Skip to main content
SpringerLink
Log in

Factors Influencing Drug Disposition of Monoclonal Antibodies in Inflammatory Bowel Disease: Implications for Personalized Medicine

  • Leading Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Monoclonal antibody (mAb) therapies have revolutionized the treatment of several chronic inflammatory diseases, including the inflammatory bowel diseases (IBD), Crohn’s disease, and ulcerative colitis. While efficacious, responses to these therapies vary considerably from patient to patient, due in part to inter- and intra-individual variability in pharmacokinetics (PK) and drug exposure. The concept of personalized medicine to monitor drug exposure and to adjust dosing in individual patients is consequently gaining acceptance as a powerful tool to optimize mAb therapy for improved outcomes in IBD. This review provides a brief overview of the different mAbs currently approved or in development for the treatment of IBD, including their presumed mechanisms of action and PK properties. Specifically described are (1) the factors known to affect mAb PK and drug exposure in patients with IBD, (2) the value of population PK/pharmacodynamic (PD) modeling to identify and understand the influence of these factors on drug exposure and effect, and (3) the clinical evidence for the potential of therapeutic drug monitoring (TDM) to improve IBD outcomes in response to mAb-based therapy. Incorporation of PK/PD parameters into clinical decision support tools has the potential to guide therapeutic decision making and aid implementation of personalized medicine strategies in patients with IBD.

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

Similar content being viewed by others

References

  1. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361:2066–78.

    PubMed  PubMed Central  CAS  Google Scholar 

  2. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390:2769–78.

    PubMed  Google Scholar 

  3. Kappelman MD, Bousvaros A, Hyams J, Markowitz J, Pfefferkorn M, Kugathasan S, et al. Intercenter variation in initial management of children with Crohn’s disease. Inflamm Bowel Dis. 2007;13:890–5.

    PubMed  Google Scholar 

  4. Frolkis AD, Dykeman J, Negron ME, Debruyn J, Jette N, Fiest KM, et al. Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies. Gastroenterology. 2013;145:996–1006.

    PubMed  Google Scholar 

  5. Hemperly A, Sandborn WJ, Vande Casteele N. Clinical pharmacology in adult and pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2018;24:2527–42.

    PubMed  Google Scholar 

  6. Yamamoto-Furusho JK. Pharmacogenetics in inflammatory bowel disease: understanding treatment response and personalizing therapeutic strategies. Pharmgenom Pers Med. 2017;10:197–204.

    CAS  Google Scholar 

  7. Vermeire S, Van Assche G, Rutgeerts P. Role of genetics in prediction of disease course and response to therapy. World J Gastroenterol. 2010;16:2609–15.

    PubMed  PubMed Central  CAS  Google Scholar 

  8. Papamichael K, Gils A, Rutgeerts P, Levesque BG, Vermeire S, Sandborn WJ, et al. Role for therapeutic drug monitoring during induction therapy with TNF antagonists in IBD: evolution in the definition and management of primary nonresponse. Inflamm Bowel Dis. 2015;21:182–97.

    PubMed  Google Scholar 

  9. Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute Clinical Guidelines C American Gastroenterological Association. Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153:827–34.

    PubMed  Google Scholar 

  10. Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases. Gastroenterology. 2017;153(835–57):e6.

    Google Scholar 

  11. Dreesen E, Bossuyt P, Mulleman D, Gils A, Pascual-Salcedo D. Practical recommendations for the use of therapeutic drug monitoring of biopharmaceuticals in inflammatory diseases. Clin Pharmacol. 2017;9:101–11.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Papamichael K, Cheifetz AS. Therapeutic drug monitoring in inflammatory bowel disease: for every patient and every drug? Curr Opin Gastroenterol. 2019;35:302–10.

    Google Scholar 

  13. Gecse KB, Cumming F, D’Haens G. Biosimilars for inflammatory bowel disease: how can healthcare professionals help address patients’ concerns? Expert Rev Gastroenterol Hepatol. 2019;13:143–55.

    PubMed  CAS  Google Scholar 

  14. Lamb CA, O’Byrne S, Keir ME, Butcher EC. Gut-selective integrin-targeted therapies for inflammatory bowel disease. J Crohns Colitis. 2018;12(Suppl 2):653–68.

    Google Scholar 

  15. Ordas 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.

    PubMed  CAS  Google Scholar 

  16. Neurath M. Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol. 2017;14:688.

    PubMed  Google Scholar 

  17. Rutella S, Fiorino G, Vetrano S, Correale C, Spinelli A, Pagano N, et al. Infliximab therapy inhibits inflammation-induced angiogenesis in the mucosa of patients with Crohn’s disease. Am J Gastroenterol. 2011;106:762–70.

    PubMed  CAS  Google Scholar 

  18. Juuti-Uusitalo K, Klunder LJ, Sjollema KA, Mackovicova K, Ohgaki R, Hoekstra D, et al. Differential effects of TNF (TNFSF2) and IFN-gamma on intestinal epithelial cell morphogenesis and barrier function in three-dimensional culture. PLoS One. 2011;6:e22967.

