Skip to main content
SpringerLink
Log in

Pharmacokinetics and Pharmacodynamics of Mepolizumab, an Anti-Interleukin-5 Monoclonal Antibody

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Mepolizumab is a fully humanized monoclonal antibody (IgG1/κ) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function. Mepolizumab blocks human IL-5 from binding to the α-chain of the IL-5 receptor complex on the eosinophil cell surface, thereby inhibiting IL-5 signalling. The pharmacokinetics of mepolizumab have been evaluated in clinical studies at doses of 0.05–10 mg/kg and at 250 mg, 750 mg and 1500 mg. Mepolizumab was eliminated slowly, with mean initial and terminal phase half-life values of approximately 2 and 20 days, respectively. Plasma clearance ranged from 0.064 to 0.163 mL/h/kg and steady-state volume of distribution ranged from 49 to 93mL/kg. Pharmacokinetics were dose proportional and time independent. Estimates based on a two-compartment intravenous infusion model from patients with asthma or healthy subjects following single doses predicted mepolizumab plasma concentrations in multiple-dose studies involving patients with hypereosinophilic syndrome (HES), asthma or eosinophilic oesophagitis. The absolute bioavailability of mepolizumab was 64–75% following subcutaneous injection and 81% following intramuscular injection. Peripheral blood eosinophil levels decreased in healthy subjects and patients with HES, asthma, eosinophilic oesophagitis or atopic dermatitis after intravenous mepolizumab infusion and subcutaneous injection. Reductions in eosinophil counts in oesophagus, sputum, skin, bone marrow, nasal lavage fluid and/or bronchial mucosa after treatment with mepolizumab were observed in placebo-controlled studies in various indications. The relationship between percentage change from baseline in blood eosinophils and mepolizumab plasma concentrations was described by an indirect pharmacological response model. The estimated maximal decrease in eosinophil count was approximately 85% from baseline and the half-maximal inhibitory concentration (IC50) was approximately 0.45 mg/mL.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood 1992; 79(12): 3101–9

    PubMed  CAS  Google Scholar 

  2. Simon D, Braathen LR, Simon H-U. Eosinophils and atopic dermatitis. Allergy 2004; 59(6): 561–70

    Article  PubMed  CAS  Google Scholar 

  3. Lopez AF, Sanderson CJ, Gamble JR, et al. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J Exp Med 1988; 167(1): 219–24

    Article  PubMed  CAS  Google Scholar 

  4. Clutterbuck EJ, Hirst EM, Sanderson CJ. Human interleukin-5(IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF. Blood 1989; 73(6): 1504–12

    PubMed  CAS  Google Scholar 

  5. Miyajima A, Mui AL, Ogorochi T, et al. Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5. Blood 1993; 82(7): 1960–74

    PubMed  CAS  Google Scholar 

  6. Hirai K, Yamaguchi M, Misaki Y, et al. Enhancement of human basophil histamine release by interleukin 5. J Exp Med 1990; 172(5): 1525–8

    Article  PubMed  CAS  Google Scholar 

  7. Bischoff SC, Brunner T, De Weck AL, et al. Interleukin 5 modifies histamine release and leukotriene generation by human basophils in response to diverse agonists. J Exp Med 1990; 172(6): 1577–82

    Article  PubMed  CAS  Google Scholar 

  8. Yoshimura-Uchiyama C, Yamaguchi M, Nagase H, et al. Comparative effects of basophil-directed growth factors. Biochem Biophys Res Commun 2003; 302(2): 201–6

    Article  PubMed  CAS  Google Scholar 

  9. Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol 2006; 24: 147–74

    Article  PubMed  CAS  Google Scholar 

  10. Sutton SA, Assa’ad AH, Rothenberg ME. Anti-IL-5 and hypereosinophilic syndromes. Clin Immunol 2005; 115(1): 51–60

    Article  PubMed  CAS  Google Scholar 

  11. Wilkins HJ, Crane MM, Copeland K, et al. Hypereosinophilic syndrome: an update. Am J Hematol 2005; 80(2): 148–57

    Article  PubMed  Google Scholar 

  12. Gleich GJ, Leiferman KM. The hypereosinophilic syndromes: still more heterogeneity. Curr Opin Immunol 2005; 17(6): 679–84

    Article  PubMed  CAS  Google Scholar 

  13. Klion AD, Bochner BS, Gleich GJ, et al. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol 2006; 117(6): 1292–302

