1983; 131: 25–33

    Article  PubMed  CAS  Google Scholar 

  37. Rajagopalan S, Gonias SL, Pizzo SV. A nonantigenic covalent streptokinase-polyethylene glycol complex with plasminogen activator function. J Clin Invest 1985; 75: 413–9

    Article  PubMed  CAS  Google Scholar 

  38. Knauf MJ, Bell DP, Hirtzer P, et al. Relationship of effective molecular size to systemic clearance in rats of recombinant interleukin-2 chemically modified with water-soluble polymers. J Biol Chem 1988; 263: 15064–70

    PubMed  CAS  Google Scholar 

  39. Working PK, Newman MS, Johnson J, et al. Safety of poly(ethylene glycol) and poly(ethylene glycol) derivatives. In: Harris JM, Zalipsky S, editors. Poly(ethylene glycol): chemistry and biological applications. San Francisco (CA): American Chemical Society, 1997: 45–59

    Chapter  Google Scholar 

  40. Bendele A, Seely J, Richey C, et al. Short communication: renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins. Toxicol Sci 1998; 42: 153–7

    Article  Google Scholar 

  41. Stewart S, Jablonowski H, Goebel FD, et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi’s sarcoma. J Clin Oncol 1998; 16: 683–91

    PubMed  CAS  Google Scholar 

  42. Suzuki S, Watanabe S, Masuko T, et al. Preparation of long-circulating immunoliposomes containing Adriamycin by a novel method to coat immunoliposomes with poly(ethylene glycol). Biochim Biophys Acta 1995; 1245: 9–16

    Article  PubMed  Google Scholar 

  43. Alberts DS, Garcia DJ. Safety aspects of pegylated liposomal doxorubicin in patients with cancer. Drugs 1997; 54 Suppl. 4: 30–5

    Article  PubMed  CAS  Google Scholar 

  44. Muggia FM. Clinical efficacy and prospects for the use of pegylated liposomal doxorubicin in the treatment of ovarian and breast cancers. Drugs 1997; 54 Suppl. 4: 22–9

    Article  PubMed  CAS  Google Scholar 

  45. Amantea MA, Forrest A, Northfelt DW, et al. Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi’s sarcoma. Clin Pharmacol Ther 1997; 61:301–11

    Article  PubMed  CAS  Google Scholar 

  46. Francis GE, Delgado C, Fisher D, et al. Polyethylene glycol modification: relevance of improved methodology to tumour targeting. J Drug Target 1996; 3: 321–40

    Article  PubMed  CAS  Google Scholar 

  47. Davis S, Abuchowski A, Park Y, et al. Alteration of the circulating life and antigenic properties of bovine adenosine deaminase in mice by attachment of polyethylene glycol. Clin Exp Immunol 1981; 46: 649–52

    PubMed  CAS  Google Scholar 

  48. Hershfield MS. Biochemistry and immunology of poly(ethylene glycol)-modified adenosine deaminase (PEG-ADA). In: Harris JM, Zalipsky S, editors. Poly(ethylene glycol): chemistry and biological applications. Philadelphia (PA): American Chemical Society, 1997: 145–54

    Chapter  Google Scholar 

  49. Hershfield MS. PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. Clin Immunol Immunopathol 1995; 76 (3 Pt 2): S228–32

    Article  PubMed  CAS  Google Scholar 

  50. Hillman BC, Sorensen RU. Management options: SCIDS with adenosine deaminase deficiency. Ann Allergy 1994; 72: 395–404

    Google Scholar 

  51. Keating MJ, Holmes R, Lerner S, et al. L-asparaginase and PEG asparaginase: past, present, and future. Leuk Lymphoma 1993; 10 Suppl.: 153–7

    Article  PubMed  Google Scholar 

  52. Khakoo S, Glue P, Grellier L, et al. Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions. Br J Clin Pharmacol 1998; 46: 563–70

    Article  PubMed  CAS  Google Scholar 

  53. Glue P, Fang J, Sabo R, et al. Peg-interferon-α2B: pharmacokinetics, pharmacodynamics, safety and preliminary efficacy data [abstract]. Hepatology 1999; 30 (4 Pt 2): 189A

    Google Scholar 

  54. Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996; 24: 778–89

    Article  PubMed  CAS  Google Scholar 

  55. Berenguer M, Wright TL. Hepatitis C virus. Adv Gastroenterol Hepatol Clin Nutr 1996; 1: 2–21

    Google Scholar 

  56. O’Brien C, Pockros P, Reddy R, et al. A double-blind, multicenter, randomized, parallel dose-comparison study of six regimens of 5kD, linear peginterferon alfa-2a compared with Roferon-A in patients with chronic hepatitis C [abstract]. Antiviral Ther 1999; 4 Suppl. 4: 15

    Google Scholar 

  57. Reddy KR, Wright TL, Pockros PJ, et al. Efficacy and safety of pegylated (40kDa) interferon α-2a compared with interferon α-2a in non-cirrhotic patients with chronic hepatitis C. Hepatology 2001; 33(2): 433–8

    Article  PubMed  CAS  Google Scholar 

  58. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon α-2a in patients with chronic hepatitis C. N Engl J Med 2000; 343: 1666–72

    Article  PubMed  CAS  Google Scholar 

  59. Heathcote EJ, Shiffman ML, Cooksley GE, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000; 343: 1673–80

    Article  PubMed  CAS  Google Scholar 

  60. Modi MW, Fried M, Reindollar RW, et al. The pharmacokinetic behavior of pegylated (40kDa) interferon alfa-2a (PEGASYS™) in chronic hepatitis C patients after multiple dosing [abstract]. Hepatology 2000; 32(4): 394A

    Google Scholar 

  61. Lam NP, Neumann AU, Gretch DR, et al. Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa. Hepatology 1997; 26: 226–31

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Financial support for this manuscript was provided by F. Hoffmann-La Roche, Ltd., Basel, Switzerland.

Author information

Authors and Affiliations

  1. Shearwater Corporation, 1112 Church St, Huntsville, Alabama, AL 35801, USA

    J. Milton Harris

  2. Hoffmann-La Roche Inc., Nutley, New Jersey, USA

    Nancy E. Martin & Marlene Modi

Authors
  1. J. Milton Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nancy E. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marlene Modi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Milton Harris.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harris, J.M., Martin, N.E. & Modi, M. Pegylation. Clin Pharmacokinet 40, 539–551 (2001). https://doi.org/10.2165/00003088-200140070-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200140070-00005

Keywords

Search

Navigation