Skip to main content
SpringerLink
Log in

Therapeutic Drug Monitoring of Biologic Agents

  • Chapter
  • First Online:
Treatment of Inflammatory Bowel Disease with Biologics

  • 1020 Accesses

Abstract

Monoclonal antibodies directed against tumor necrosis factor (TNF)-α have markedly impacted the course of Crohn’s disease and ulcerative colitis. However, it was recognized early on that these complex compounds are also potentially immunogenic, prompting the host to develop an antibody response to these medications. Anti-drug antibodies can increase drug clearance or directly impact the TNF binding site. In addition, there can be significant heterogeneity regarding the host metabolism of these biologic therapies.

The use of measuring anti-TNF drug levels and antibodies generated against these medications to guide medical decision-making, also known as therapeutic drug monitoring (TDM), allows clinicians to potentially maximize the use of these therapies. Assays assessing these drug and antibody levels have been used extensively for infliximab and adalimumab and are most commonly performed when drug levels are at their nadir, as a trough level.

Historically, TDM assays for infliximab and adalimumab have been used in a reactive fashion, i.e., when an individual patient with inflammatory bowel disease has lost response or not responded, and several studies support this. More recent studies have also begun to examine the potential benefit of prospectively monitoring drug and antibody levels during induction and maintenance in patients who are clinically doing well, i.e., in a proactive fashion. Initial results of the application of these assays are promising though further research is required. Moreover, further research will be required to determine the applicability of such methods with newer biologic therapies as they become available.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2013;4:CD000545.

    Google Scholar 

  2. Timmer A, McDonald JW, Tsoulis DJ, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;9:CD000478.

    Google Scholar 

  3. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med. 1997;337(15):1029–35.

    Article  CAS  PubMed  Google Scholar 

  4. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359(9317):1541–9.

    Article  CAS  PubMed  Google Scholar 

  5. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353(23):2462–76.

    Article  CAS  PubMed  Google Scholar 

  6. Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146(2):392–400.e393.

    Article  CAS  PubMed  Google Scholar 

  7. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383–95.

    Article  CAS  PubMed  Google Scholar 

  8. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology. 2006;130(2):323–33; quiz 591.

    Article  CAS  PubMed  Google Scholar 

  9. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):85–95; quiz e14-85.

    Article  CAS  PubMed  Google Scholar 

  10. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357(3):228–38.

    Article  CAS  PubMed  Google Scholar 

  11. Lichtenstein GR, Thomsen OO, Schreiber S, et al. Continuous therapy with certolizumab pegol maintains remission of patients with Crohn’s disease for up to 18 months. Clin Gastroenterol Hepatol. 2010;8(7):600–9.

    Article  CAS  PubMed  Google Scholar 

  12. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353(18):1912–25.

    Article  CAS  PubMed  Google Scholar 

  13. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med. 2005;353(4):362–8.

    Article  PubMed  Google Scholar 

  14. Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut. 2017;66(5):839–51.

    Google Scholar 

  15. Cassinotti A, Travis S. Incidence and clinical significance of immunogenicity to infliximab in Crohn’s disease: a critical systematic review. Inflamm Bowel Dis. 2009;15(8):1264–75.

    Article  PubMed  Google Scholar 

  16. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007;56(9):1232–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142(2):257–65; e251-253.

    Article  CAS  PubMed  Google Scholar 

  18. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007;357(3):239–50.

    Article  CAS  PubMed  Google Scholar 

  19. Ben-Horin S, Yavzori M, Katz L, et al. The immunogenic part of infliximab is the F(ab’)2, but measuring antibodies to the intact infliximab molecule is more clinically useful. Gut. 2011;60(1):41–8.

    Article  CAS  PubMed  Google Scholar 

  20. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699–710.

    Article  CAS  PubMed  Google Scholar 

  21. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348(7):601–8.

    Article  CAS  PubMed  Google Scholar 

  22. Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology. 2003;124(4):917–24.

    Article  CAS  PubMed  Google Scholar 

  23. 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(10):1248–54.

    Article  CAS  PubMed  Google Scholar 

  24. Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49–54.

    Article  CAS  PubMed  Google Scholar 

  25. Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology. 2009;137(5):1628–40.

    Article  CAS  PubMed  Google Scholar 

  26. Sandborn WJ, Abreu MT, D’Haens G, et al. Certolizumab pegol in patients with moderate to severe Crohn’s disease and secondary failure to infliximab. Clin Gastroenterol Hepatol. 2010;8(8):688–695.e682.

    Article  CAS  PubMed  Google Scholar 

  27. Imaeda H, Takahashi K, Fujimoto T, et al. Clinical utility of newly developed immunoassays for serum concentrations of adalimumab and anti-adalimumab antibodies in patients with Crohn’s disease. J Gastroenterol. 2014;49(1):100–9.

    Google Scholar 

  28. Lichtenstein GR. Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response. Ther Adv Gastroenterol. 2013;6(4):269–93.

    Article  CAS  Google Scholar 

  29. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(8):493–507.

    Article  CAS  PubMed  Google Scholar 

  30. Scott FI, Lichtenstein GR. Therapeutic drug monitoring of anti-TNF therapy in inflammatory bowel disease. Curr Treat Options Gastroenterol. 2014;12(1):59–75.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology. 2008;134(7):1861–8.

    Article  PubMed  Google Scholar 

  32. Reinisch W, Feagan BG, Rutgeerts PJ, et al. Infliximab concentration and clinical outcome in patients with ulcerative colitis. Gastroenterology. 2012;142(5):S114; [Abstract].