    Article  PubMed  Google Scholar 

  14. Roufosse F, Goldman M, Cogan E. Hypereosinophilic syndrome: lympho proliferative and myeloproliferative variants. Semin Respir Crit Care Med 2006; 27(2): 158–70

    Article  PubMed  Google Scholar 

  15. Pardanani A, Ketterling RP, Li CY, et al. FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature. Leuk Res 2006; 30(8): 965–70

    Article  PubMed  CAS  Google Scholar 

  16. Klion AD. Approach to the therapy of hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007; 27(3): 551–60

    Article  PubMed  Google Scholar 

  17. Gupte AR, Draganov PV. Eosinophilic esophagitis. World J Gastroenterol 2009; 15(1): 17–24

    Article  PubMed  Google Scholar 

  18. Straumann A, Hruz P. What’s new in the diagnosis and therapy of eosinophilic esophagitis?. Curr Opin Gastroenterol 2009; 25(4): 366–71

    Article  PubMed  CAS  Google Scholar 

  19. Garrean C, Hirano I. Eosinophilic esophagitis: pathophysiology and optimal management. Curr Gastroenterol Rep 2009; 11(3): 175–81

    Article  PubMed  Google Scholar 

  20. Kariyawasam HH, Robinson DS. The eosinophil: the cell and its weapons, the cytokines, its locations. Semin Respir Crit Care Med 2006; 27(2): 117–27

    Article  PubMed  Google Scholar 

  21. Adamko DJ, Odemuyiwa SO, Vethanayagam D, et al. The rise of the phoenix: the expanding role of the eosinophil in health and disease. Allergy 2005; 60(1): 13–22

    Article  PubMed  CAS  Google Scholar 

  22. Oldhoff JM, Darsow U, Werfel T, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy 2005; 60(5): 693–6

    Article  PubMed  CAS  Google Scholar 

  23. Garrett JK, Jameson SC, Thomson B, et al. Anti-interleukin-5(mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol 2004; 113(1): 115–9

    Article  PubMed  CAS  Google Scholar 

  24. Egan RW, Athwal D, Bodmer MW, et al. Effect of Sch 55700, a humanized monoclonal antibody to human interleukin-5, on eosinophilic responses and bronchial hyperreactivity. Arzneimittelforschung 1999; 49(9): 779–90

    PubMed  CAS  Google Scholar 

  25. Kips JC, O’Connor BJ, Langley SJ, et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med 2003; 167(12): 1655–9

    Article  PubMed  Google Scholar 

  26. Klion AD, Law MA, Noel P, et al. Safety and efficacy of the monoclonal antiinterleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome. Blood 2004; 103(8): 2939–41

    Article  PubMed  CAS  Google Scholar 

  27. Walsh GM. Reslizumab, a humanized anti-IL-5 mAb for the treatment of eosinophil-mediated inflammatory conditions. Curr Opin Mol Ther 2009; 11(3): 329–36

    PubMed  CAS  Google Scholar 

  28. Cook R, Applebaum R, Cusimano D, et al. Biological and biophysical characteristics of SB 240563, a high affinity humanized monoclonal antibody to IL-5 [abstract]. Am J Respir Crit Care Med 1998; 157: A604

    Google Scholar 

  29. Haig AE, Hart T, North S, et al. Mepolizumab investigators’ brochure. Brentford: GlaxoSmithKline, 2008(Data on file)

    Google Scholar 

  30. Hart TK, Cook RM, Zia-Amirhosseini P, et al. Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys. J Allergy Clin Immunol 2001; 108(2): 250–7

    Article  PubMed  CAS  Google Scholar 

  31. Zia-Amirhosseini P, Minthorn E, Benincosa LJ, et al. Pharmacokinetics and pharmacodynamics of SB-240563, a humanized monoclonal antibody directed to human interleukin-5, in monkeys. J Pharmacol Exp Ther 1999; 291(3): 1060–7

    PubMed  CAS  Google Scholar 

  32. Schofield JP. An open, randomized, parallel group study to assess the bioavailability following administration at 3 subcutaneous sites and 1 intramuscular site relative to intravenous administration of single 250 mg doses of SB-240563 to healthy volunteers. Brentford: GlaxoSmithKline, 2002 (Data on file)

    Google Scholar 

  33. Barnes P, Holgate ST, Stark PJ. A double blind, placebo controlled, dose rising study to assess safety, pharmacokinetics and effect on the early and late phase response to allergen challenge of SB-240563 in male patients with mild asthma. Brentford: GlaxoSmithKline, 1999(Data on file)

    Google Scholar 

  34. Freestone S. A double blind, placebo controlled, dose rising study to assess safety and pharmacokinetics of SB-240563 in male patients with mild asthma. Brentford: GlaxoSmithKline, 1998(Data on file)

    Google Scholar 

  35. Freestone S. A double-blind, placebo controlled, parallel group study to assess the tolerability and pharmacokinetics of three 250 mg subcutaneous doses of SB-240563 in male and female patients with asthma. Brentford: GlaxoSmithKline, 2001(Data on file)

    Google Scholar 

  36. Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy 1969; 13: 1–110

    PubMed  CAS  Google Scholar 

  37. Mould DR, Sweeney KR. The pharmacokinetics and pharmacodynamics of monoclonal antibodies-mechanistic modeling applied to drug development. Curr Opin Drug Discov Devel 2007; 10(1): 84–96

    PubMed  CAS  Google Scholar 

  38. Flood-Page PT, Menzies-Gow AN, Kay AB, et al. Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003; 167(2): 199–204

    Article  PubMed  Google Scholar 

  39. Menzies-Gow A, Robinson DS. Eosinophils, eosinophilic cytokines (interleukin-5), and antieosinophilic therapy in asthma. Curr Opin Pulm Med 2002; 8(1): 33–8

    Article  PubMed  Google Scholar 

  40. Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990; 323(15): 1033–9

    Article  PubMed  CAS  Google Scholar 

  41. Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360(9347): 1715–21

    Article  PubMed  Google Scholar 

  42. Hamid Q, Azzawi M, Ying S, et al. Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma. J Clin Invest 1991; 87(5): 1541–6

    Article  PubMed  CAS  Google Scholar 

  43. Humbert M, Corrigan CJ, Kimmitt P, et al. Relationship between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma. Am J Respir Crit Care Med 1997; 156(3 Pt 1): 704–8

    PubMed  CAS  Google Scholar 

  44. Robinson D, Hamid Q, Bentley A, et al. Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. J Allergy Clin Immunol 1993; 92(2): 313–24

    Article  PubMed  CAS  Google Scholar 

  45. Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356(9248): 2144–8

    Article  PubMed  CAS  Google Scholar 

  46. Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007; 176(11): 1062–71

    Article  PubMed  CAS  Google Scholar 

  47. Phipps S, Flood-Page P, Menzies-Gow A, et al. Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin. J Invest Dermatol 2004; 122(6): 1406–12

    Article  PubMed  CAS  Google Scholar 

  48. Kay AB. A double blind, placebo controlled, parallel group study to assess the effect of 750 mg SB-240563(anti-IL-5) on clinical features, cutaneous late-phase reactions and bronchial, nasal, skin, bone marrow and blood eosinophils in male and female patients with atopic asthma. Brentford: GlaxoSmithKline, 2002(Data on file)

    Google Scholar 

  49. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360(10): 973–84

    Article  PubMed  CAS  Google Scholar 

  50. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360(10): 985–93

    Article  PubMed  CAS  Google Scholar 

  51. Chusid MJ, Dale DC, West BC, et al. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975; 54(1): 1–27

    Article  CAS  Google Scholar 

  52. Schrezenmeier H, Thome SD, Tewald F, et al. Interleukin-5 is the predominant eosinophilopoietin produced by cloned T lymphocytes in hypereosinophilic syndrome. Exp Hematol 1993; 21(2): 358–65

    PubMed  CAS  Google Scholar 

  53. Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med 2008; 358(12): 1215–28

    Article  PubMed  CAS  Google Scholar 

  54. Rothenberg M. A multicenter, randomized, double-blind, placebo-controlled, parallel group phase III study to evaluate corticosteroid-reduction and -sparing effects of mepolizumab 750mg intravenously in subjects with hypereosinophilic syndrome (HES), and to evaluate the efficacy and safety of mepolizumab in controlling the clinical signs and symptoms of HES over nine months. Brentford: GlaxoSmithKline, 2008(Data on file)

    Google Scholar 

  55. Plötz SG, Simon H-U, Darsow U, et al. Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis. N Engl J Med 2003; 349(24): 2334–9

    Article  PubMed  Google Scholar 

  56. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment sponsored by the American Gastroenterological Association (AGA) Institute and North American Society of Pediatric Gas-troenterology, Hepatology, and Nutrition. Gastroenterology 2007; 133(4): 1342–63

    Article  PubMed  CAS  Google Scholar 

  57. Mishra A, Hogan SP, Brandt EB, et al. IL-5 promotes eosinophil trafficking to the esophagus. J Immunol 2002; 168(5): 2464–9

    PubMed  CAS  Google Scholar 

  58. Mishra A, Hogan SP, Brandt EB, et al. An etiological role for aeroaller-gens and eosinophils in experimental esophagitis. J Clin Invest 2001; 107(1): 83–90

    Article  PubMed  CAS  Google Scholar 

  59. Akei HS, Mishra A, Blanchard C, et al. Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice. Gastroenterology 2005; 129(3): 985–94

    Article  PubMed  CAS  Google Scholar 

  60. Straumann A, Conus S, Grzonka P, et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomized, placebo-controlled, double-blind trial. Gut 2010; 59(1): 21–30

    Article  PubMed  CAS  Google Scholar 

  61. Stein ML, Collins MH, Villanueva JM, et al. Anti-IL-5(mepolizumab) therapy for eosinophilic esophagitis. J Allergy Clin Immunol 2006; 118(6): 1312–9

    Article  PubMed  CAS  Google Scholar 

  62. Kapp A. The role of eosinophils in the pathogenesis of atopic dermatitis-eosinophil granule proteins as markers of disease activity. Allergy 1993; 48(1): 1–5

    Article  PubMed  CAS  Google Scholar 

  63. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 2004; 93(11): 2645–68

    Article  PubMed  CAS  Google Scholar 

  64. Hinton PR, Xiong JM, Johlfs MG, et al. An engineered human IgG1 antibody with longer serum half-life. J Immunol 2006; 176(1): 346–56

    PubMed  CAS  Google Scholar 

  65. Hinton PR, Johlfs MG, Xiong JM, et al. Engineered human IgG antibodies with longer serum half-lives in primates. J Biol Chem 2004; 279(8): 6213–6

    Article  PubMed  CAS  Google Scholar 

  66. Busse WW, Ring J, Huss-Marp J, et al. A review of treatment with mepolizumab, an anti-IL-5 mAb, in hypereosinophilic syndromes and asthma. J Allergy Clin Immunol 2010; 125(4): 803–13

    Article  PubMed  CAS  Google Scholar 

  67. Kim S, Marigowda G, Oren E, et al. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol 2010; 125(6): 1336–43

    Article  PubMed  CAS  Google Scholar 

  68. Tang L, Persky AM, Hochhaus G, et al. Pharmacokinetic aspects of biotechnology products. J Pharm Sci 2004; 93(9): 2184–204

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Editorial support in the form of writing assistance with outline and draft development, assembling tables and figures, collating author comments, grammatical editing and referencing was provided by Dr Elaine F. Griffin at Evidence Scientific Solutions and was funded by GlaxoSmithKline.

The pharmacokinetic/pharmacodynamic modelling presented in study SB-240563/035 was completed by Bela Patel, an employee of GlaxoSmithKline.

Studies SB-240563/001, SB-240563/006, SB-240563/017, SB-240563/018, SB-240563/035, SB-240563/036, SB-240563/045, MHE100185, MHE100901 and MEE103226, which are discussed in this paper, were funded by GlaxoSmithKline. All authors are employees of GlaxoSmithKline and own shares in GlaxoSmithKline.

Author information

Authors and Affiliations

  1. Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina, 27709-3398, USA

    Deborah A. Smith

  2. GlaxoSmithKline, Collegeville, Pennsylvania, USA

    Elisabeth A. Minthorn

  3. GlaxoSmithKline, Stevenage, UK

    Misba Beerahee

Authors
  1. Deborah A. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisabeth A. Minthorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Misba Beerahee
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Smith, D.A., Minthorn, E.A. & Beerahee, M. Pharmacokinetics and Pharmacodynamics of Mepolizumab, an Anti-Interleukin-5 Monoclonal Antibody. Clin Pharmacokinet 50, 215–227 (2011). https://doi.org/10.2165/11584340-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11584340-000000000-00000

Keywords

Search

Navigation