The AAPS Journal

, Volume 15, Issue 1, pp 172–182 | Cite as

The Utility of Modeling and Simulation Approaches to Evaluate Immunogenicity Effect on the Therapeutic Protein Pharmacokinetics

  • Juan Jose Perez Ruixo
  • Peiming Ma
  • Andrew T. Chow
Review Article Theme: Impact of Immunogenicity on PK/PD of Protein Therapeutics

Abstract

While therapeutic proteins (TP), particularly recombinant human proteins and fully human monoclonal antibodies, are designed to have a low immunogenic potential in humans, a clinical immune response does sometimes occur and cannot be predicted from preclinical studies. Changes in TP pharmacokinetics may be perceived as an early indication of antibody formation and serve as a surrogate for later changes in efficacy and safety in individual subjects. Given the substantial increase in number of biological products, including biosimilars, there is an urgent need to quantitatively predict and quantify the immune response and any consequential changes in TP pharmacokinetics. The purpose of this communication is to review the utility of population-based modeling and simulation approaches developed to date for investigating the development of an immune response and assessing its impact on TP pharmacokinetics. Two examples of empirical modeling approaches for pharmacokinetic assessment are presented. The first example presents methods to analyze pharmacokinetic data in the presence of anti-drug antibody (ADA) and confirm the effect of immunogenicity on TP pharmacokinetics in early phases of drug development. The second example provides a framework to analyze pharmacokinetic data in the absence or with very low incidence of ADA and confirm with enough power the lack of an immunogenicity effect on TP pharmacokinetics in late phases of drug development. Finally, a theoretical mechanism-based modeling framework is presented to mathematically relate the complex interaction among TP, their targets, and ADA.

Key words

immunogenicity modeling and simulation pharmacokinetics therapeutic proteins 

REFERENCES

  1. 1.
    Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov. 2002;1:457–62.PubMedCrossRefGoogle Scholar
  2. 2.
    Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther. 2002;24:1720–40.PubMedCrossRefGoogle Scholar
  3. 3.
    Schellekens H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol Dial Transplant. 2005;20 Suppl 6:3–9.Google Scholar
  4. 4.
    Singh K. Impact of product-related factors ion immunogenicity of biotherapeutics. J Pharm Sci. 2011;100:354–87.PubMedCrossRefGoogle Scholar
  5. 5.
    Vermeire S, Noman M, Van Assche G, Baert F, D’Haens G, Rutgeerts P. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56:1226–31.PubMedCrossRefGoogle Scholar
  6. 6.
    Kokate CK, Jalalpure SS, Hurakadle PJ. Textbook of pharmaceutical biotechnology. New Delhi: Elsevier; 2011. p. 22–23.Google Scholar
  7. 7.
    Gell PGH, Coombs RRA, editors. Clinical aspects of immunology. 1st ed. Oxford: Blackwell; 1963.Google Scholar
  8. 8.
    Tabrizi MT, Tseng C-ML, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11:81–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Schellekens H. How to predict and prevent the immunogenicity of therapeutic proteins. Biotechnol Annu Rev. 2008;14:191–202.PubMedCrossRefGoogle Scholar
  10. 10.
    Gorovits B. Immunogenicity: prediction, detection and effective assay development. Bioanalysis. 2010;2:1539–45.PubMedCrossRefGoogle Scholar
  11. 11.
    Putnam WS, Prabhu S, Zheng Y, Subramanyam M, Wang YMC. Pharmacokinetic, pharmacodynamic and immunogenicity comparability assessment strategies for monoclonal antibodies. Trends Biotechnol. 2010;28:509–16.PubMedCrossRefGoogle Scholar
  12. 12.
    FDA. FDA guidance for industry: population pharmacokinetics. 1999. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072137.pdf. Accessed 2 Nov 2012.
  13. 13.
    CHMP. CHMP guideline on reporting the result of population pharmacokinetic analyses. Doc. Ref. EMEA/CHMP/EWP/185990/06. 2007. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003067.pdf. Accessed 2 Nov 2012.
  14. 14.
    Richards SM. Immunologic considerations for enzyme replacement therapy in the treatment of lysosomal storage disorders. Clin Appl Immunol Rev. 2002;2:241–53.CrossRefGoogle Scholar
  15. 15.
    Bonate PL, Sung C, Welch K, Richards S. Conditional modeling of antibody titers using a zero-inflated poisson random effects model: application to Fabrazyme. J Pharmacokinet Pharmacodyn. 2009;36:443–59.PubMedCrossRefGoogle Scholar
  16. 16.
    Kianifard F, Gallo PP. Poisson regression analysis in clinical research. J Biopharm Stat. 1995;5:115–29.PubMedCrossRefGoogle Scholar
  17. 17.
    Bendtzen K, Ainsworth M, Steenholdt C, Thomsen OØ, Brynskov J. Individual medicine in inflammatory bowel disease: monitoring bioavailability, pharmacokinetics and immunogenicity of anti-tumour necrosis factor-alpha antibodies. Scand J Gastroenterol. 2009;44:774–81.PubMedCrossRefGoogle Scholar
  18. 18.
    Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91:635–46.PubMedCrossRefGoogle Scholar
  19. 19.
    Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:633–59.Google Scholar
  20. 20.
    Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84:548–58.PubMedCrossRefGoogle Scholar
  21. 21.
    Kakkar T, Sung C, Gibiansky L, Vu T, Narayanan A, Lin SL, et al. Population PK and IgE pharmacodynamic analysis of a fully human monoclonal antibody against IL4 receptor. Pharm Res. 2011;28:2530–42.PubMedCrossRefGoogle Scholar
  22. 22.
    Gibiansky L, Gibiansky E, Kakkar T, Ma P. Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn. 2008;35:573–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn. 2001;28:507–32.PubMedCrossRefGoogle Scholar
  24. 24.
    Xu ZH, Lee H, Vu T, Hu C, Yan H, Baker D, et al. Population pharmacokinetics of golimumab in patients with ankylosing spondylitis: impact of body weight and immunogenicity. Int J Clin Pharmacol Ther. 2010;48:596–607.PubMedGoogle Scholar
  25. 25.
    Mahmood I, Green MD. Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins. Clin Pharmacokinet. 2005;44:331–47.PubMedCrossRefGoogle Scholar
  26. 26.
    Ternant D, Aubourg A, Magdelaine-Beuzelin C, Degenne D, Watier H, Picon L, et al. Infliximab pharmacokinetics in inflammatory bowel disease patients. Ther Drug Monit. 2008;30:523–9.PubMedGoogle Scholar
  27. 27.
    Zhu Y, Hu C, Lu M, Liao S, Marini JC, Yohrling J, Yeilding N, Davis HM, Zhou H. Population pharmacokinetic modeling of ustekinumab, a human monoclonal antibody targeting IL-12/23p40, in patients with moderate to severe plaque psoriasis. J Clin Pharmacol. 2009;49:162–75.PubMedCrossRefGoogle Scholar
  28. 28.
    Fasanmade AA, Adedokun OJ, Ford J, Hernandez D, Johanns J, Hu C, et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol. 2009;65:1211–28.PubMedCrossRefGoogle Scholar
  29. 29.
    CHMP. Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. Doc. Ref. EMEA/CHMP/BMWP/14327/2006. 2007. http://www.tga.gov.au/pdf/euguide/bmwp1432706en.pdf. Accessed 2 Nov 2012.
  30. 30.
    Weeraratne D, Chen A, Pennucci JJ, Wu CY, Zhang K, Wright J, et al. Incidence of anti-panitumumab antibodies is low and has no apparent impact on pharmacokinetic or safety profiles in clinical trials of panitumumab plus chemotherapy. BMC Clin Pharmacol. 2011;11:17.PubMedCrossRefGoogle Scholar
  31. 31.
    Hecht JR, Patnaik A, Berlin J, Venook A, Malik I, Tchekmedyian S, Navale L, Amado RG, Meropol NJ. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer. 2007;110:980–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658–64.PubMedCrossRefGoogle Scholar
  33. 33.
    Ma P, Yang BB, Wang YM, Peterson M, Narayanan A, Sutjandra L, et al. Population pharmacokinetic analysis of panitumumab in patients with advanced solid tumors. J Clin Pharmacol. 2009;49:1142–56.PubMedCrossRefGoogle Scholar
  34. 34.
    Olsson-Gisleskog P, Karlsson MO, Beal SL. Use of prior information to stabilize a population data analysis. J Pharmacokinet Pharmacodyn. 2002;29:473–505.CrossRefGoogle Scholar
  35. 35.
    Cella M, Gorter de Vries F, Burger D, Danhof M, Della Pasqua O. A model-based approach to dose selection in early pediatric development. Clin Pharmacol Ther. 2010;87:294–302.PubMedCrossRefGoogle Scholar
  36. 36.
    Perez-Ruixo JJ, Doshi S, Chow AT. Application of pharmacokinetic–pharmacodynamic modeling and simulation for erythropoietic stimulating agents. In: Kimko HHC, Peck CC, editors. Clinical trial simulations. Applications and trends. New York: Springer; 2010. p. 311–28.Google Scholar
  37. 37.
    Wang YM, Krzyzansky W, Doshi S, Xiao JJ, Pérez-Ruixo JJ, Chow AT. Pharmacodynamics-mediated drug disposition (PDMDD) and precursor pool lifespan model for single dose of romiplostim in healthy subjects. AAPS J. 2010;12:729–40.PubMedCrossRefGoogle Scholar
  38. 38.
    Lecluse LL, Driessen RJ, Spuls PI, de Jong EM, Stapel SO, van Doorn MB, et al. Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. Arch Dermatol. 2010;146:127–32.PubMedCrossRefGoogle Scholar
  39. 39.
    de Vries MK, Wolbink GJ, Stapel SO, de Groot ER, Dijkmans BA, Aarden LA, et al. Inefficacy of infliximab in ankylosing spondylitis is correlated with antibody formation. Ann Rheum Dis. 2007;66:133–4.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  • Juan Jose Perez Ruixo
    • 1
  • Peiming Ma
    • 1
  • Andrew T. Chow
    • 1
  1. 1.Quantitative Pharmacology, Department of Pharmacokinetics and Drug MetabolismAmgen Inc.Thousand OaksUSA

Personalised recommendations