    PubMed  PubMed Central  CAS  Google Scholar 

  19. Atreya R, Zimmer M, Bartsch B, Waldner MJ, Atreya I, Neumann H, et al. Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14(+) macrophages. Gastroenterology. 2011;141:2026–38.

    PubMed  CAS  Google Scholar 

  20. Van den Brande JM, Koehler TC, Zelinkova Z, Bennink RJ, te Velde AA, ten Cate FJ, et al. Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn’s disease. Gut. 2007;56:509–17.

    PubMed  Google Scholar 

  21. Meijer MJ, Mieremet-Ooms MA, van Duijn W, van der Zon AM, Hanemaaijer R, Verheijen JH, et al. Effect of the anti-tumor necrosis factor-alpha antibody infliximab on the ex vivo mucosal matrix metalloproteinase-proteolytic phenotype in inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:200–10.

    PubMed  Google Scholar 

  22. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244–7.

    PubMed  CAS  Google Scholar 

  23. Lin L, Liu X, Wang D, Zheng C. Efficacy and safety of antiintegrin antibody for inflammatory bowel disease: a systematic review and meta-analysis. Medicine (Baltimore). 2015;94:e556.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353:1912–25.

    PubMed  CAS  Google Scholar 

  25. Parikh A, Leach T, Wyant T, Scholz C, Sankoh S, Mould DR, et al. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm Bowel Dis. 2012;18:1470–9.

    PubMed  Google Scholar 

  26. Vermeire S, O’Byrne S, Keir M, Williams M, Lu TT, Mansfield JC, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet. 2014;384:309–18.

    PubMed  CAS  Google Scholar 

  27. Duijvestein M, D’Haens GR. Rational and clinical development of the anti-MAdCAM monoclonal antibody for the treatment of IBD. Expert Opin Biol Ther. 2019;19:361–6.

    PubMed  CAS  Google Scholar 

  28. Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375:1946–60.

    PubMed  CAS  Google Scholar 

  29. Deepak P, Sandborn WJ. Ustekinumab and anti-interleukin-23 agents in Crohn’s disease. Gastroenterol Clin North Am. 2017;46:603–26.

    PubMed  Google Scholar 

  30. Feagan BG, Sandborn WJ, D’Haens G, Panes J, Kaser A, Ferrante M, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2017;389:1699–709.

    PubMed  CAS  Google Scholar 

  31. Feagan BG, Panes J, Ferrante M, Kaser A, D’Haens GR, Sandborn WJ, et al. Risankizumab in patients with moderate to severe Crohn’s disease: an open-label extension study. Lancet Gastroenterol Hepatol. 2018;3:671–80.

    PubMed  Google Scholar 

  32. Janeway CA, Travers P, Walport M, Shlomchik MJ. Immunobiology: the immune system in health and disease. 5th ed. New York: Garland Science; 2001.

    Google Scholar 

  33. Reilly RM, Domingo R, Sandhu J. Oral delivery of antibodies. Future pharmacokinetic trends. Clin Pharmacokinet. 1997;32:313–23.

    PubMed  CAS  Google Scholar 

  34. Daugherty AL, Mrsny RJ. Formulation and delivery issues for monoclonal antibody therapeutics. Adv Drug Deliv Rev. 2006;58:686–706.

    PubMed  CAS  Google Scholar 

  35. Zhao L, Ji P, Li Z, Roy P, Sahajwalla CG. The antibody drug absorption following subcutaneous or intramuscular administration and its mathematical description by coupling physiologically based absorption process with the conventional compartment pharmacokinetic model. J Clin Pharmacol. 2013;53:314–25.

    PubMed  CAS  Google Scholar 

  36. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84:548–58.

    PubMed  CAS  Google Scholar 

  37. Ryman JT, Meibohm B. Pharmacokinetics of monoclonal antibodies. CPT Pharmacomet Syst Pharmacol. 2017;6:576–88.

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  39. Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn. 2001;28:507–32.

    PubMed  CAS  Google Scholar 

  40. Gessner JE, Heiken H, Tamm A, Schmidt RE. The IgG Fc receptor family. Ann Hematol. 1998;76:231–48.

    PubMed  CAS  Google Scholar 

  41. Gibiansky L, Passey C, Roy A, Bello A, Gupta M. Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma. J Pharmacokinet Pharmacodyn. 2016;43:243–57.

    PubMed  CAS  Google Scholar 

  42. Brandse JF, van den Brink GR, Wildenberg ME, van der Kleij D, Rispens T, Jansen JM, et al. Loss of infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis. Gastroenterology. 2015;149(350–5):e2.

    Google Scholar 

  43. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–25.

    PubMed  CAS  Google Scholar 

  44. Kontermann RE. Strategies for extended serum half-life of protein therapeutics. Curr Opin Biotechnol. 2011;22:868–76.

    PubMed  CAS  Google Scholar 

  45. Morell A, Terry WD, Waldmann TA. Metabolic properties of IgG subclasses in man. J Clin Investig. 1970;49:673–80.

    PubMed  CAS  Google Scholar 

  46. Tabrizi MA, Tseng CM, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11:81–8.

    PubMed  CAS  Google Scholar 

  47. Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:633–59.

    PubMed  CAS  Google Scholar 

  48. Ward MG, Sparrow MP, Roblin X. Therapeutic drug monitoring of vedolizumab in inflammatory bowel disease: current data and future directions. Ther Adv Gastroenterol. 2018;11:1–10.

    Google Scholar 

  49. Billiet T, Dreesen E, Cleynen I, Wollants WJ, Ferrante M, Van Assche G, et al. A genetic variation in the neonatal Fc-receptor affects anti-TNF drug concentrations in inflammatory bowel diseasel. Am J Gastroenterol. 2016;111:1438–45.

    PubMed  CAS  Google Scholar 

  50. Hindryckx P, Novak G, Vande Casteele N, Khanna R, Laukens D, Jairath V, et al. Incidence, prevention and management of anti-drug antibodies against therapeutic antibodies in inflammatory bowel disease: a practical overview. Drugs. 2017;77:363–77.

    PubMed  CAS  Google Scholar 

  51. Vande Casteele N. Assays for measurement of TNF antagonists in practice. Frontline Gastroenterol. 2017;8:236–42.

    Google Scholar 

  52. Vande Casteele N, Gils A, Singh S, Ohrmund L, Hauenstein S, Rutgeerts P, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108:962–71.

    PubMed  Google Scholar 

  53. Bendtzen K. Immunogenicity of anti-TNF-alpha biotherapies: II. Clinical relevance of methods used for anti-drug antibody detection. Front Immunol. 2015;6:109.

    PubMed  PubMed Central  Google Scholar 

  54. Xu Z, Davis HM, Zhou H. Clinical impact of concomitant immunomodulators on biologic therapy: pharmacokinetics, immunogenicity, efficacy and safety. J Clin Pharmacol. 2015;55(Suppl 3):60–74.

    Google Scholar 

  55. Thomas SS, Borazan N, Barroso N, Duan L, Taroumian S, Kretzmann B, et al. Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases. A systematic review and meta-analysis. BioDrugs. 2015;29:241–58.

    PubMed  CAS  Google Scholar 

  56. Adedokun OJ, Sandborn WJ, Feagan BG, Rutgeerts P, Xu Z, Marano CW, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology. 2014;147(1296–307):e5.

    Google Scholar 

  57. Fasanmade AA, Adedokun OJ, Blank M, Zhou H, Davis HM. Pharmacokinetic properties of infliximab in children and adults with Crohn’s disease: a retrospective analysis of data from 2 phase III clinical trials. Clin Ther. 2011;33:946–64.

    PubMed  CAS  Google Scholar 

  58. 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.

    PubMed  PubMed Central  CAS  Google Scholar 

  59. Xu Z, Seitz K, Fasanmade A, Ford J, Williamson P, Xu W, et al. Population pharmacokinetics of infliximab in patients with ankylosing spondylitis. J Clin Pharmacol. 2008;48:681–95.

    PubMed  CAS  Google Scholar 

  60. Baert F, Kondragunta V, Lockton S, Vande Casteele N, Hauenstein S, Singh S, et al. Antibodies to adalimumab are associated with future inflammation in Crohn’s patients receiving maintenance adalimumab therapy: a post hoc analysis of the Karmiris trial. Gut. 2016;65:1126–31.

    PubMed  CAS  Google Scholar 

  61. 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.

    PubMed  PubMed Central  CAS  Google Scholar 

  62. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–21.

    PubMed  CAS  Google Scholar 

  63. Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012;367:1519–28.

    PubMed  CAS  Google Scholar 

  64. Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetics parameters. I. Michaelis–Menten model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm. 1980;8:553–71.

    PubMed  CAS  Google Scholar 

  65. Sheiner LB, Rosenberg B, Melmon KL. Modelling of individual pharmacokinetics for computer-aided drug dosage. Comput Biomed Res. 1972;5:411–59.

    PubMed  CAS  Google Scholar 

  66. Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacomet Syst Pharmacol. 2012;1:e6.

    CAS  Google Scholar 

  67. Passot C, Pouw MF, Mulleman D, Bejan-Angoulvant T, Paintaud G, Dreesen E, et al. Therapeutic drug monitoring of biopharmaceuticals may benefit from pharmacokinetic and pharmacokinetic–pharmacodynamic modeling. Ther Drug Monit. 2017;39:322–6.

    PubMed  CAS  Google Scholar 

  68. Sani SN, Siwale RC. Multicompartment models: intravenous bolus administration. In: Shargel L, Yu ABC, editors. Applied biopharmaceutics & pharmacokinetics. 7th ed. New York: McGraw-Hill Education; 2016. p. 97–130.

    Google Scholar 

  69. Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development—part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacomet Syst Pharmacol. 2013;2:e38.

    CAS  Google Scholar 

  70. Standing JF. Understanding and applying pharmacometric modelling and simulation in clinical practice and research. Br J Clin Pharmacol. 2017;83:247–54.

    PubMed  Google Scholar 

  71. Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, et al. A guide to rational dosing of monoclonal antibodies. Clin Pharmacokinet. 2012;51:119–35.

    PubMed  CAS  Google Scholar 

  72. Aubourg A, Picon L, Lecomte T, Bejan-Angoulvant T, Paintaud G, Ternant D. A robust estimation of infliximab pharmacokinetic parameters in Crohn’s disease. Eur J Clin Pharmacol. 2015;71:1541–2.

    PubMed  Google Scholar 

  73. Brandse JF, Mathot RA, van der Kleij D, Rispens T, Ashruf Y, Jansen JM, et al. Pharmacokinetic features and presence of antidrug antibodies associate with response to infliximab induction therapy in patients with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2016;14:251.e1–2–258.e1–2.

    Google Scholar 

  74. Brandse JF, Mould D, Smeekes O, Ashruf Y, Kuin S, Strik A, et al. A real-life population pharmacokinetic study reveals factors associated with clearance and immunogenicity of infliximab in inflammatory bowel disease. Inflamm Bowel Dis. 2017;23:650–60.

    PubMed  Google Scholar 

  75. Dotan I, Ron Y, Yanai H, Becker S, Fishman S, Yahav L, et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis. 2014;20:2247–59.

    PubMed  Google Scholar 

  76. Dreesen E, Faelens R, Van Assche G, Ferrante M, Vermeire S, Gils A, et al. Optimising infliximab induction dosing for patients with ulcerative colitis. Br J Clin Pharmacol. 2019;85:782–95.

    PubMed  CAS  Google Scholar 

  77. Passot C, Mulleman D, Bejan-Angoulvant T, Aubourg A, Willot S, Lecomte T, et al. The underlying inflammatory chronic disease influences infliximab pharmacokinetics. MAbs. 2016;8:1407–16.

    PubMed  PubMed Central  CAS  Google Scholar 

  78. Petitcollin A, Brochard C, Siproudhis L, Tron C, Verdier MC, Lemaitre F, et al. Pharmacokinetic parameters of infliximab influence the rate of relapse after de-escalation in adults with inflammatory bowel diseases. Clin Pharmacol Ther. 2019. https://doi.org/10.1002/cpt.1429.

    Article  PubMed  Google Scholar 

  79. 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.

    PubMed  CAS  Google Scholar 

  80. Ternant D, Passot C, Aubourg A, Goupille P, Desvignes C, Picon L, et al. Model-based therapeutic drug monitoring of infliximab using a single serum trough concentration. Clin Pharmacokinet. 2018;57:1173–84.

    PubMed  CAS  Google Scholar 

  81. Buurman DJ, Maurer JM, Keizer RJ, Kosterink JG, Dijkstra G. Population pharmacokinetics of infliximab in patients with inflammatory bowel disease: potential implications for dosing in clinical practice. Aliment Pharmacol Ther. 2015;42:529–39.

    PubMed  CAS  Google Scholar 

  82. Petitcollin A, Leuret O, Tron C, Lemaitre F, Verdier MC, Paintaud G, et al. Modeling immunization to infliximab in children with Crohn’s disease using population pharmacokinetics: a pilot study. Inflamm Bowel Dis. 2018;24:1745–54.

    PubMed  Google Scholar 

  83. Berends SE, Strik AS, Van Selm JC, Lowenberg M, Ponsioen CY, D’Haens GR, et al. Explaining interpatient variability in adalimumab pharmacokinetics in patients with Crohn’s disease. Ther Drug Monit. 2018;40:202–11.

    PubMed  CAS  Google Scholar 

  84. Ternant D, Karmiris K, Vermeire S, Desvignes C, Azzopardi N, Bejan-Angoulvant T, et al. Pharmacokinetics of adalimumab in Crohn’s disease. Eur J Clin Pharmacol. 2015;71:1155–7.

    PubMed  Google Scholar 

  85. Vande Casteele N, Baert F, Bian S, Dreesen E, Compernolle G, Van Assche G, et al. Subcutaneous absorption contributes to observed interindividual variability in adalimumab serum concentrations in Crohn’s disease: a prospective multicentre study. J Crohns Colitis. 2019. https://doi.org/10.1093/ecco-jcc/jjz050.

    Article  PubMed  Google Scholar 

  86. Sharma S, Eckert D, Hyams JS, Mensing S, Thakkar RB, Robinson AM, et al. Pharmacokinetics and exposure-efficacy relationship of adalimumab in pediatric patients with moderate to severe Crohn’s disease: results from a randomized, multicenter, phase-3 study. Inflamm Bowel Dis. 2015;21:783–92.

    PubMed  Google Scholar 

  87. Wade JR, Parker G, Kosutic G, Feagen BG, Sandborn WJ, Laveille C, et al. Population pharmacokinetic analysis of certolizumab pegol in patients with Crohn’s disease. J Clin Pharmacol. 2015;55:866–74.