    Article  Google Scholar 

  33. Cornillie F, Hanauer SB, Diamond RH, 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(11):1721–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Reinisch W, Colombel JF, Sandborn WJ, et al. Factors associated with short- and long-term outcomes of therapy for Crohn’s disease. Clin Gastroenterol Hepatol. 2015;13(3):539–547.e532.

    Article  PubMed  Google Scholar 

  35. Ungar B, Levy I, Yavne Y, et al. Optimizing anti-TNF-alpha therapy: serum levels of infliximab and adalimumab associate with mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2016;14(4):550–57.

    Google Scholar 

  36. Li J, Paulson SK, Chiu Y-L, Robinson A, Lomax KG, Pollac PF. Evaluation of potential correlations between serum adalimumab concentration and remission in patients with Crohn’s disease in classic I and II. Gastroenterology. 2010;138(5):S101; [Abstract].

    Google Scholar 

  37. Sandborn WJ, Schreiber S, Hanauer SB, Colombel JF, Bloomfield R, Lichtenstein GR. Reinduction with certolizumab pegol in patients with relapsed Crohn’s disease: results from the PRECiSE 4 Study. Clin Gastroenterol Hepatol. 2010;8(8):696–702.e691.

    Article  CAS  PubMed  Google Scholar 

  38. Sandborn WJ, Hanauer SB, Pierre-Louis B, Lichtenstein GR. Certolizumab pegol plasma concentration and clinical remission in Crohn’s disease. Gastroenterology. 2012;142(5):S563; [Abstract Su2079].

    Article  Google Scholar 

  39. Adedokun OJ, Xu Z, Marano CW, 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. 2016;11(1):35–46.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Scott FI, Lichtenstein GR. Advances in therapeutic drug monitoring of biologic therapies in inflammatory bowel disease: 2015 in review. Curr Treat Options Gastroenterol. 2016;14(1):91–102.

    Article  PubMed  Google Scholar 

  41. Wang SL, Ohrmund L, Hauenstein S, et al. Development and validation of a homogeneous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum. J Immunol Methods. 2012;382(1–2):177–88.

    Article  CAS  PubMed  Google Scholar 

  42. Vaughn BP, Sandborn WJ, Cheifetz AS. Biologic concentration testing in inflammatory bowel disease. Inflamm Bowel Dis. 2015;21(6):1435–42.

    PubMed  PubMed Central  Google Scholar 

  43. Ben-Horin S, Waterman M, Kopylov U, et al. Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(4):444–7.

    Article  CAS  PubMed  Google Scholar 

  44. Afif W, Loftus EV Jr, Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105(5):1133–9.

    Article  CAS  PubMed  Google Scholar 

  45. Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108(6):962–71.

    Article  PubMed  Google Scholar 

  46. Pariente B, Pineton de Chambrun G, Krzysiek R, et al. Trough levels and antibodies to infliximab may not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18(7):1199–206.

    Article  PubMed  Google Scholar 

  47. Yanai H, Lichtenstein L, Assa 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(3):522–530.e522.

    Article  CAS  PubMed  Google Scholar 

  48. Velayos FS, Kahn JG, Sandborn WJ, Feagan BG. A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn’s disease who lose responsiveness to infliximab. Clin Gastroenterol Hepatol. 2013;11(6):654–66.

    Article  PubMed  Google Scholar 

  49. Velayos F. Reply: to PMID 23357488. Clin Gastroenterol Hepatol. 2014;12(2):346.

    Article  PubMed  Google Scholar 

  50. Steenholdt C, Brynskov J, Thomsen OO, 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(6):919–27.

    Google Scholar 

  51. Vaughn BP, Martinez-Vazquez M, Patwardhan VR, Moss AC, Sandborn WJ, Cheifetz AS. Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study. Inflamm Bowel Dis. 2014;20(11):1996–2003.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148(7):1320–1329.e1323.

    Article  CAS  PubMed  Google Scholar 

  53. OP029. Drug-concentration versus symptom-driven dose adaptation of Infliximab in patients with active Crohn’s disease: a prospective, randomised, multicentre trial (Tailorix). J Crohns Colitis. 2016;10(Suppl 1):S24.21–S24.

    Article  Google Scholar 

  54. Papamichael K, Van Stappen T, Jairath V, et al. Review article: pharmacological aspects of anti-TNF biosimilars in inflammatory bowel diseases. Aliment Pharmacol Ther. 2015;42(10):1158–69.

    Article  CAS  PubMed  Google Scholar 

  55. Park W, Hrycaj P, Jeka S, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013;72(10):1605–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72(10):1613–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Crohn’s and Colitis Center, University of Colorado Anschutz Medical Campus, 1635 Aurora Court, Room 2.031, Mail Stop F735, Aurora, CO, 80045, USA

    Frank I. Scott

  2. Division of Gastroenterology, Penn Presbyterian Medical Center, 218 Wright-Saunders Building, 51 N 39th Street, Philadelphia, PA, 19104, USA

    Mark T. Osterman

Authors
  1. Frank I. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark T. Osterman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark T. Osterman .

Editor information

Editors and Affiliations

  1. Beth Israel Deaconess Medical Center Center for Inflammatory Bowel Disease, Harvard Medical School, Boston, Massachusetts, USA

    Adam S. Cheifetz

  2. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Joseph D. Feuerstein

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Cite this chapter

Scott, F.I., Osterman, M.T. (2018). Therapeutic Drug Monitoring of Biologic Agents. In: Cheifetz, A., Feuerstein, J. (eds) Treatment of Inflammatory Bowel Disease with Biologics . Springer, Cham. https://doi.org/10.1007/978-3-319-60276-9_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-60276-9_8

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-60275-2

  • Online ISBN: 978-3-319-60276-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation