Linking interleukin-6 receptor blockade with tocilizumab and its hematological effects using a modeling approach

  • Leonid Gibiansky
  • Nicolas Frey


Tocilizumab is a recombinant humanized antihuman interleukin-6 receptor monoclonal antibody, which inhibits binding of IL-6 to its soluble (sIL-6R) and membrane-expressed (mIL-6R) receptors. The work investigated whether the observed decline in peripheral neutrophil and platelet counts after tocilizumab administration can be directly explained by tocilizumab IL-6R blockade, thus demonstrating the mechanism of tocilizumab action. Tocilizumab and total sIL-6R concentrations, neutrophil and platelet counts from 4 phase 3 studies in rheumatoid arthritis patients were available. Patients received 4 or 8 mg/kg tocilizumab intravenous infusions every 4 weeks for a total of 6 doses. A population approach was applied to describe the relationship between tocilizumab and sIL-6R concentrations and subsequent changes in neutrophil and platelet counts. Following tocilizumab administration, concentrations of total sIL-6R increased, while neutrophil and platelet counts declined. These changes were transient, with counts returning to their respective baseline levels soon after tocilizumab is eliminated from the body. Tocilizumab concentrations were described by a two compartment model with parallel linear and Michaelis–Menten elimination. The quasi-steady-state target-mediated drug disposition model described tocilizumab relationships to total sIL-6R, which allowed computation of unobserved unbound sIL-6R concentrations. The neutrophil counts were described as a direct function of unbound sIL-6R concentrations. The platelet counts were described by the transit-compartment life-span model with inhibition of production that depended on the unbound sIL-6R concentrations. Thus, the observed changes in sIL-6R, neutrophil, and platelet data are consistent with the tocilizumab mechanism of action and can be fully explained by tocilizumab binding to sIL-6R and mIL-6R.


Interleukin-6 receptor Mechanism of action Neutrophils Platelets Rheumatoid arthritis Tocilizumab Target-mediated drug disposition 

Supplementary material

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Supplementary material 1 (DOC 2121 kb)


  1. 1.
    Fonseca JE, Santos MJ, Canhao H, Choy E (2009) Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmun Rev 8:538–542PubMedCrossRefGoogle Scholar
  2. 2.
    Rose-John S, Waetzig GH, Scheller J, Grotzinger J, Seegert D (2007) The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin Ther Targets 11:613–624PubMedCrossRefGoogle Scholar
  3. 3.
    Mullberg J, Schooltink H, Stoyan T, Gunther M, Graeve L, Buse G, Mackiewicz A, Heinrich PC, Rose-John S (1993) The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol 23:473–480PubMedCrossRefGoogle Scholar
  4. 4.
    Horiuchi S, Koyanagi Y, Zhou Y, Miyamoto H, Tanaka Y, Waki M, Matsumoto A, Yamamoto M, Yamamoto N (1994) Soluble interleukin-6 receptors released from T cell or granulocyte/macrophage cell lines and human peripheral blood mononuclear cells are generated through an alternative splicing mechanism. Eur J Immunol 24:1945–1948PubMedCrossRefGoogle Scholar
  5. 5.
    Le Goff B, Blanchard F, Berthelot JM, Heymann D, Maugars Y (2010) Role for interleukin-6 in structural joint damage and systemic bone loss in rheumatoid arthritis. Joint Bone Spine 77:201–205PubMedCrossRefGoogle Scholar
  6. 6.
    Madhok R, Crilly A, Watson J, Capell HA (1993) Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 52:232–234PubMedCrossRefGoogle Scholar
  7. 7.
    Sack U, Kinne RW, Marx T, Heppt P, Bender S, Emmrich F (1993) Interleukin-6 in synovial fluid is closely associated with chronic synovitis in rheumatoid arthritis. Rheumatol Int 13:45–51PubMedCrossRefGoogle Scholar
  8. 8.
    Emery P, Keystone E, Tony HP, Cantagrel A, van VR, Sanchez A, Alecock E, Lee J, Kremer J (2008) IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 67:1516–1523PubMedCrossRefGoogle Scholar
  9. 9.
    Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, Woodworth T, Gomez-Reino JJ (2008) Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 58:2968–2980PubMedCrossRefGoogle Scholar
  10. 10.
    Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R (2008) Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371:987–997PubMedCrossRefGoogle Scholar
  11. 11.
    Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, Siri DA, Tomsic M, Alecock E, Woodworth T, Genovese MC (2010) Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 69:88–96PubMedCrossRefGoogle Scholar
  12. 12.
    Stubenrauch K, Wessels U, Birnboeck H, Ramirez F, Jahreis A, Schleypen J (2010) Subset analysis of patients experiencing clinical events of a potentially immunogenic nature in the pivotal clinical trials of tocilizumab for rheumatoid arthritis: Evaluation of an antidrug antibody ELISA using clinical adverse event-driven immunogenicity testing. Clin Ther 32(9):1597PubMedCrossRefGoogle Scholar
  13. 13.
    Levy G (1994) Pharmacologic target-mediated drug disposition. Clin Pharmacol Ther 56:248–252PubMedCrossRefGoogle Scholar
  14. 14.
    Mager DE, Jusko WJ (2001) General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn 28:507–532PubMedCrossRefGoogle Scholar
  15. 15.
    Gibiansky L, Gibiansky E (2009) Target-mediated drug disposition model: relationships with indirect response models and application to population PK-PD analysis. J Pharmacokinet Pharmacodyn 36:341–351PubMedCrossRefGoogle Scholar
  16. 16.
    Gibiansky L, Gibiansky E (2010) Target-mediated drug disposition model for drugs that bind to more than one target. J Pharmacokinet Pharmacodyn 37:323–346PubMedCrossRefGoogle Scholar
  17. 17.
    Suwa T, Hogg JC, English D, Van Eeden SF (2000) Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow. Am J Physiol Heart Circ Physiol 279:H2954–H2960PubMedGoogle Scholar
  18. 18.
    Nakahata T, Yasukawa K. Method for increasing platelets by administering soluble interleukin-6R receptor. Stem Cell Institute. February 22, 2000; Available at:
  19. 19.
    De Benedetti F, Massa M, Robbioni P, Ravelli A, Burgio GR, Martini A (1991) Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum 34:1158–1163PubMedCrossRefGoogle Scholar
  20. 20.
    Mager DE, Krzyzanski W (2005) Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition. Pharm Res 22:1589–1596PubMedCrossRefGoogle Scholar
  21. 21.
    Gibiansky L, Gibiansky E, Kakkar T, Ma P (2008) Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn 35:573–591PubMedCrossRefGoogle Scholar
  22. 22.
    Gibiansky L, Gibiansky E (2009) Target-mediated drug disposition model: approximations, identifiability of model parameters and applications to the population pharmacokinetic-pharmacodynamic modeling of biologics. Expert Opin Drug Metab Toxicol 5:803–812PubMedCrossRefGoogle Scholar
  23. 23.
    Yan X, Mager DE, Krzyzanski W (2010) Selection between Michaelis–Menten and target-mediated drug disposition pharmacokinetic models. J Pharmacokinet Pharmacodyn 37:25–47PubMedCrossRefGoogle Scholar
  24. 24.
    Gibiansky L, Gibiansky E (2009) Mechanistic interpretation of indirect-response models for drugs with target-mediated disposition. American Conference on Pharmacometrics; October 4–7, 2009Google Scholar
  25. 25.
    Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO (2002) Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 20:4713–4721PubMedCrossRefGoogle Scholar
  26. 26.
    Joerger M, Huitema AD, Richel DJ, Dittrich C, Pavlidis N, Briasoulis E, Vermorken JB, Strocchi E, Martoni A, Sorio R, Sleeboom HP, Izquierdo MA, Jodrell DI, Calvert H, Boddy AV, Hollema H, Fety R, Van d V, Hempel G, Chatelut E, Karlsson M, Wilkins J, Tranchand B, Schrijvers AH, Twelves C, Beijnen JH, Schellens JH (2007) Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group. Clin Cancer Res 13:6410–6418PubMedCrossRefGoogle Scholar
  27. 27.
    Beal SL, Sheiner LB, Boeckmann AJ (2007) NONMEM Users Guide. Icon Development Solutions, EllicottGoogle Scholar
  28. 28.
    Beal S, Sheiner L (2006) NONMEM users guides: part I–VIII. University of California at San Francisco, San FranciscoGoogle Scholar
  29. 29.
    Karlsson MO, Savic RM (2007) Diagnosing model diagnostics. Clin Pharmacol Ther 82:17–20PubMedCrossRefGoogle Scholar
  30. 30.
    Yano Y, Beal SL, Sheiner LB (2001) Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn 28:171–192PubMedCrossRefGoogle Scholar
  31. 31.
    Wang DW, Zhang S (2011) Standardized visual predictive check versus visual predictive check for model evaluation. J Clin Pharmacol, doi:  10.1177/0091270010390040
  32. 32.
    Mentre F, Escolano S (2006) Prediction discrepancies for the evaluation of nonlinear mixed-effects models. J Pharmacokinet Pharmacodyn 33:345–367PubMedCrossRefGoogle Scholar
  33. 33.
    Brendel K, Comets E, Laffont C, Laveille C, Mentre F (2006) Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res 23:2036–2049PubMedCrossRefGoogle Scholar
  34. 34.
    Mihara M, Kasutani K, Okazaki M, Nakamura A, Kawai S, Sugimoto M, Matsumoto Y, Ohsugi Y (2005) Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol 5(12):1731–1740PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.QuantPharm LLCNorth PotomacUSA
  2. 2.F Hoffman-La Roche Ltd, Pharma Research and Early Development (pRED) and Translational Research Sciences (TRS)NutleyUSA

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