    PubMed  PubMed Central  CAS  Google Scholar 

  88. Vande Casteele N, Mould DR, Coarse J, Hasan I, Gils A, Feagan B, et al. Accounting for pharmacokinetic variability of certolizumab pegol in patients with Crohn’s disease. Clin Pharmacokinet. 2017;56:1513–23.

    PubMed  CAS  Google Scholar 

  89. Xu Y, Adedokun OJ, Chan D, Hu C, Xu Z, Strauss RS, et al. Population pharmacokinetics and exposure-response modeling analyses of golimumab in children with moderately to severely active ulcerative colitis. J Clin Pharmacol. 2018;59:590–604.

    PubMed  Google Scholar 

  90. Adedokun OJ, Xu Z, Liao S, Marano C, Strauss R, Zhang H, et al. Sa1935 Population pharmacokinetic modeling analysis of golimumab in adult patients with moderately to severely active ulcerative colitis. Gastroenterology. 2016;150(Suppl 1):408.

    Google Scholar 

  91. Kantasiripitak W, Dreesen E, Detrez I, Stefanovic S, Vermeire S, Ferrante M, et al. A population pharmacokinetic and exposure-response model of golimumab for targeting endoscopic remission in patients with ulcerative colitis. In: Poster session presented at: annual meeting of the population approach group in Europe; 2019 Jun 11–14; Stockholm, Sweden.

  92. Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:85–95.

    PubMed  CAS  Google Scholar 

  93. Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(96–109):e1.

    Google Scholar 

  94. Rutgeerts P, Feagan BG, Marano CW, Padgett L, Strauss R, Johanns J, et al. Randomised clinical trial: a placebo-controlled study of intravenous golimumab induction therapy for ulcerative colitis. Aliment Pharmacol Ther. 2015;42:504–14.

    PubMed  PubMed Central  CAS  Google Scholar 

  95. Brunner HI, Ruperto N, Tzaribachev N, Horneff G, Chasnyk VG, Panaviene V, et al. Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial. Ann Rheum Dis. 2018;77:21–9.

    PubMed  CAS  Google Scholar 

  96. Hyams JS, Chan D, Adedokun OJ, Padgett L, Turner D, Griffiths A, et al. Subcutaneous golimumab in pediatric ulcerative colitis: pharmacokinetics and clinical benefit. Inflamm Bowel Dis. 2017;23:2227–37.

    PubMed  Google Scholar 

  97. Rosario M, Dirks NL, Gastonguay MR, Fasanmade AA, Wyant T, Parikh A, et al. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther. 2015;42:188–202.

    PubMed  PubMed Central  CAS  Google Scholar 

  98. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699–710.

    PubMed  CAS  Google Scholar 

  99. Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment had failed. Gastroenterology. 2014;147(618–27):e3.

    Google Scholar 

  100. Suleiman AA, Khatri A, Minocha M, Othman AA. Population pharmacokinetics of the interleukin-23 inhibitor risankizumab in subjects with psoriasis and Crohn’s disease: analyses of phase I and II trials. Clin Pharmacokinet. 2019;58:375–87.

    PubMed  CAS  Google Scholar 

  101. Duffull SB, Wright DF, Winter HR. Interpreting population pharmacokinetic-pharmacodynamic analyses - a clinical viewpoint. Br J Clin Pharmacol. 2011;71:807–14.

    PubMed  PubMed Central  CAS  Google Scholar 

  102. Strik AS, Berends SE, Mould DR, Mathot R, Ponsioen C, van den Brande J, et al. 832 - Dashboard driven dosing of infliximab is superior to conventional treatment in inflammatory bowel disease: the precision randomized controlled trial. Gastroenterology. 2019;156(Suppl 1):180–1.

    Google Scholar 

  103. Bulik CC, Bader JC, Zhang L, Van Wart SA, Rubino CM, Bhavnani SM, et al. PK-PD Compass: bringing infectious diseases pharmacometrics to the patient’s bedside. J Pharmacokinet Pharmacodyn. 2017;44:161–77.

    PubMed  Google Scholar 

  104. Hoseyni H, Xu Y, Zhou H. Therapeutic drug monitoring of biologics for inflammatory bowel disease: an answer to optimized treatment? J Clin Pharmacol. 2018;58:864–76.

    PubMed  CAS  Google Scholar 

  105. Nakase H, Motoya S, Matsumoto T, Watanabe K, Hisamatsu T, Yoshimura N, et al. Significance of measurement of serum trough level and anti-drug antibody of adalimumab as personalised pharmacokinetics in patients with Crohn’s disease: a subanalysis of the DIAMOND trial. Aliment Pharmacol Ther. 2017;46:873–82.

    PubMed  PubMed Central  CAS  Google Scholar 

  106. Juncadella A, Papamichael K, Vaughn BP, Cheifetz AS. Maintenance adalimumab concentrations are associated with biochemical, endoscopic, and histologic remission in inflammatory bowel disease. Dig Dis Sci. 2018;63:3067–73.

    PubMed  CAS  Google Scholar 

  107. Roblin X, Marotte H, Rinaudo M, Del Tedesco E, Moreau A, Phelip JM, et al. Association between pharmacokinetics of adalimumab and mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2014;12(80–4):e2.

    Google Scholar 

  108. Ungar B, Levy I, Yavne Y, Yavzori M, Picard O, Fudim E, et al. Optimizing anti-TNF-alpha therapy: serum levels of infliximab and adalimumab are associated with mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2016;14(550–7):e2.

    Google Scholar 

  109. Arias MT, Vande Casteele N, Vermeire S, de Buck van Overstraeten A, Billiet T, Baert F, et al. A panel to predict long-term outcome of infliximab therapy for patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2015;13:531–8.

    PubMed  Google Scholar 

  110. Cornillie F, Hanauer SB, Diamond RH, Wang J, Tang KL, Xu Z, et al. Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. Gut. 2014;63:1721–7.

    PubMed  PubMed Central  CAS  Google Scholar 

  111. Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4:1248–54.

    PubMed  CAS  Google Scholar 

  112. Vande Casteele N, Feagan BG, Vermeire S, Yassine M, Coarse J, Kosutic G, et al. Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn’s disease. Aliment Pharmacol Ther. 2018;47:229–37.

    PubMed  CAS  Google Scholar 

  113. Adedokun OJ, Xu Z, Marano CW, Strauss R, Zhang H, Johanns J, et al. Pharmacokinetics and exposure-response relationship of golimumab in patients with moderately-to-severely active ulcerative colitis: results from phase 2/3 PURSUIT induction and maintenance studies. J Crohns Colitis. 2017;11:35–46.

    PubMed  Google Scholar 

  114. Restellini S, Khanna R, Afif W. Therapeutic drug monitoring with ustekinumab and vedolizumab in inflammatory bowel disease. Inflamm Bowel Dis. 2018;24:2165–72.

    PubMed  Google Scholar 

  115. Dreesen E, Verstockt B, Bian S, de Bruyn M, Compernolle G, Tops S, et al. Evidence to support monitoring of vedolizumab trough concentrations in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2018;16(1937–46):e8.

    Google Scholar 

  116. Liefferinckx C, Minsart C, Cremer A, Amininejad L, Tafciu V, Quertinmont E, et al. Early vedolizumab trough levels at induction in inflammatory bowel disease patients with treatment failure during maintenance. Eur J Gastroenterol Hepatol. 2019;31:478–85.

    PubMed  CAS  Google Scholar 

  117. Osterman MT, Rosario M, Lasch K, Barocas M, Wilbur JD, Dirks NL, et al. Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimisation. Aliment Pharmacol Ther. 2019;49:408–18.

    PubMed  PubMed Central  CAS  Google Scholar 

  118. Rosario M, French JL, Dirks NL, Sankoh S, Parikh A, Yang H, et al. Exposure-efficacy relationships for vedolizumab induction therapy in patients with ulcerative colitis or Crohn’s disease. J Crohns Colitis. 2017;11:921–9.

    PubMed  Google Scholar 

  119. Ungar B, Kopylov U, Yavzori M, Fudim E, Picard O, Lahat A, et al. Association of vedolizumab level, anti-drug antibodies, and alpha4beta7 occupancy with response in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2018;16(697–705):e7.

    Google Scholar 

  120. Peyrin-Biroulet L, Danese S, Argollo M, Pouillon L, Peppas S, Gonzalez-Lorenzo M, et al. Loss of response to vedolizumab and ability of dose intensification to restore response in patients with Crohn’s disease or ulcerative colitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2019;17(838–46):e2.

    Google Scholar 

  121. Paul S, Williet N, Di Bernado T, Berger AE, Boschetti G, Filippi J, et al. Soluble mucosal addressin cell adhesion molecule 1 and retinoic acid are potential tools for therapeutic drug monitoring in patients with inflammatory bowel disease treated with vedolizumab: a proof of concept study. J Crohns Colitis. 2018;12:1089–96.

    Google Scholar 

  122. Battat R, Dulai PS, Vande Casteele N, Evans E, Hester KD, Webster E, et al. Biomarkers are associated with clinical and endoscopic outcomes with vedolizumab treatment in ulcerative colitis. Inflamm Bowel Dis. 2019;25:410–20.

    PubMed  Google Scholar 

  123. Ma C, Battat R, Jairath V, Vande Casteele N. Advances in therapeutic drug monitoring for small-molecule and biologic therapies in inflammatory bowel disease. Curr Treat Options Gastroenterol. 2019;17:127–45.

    PubMed  Google Scholar 

  124. Gisbert JP, Panes J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009;104:760–7.

    PubMed  CAS  Google Scholar 

  125. Qiu Y, Chen BL, Mao R, Zhang SH, He Y, Zeng ZR, et al. Systematic review with meta-analysis: loss of response and requirement of anti-TNFalpha dose intensification in Crohn’s disease. J Gastroenterol. 2017;52:535–54.

    PubMed  CAS  Google Scholar 

  126. Peyrin-Biroulet L, Sandborn W, Sands BE, Reinisch W, Bemelman W, Bryant RV, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110:1324–38.

    PubMed  CAS  Google Scholar 

  127. Papamichael K, Vajravelu RK, Vaughn BP, Osterman MT, Cheifetz AS. Proactive infliximab monitoring following reactive testing is associated with better clinical outcomes than reactive testing alone in patients with inflammatory bowel disease. J Crohns Colitis. 2018;12:804–10.

    PubMed  Google Scholar 

  128. Ye BD, McGovern DP. Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility. Expert Rev Clin Immunol. 2016;12:1091–107.

    PubMed  PubMed Central  CAS  Google Scholar 

  129. Steenholdt C, Brynskov J, Thomsen OO, Munck LK, Fallingborg J, Christensen LA, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2014;63:919–27.

    PubMed  Google Scholar 

  130. Guidi L, Pugliese D, Panici Tonucci T, Berrino A, Tolusso B, Basile M, et al. Therapeutic drug monitoring is more cost-effective than a clinically-based approach in the management of loss of response to infliximab in inflammatory bowel disease: an observational multi-centre study. J Crohns Colitis. 2018;12:1079–88.

    Google Scholar 

  131. Kelly OB, Donnell SO, Stempak JM, Steinhart AH, Silverberg MS. Therapeutic drug monitoring to guide infliximab dose adjustment is associated with better endoscopic outcomes than clinical decision making alone in active inflammatory bowel disease. Inflamm Bowel Dis. 2017;23:1202–9.

    PubMed  Google Scholar 

  132. Yanai H, Lichtenstein L, Assa A, Mazor Y, Weiss B, Levine A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13(522–30):e2.

    Google Scholar 

  133. Roblin X, Rinaudo M, Del Tedesco E, Phelip JM, Genin C, Peyrin-Biroulet L, et al. Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases. Am J Gastroenterol. 2014;109:1250–6.

    PubMed  CAS  Google Scholar 

  134. Williet N, Boschetti G, Fovet M, Di Bernado T, Claudez P, Del Tedesco E, et al. Association between low trough levels of vedolizumab during induction therapy for inflammatory bowel diseases and need for additional doses within 6 months. Clin Gastroenterol Hepatol. 2017;15(1750–7):e3.

    Google Scholar 

  135. Papamichael K, Juncadella A, Wong D, Rakowsky S, Sattler LA, Campbell JP, et al. Proactive therapeutic drug monitoring of adalimumab is associated with better long-term outcomes compared to standard of care in patients with inflammatory bowel disease. J Crohns Colitis. 2019. https://doi.org/10.1093/ecco-jcc/jjz018.

    Article  PubMed  Google Scholar 

  136. Vande Casteele N, Ferrante M, Van Assche G, Ballet V, Compernolle G, Van Steen K, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148(1320–9):e3.

    Google Scholar 

  137. D’Haens G, Vermeire S, Lambrecht G, Baert F, Bossuyt P, Pariente B, et al. Increasing infliximab dose based on symptoms, biomarkers, and serum drug concentrations does not increase clinical, endoscopic, and corticosteroid-free remission in patients with active luminal Crohn’s disease. Gastroenterology. 2018;154(1343–51):e1.

    Google Scholar 

  138. Assa A, Matar M, Turner D, Broide E, Weiss B, Ledder O, et al. OP18 Proactive adalimumab trough measurements increase corticosteroid free clinical remission in paediatric patients with Crohn’s disease: the paediatric Crohn’s disease adalimumab-level-based optimisation treatment (PAILOT) trial. J Crohns Colitis. 2019;13(Suppl 1):012–13.

    Google Scholar 

  139. Wojciechowski J, Upton RN, Mould DR, Wiese MD, Foster DJR. Infliximab maintenance dosing in inflammatory bowel disease: an example for in silico assessment of adaptive dosing strategies. AAPS J. 2017;19:1136–47.

    PubMed  CAS  Google Scholar 

  140. Dreesen E, Verstockt B, Vermeire S, Ferrante M, Gils A. P342 A population pharmacokinetic model to support therapeutic drug monitoring during vedolizumab therapy. J Crohns Colitis. 2019;13(Suppl 1):273–4.

    Google Scholar 

  141. Van Stappen T, Bollen L, Vande Casteele N, Papamichael K, Van Assche G, Ferrante M, et al. Rapid test for infliximab drug concentration allows immediate dose adaptation. Clin Transl Gastroenterol. 2016;7:e206.

    PubMed  PubMed Central  Google Scholar 

  142. Yarur AJ, Jain A, Sussman DA, Barkin JS, Quintero MA, Princen F, et al. The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study. Gut. 2016;65:249–55.

    PubMed  CAS  Google Scholar 

  143. Yoshihara T, Shinzaki S, Kawai S, Fujii H, Iwatani S, Yamaguchi T, et al. Tissue drug concentrations of anti-tumor necrosis factor agents are associated with the long-term outcome of patients with Crohn’s disease. Inflamm Bowel Dis. 2017;23:2172–9.

    PubMed  Google Scholar 

  144. Guo Y, Zong S, Pu Y, Xu B, Zhang T, Wang B. Advances in pharmaceutical strategies enhancing the efficiencies of oral colon-targeted delivery systems in inflammatory bowel disease. Molecules. 2018;23:e1622.

    PubMed  Google Scholar 

  145. Zeeshan M, Ali H, Khan S, Khan SA, Weigmann B. Advances in orally-delivered pH-sensitive nanocarrier systems; an optimistic approach for the treatment of inflammatory bowel disease. Int J Pharm. 2019;558:201–14.

    PubMed  CAS  Google Scholar 

  146. l’Ami MJ, Krieckaert CL, Nurmohamed MT, van Vollenhoven RF, Rispens T, Boers M, et al. Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial. Ann Rheum Dis. 2018;77:484–7.

    PubMed  Google Scholar 

  147. Adedokun OJ, Xu Z, Gasink C, Jacobstein D, Szapary P, Johanns J, et al. Pharmacokinetics and exposure response relationships of ustekinumab in patients with Crohn’s disease. Gastroenterology. 2018;154:1660–71.

    PubMed  CAS  Google Scholar 

  148. Rosario M, Polhamus D, Chen C, Sun W, Dirks N. P490 A vedolizumab population pharmacokinetic model including intravenous and subcutaneous formulations for patients with ulcerative colitis. J Crohns Colitis. 2019;13(Suppl 1):357.

    Google Scholar 

  149. FDA. Clinical pharmacology and biopharmaceutics review(s): application number: 761044Orig1s000 (ustekinumab - Stelara). 2016. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761044Orig1s000ClinPharmR.pdf. Accessed 05 June 2019.

  150. Hemperly A, Vande Casteele N. Clinical pharmacokinetics and pharmacodynamics of infliximab in the treatment of inflammatory bowel disease. Clin Pharmacokinet. 2018;57:929–42.

    PubMed  CAS  Google Scholar 

  151. Verstockt B, Moors G, Bian S, Van Stappen T, Van Assche G, Vermeire S, et al. Influence of early adalimumab serum levels on immunogenicity and long-term outcome of anti-TNF naive Crohn’s disease patients: the usefulness of rapid testing. Aliment Pharmacol Ther. 2018;48:731–9.

    PubMed  CAS  Google Scholar 

  152. FDA. TYSABRI. [package insert]. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125104s960s963lbl.pdf. Accessed 15 Mar 2019.

  153. Rutgeerts P, Colombel JF, Reinisch W, Feagan BG, Rachmilewitz D, Olson A, et al. Infliximab induces and maintains mucosal healing in patients with active ulcerative colitis: the ACT trial experience. Gut. 2005;54(Suppl 7):A58.

    Google Scholar 

  154. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.

    PubMed  CAS  Google Scholar 

  155. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–9.

    PubMed  CAS  Google Scholar 

  156. Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132:863–73.

    PubMed  CAS  Google Scholar 

  157. Hyams JS, Griffiths A, Markowitz J, Baldassano RN, Faubion WA Jr, Colletti RB, et al. Safety and efficacy of adalimumab for moderate to severe Crohn’s disease in children. Gastroenterology. 2012;143:365–74.e2.

    Google Scholar 

  158. Papp KA, Blauvelt A, Bukhalo M, Gooderham M, Krueger JG, Lacour JP, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017;376:1551–60.

    PubMed  CAS  Google Scholar 

  159. Krueger JG, Ferris LK, Menter A, Wagner F, White A, Visvanathan S, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015;136:116–24.e7.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Robarts Clinical Trials, Inc., London, ON, Canada

    Pavine L. C. Lefevre, Lisa M. Shackelton & Niels Vande Casteele

  2. Division of Gastroenterology, Department of Medicine, School of Medicine, IBD Center, University of California San Diego, 9500 Gilman Drive #0956, La Jolla, CA, 92093, USA

    Niels Vande Casteele

Authors
  1. Pavine L. C. Lefevre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa M. Shackelton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Niels Vande Casteele
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Niels Vande Casteele.

Ethics declarations

Conflict of interest

PLCL and LMS have nothing to disclose. NVC reports research support from R-Biopharm and Takeda and consulting fees from Boehringer Ingelheim, Janssen, Pfizer, Progenity, Prometheus, and Takeda, outside of the submitted work.

Funding

NVC holds a Research Scholar Award form the American Gastroenterological Association (AGA).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lefevre, P.L.C., Shackelton, L.M. & Vande Casteele, N. Factors Influencing Drug Disposition of Monoclonal Antibodies in Inflammatory Bowel Disease: Implications for Personalized Medicine. BioDrugs 33, 453–468 (2019). https://doi.org/10.1007/s40259-019-00366-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40259-019-00366-1

Search

Navigation