Therapeutic Drug Monitoring in Inflammatory Bowel Disease: Current State and Future Perspectives

  • Niels Vande Casteele
  • Brian G. Feagan
  • Ann Gils
  • Séverine Vermeire
  • Reena Khanna
  • William J. Sandborn
  • Barrett G. Levesque
Inflammatory Bowel Disease (S Hanauer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Inflammatory Bowel Disease


Current available anti-inflammatory drugs, in particular monoclonal antibodies directed against the cytokine tumor necrosis factor α (TNF), have greatly enhanced the treatment of inflammatory bowel diseases (IBD). Although many patients respond to ant-TNF therapy, a proportion of patients will not respond (primary non-response) or will lose response to the drug over time (secondary non-response). This loss of response can be caused by patient, TNF-inhibitor, or disease-related factors influencing the pharmacokinetics and pharmacodynamics of the drug. Therefore, monitoring pharmacological parameters (i.e. therapeutic drug monitoring) may help guide therapeutic decisions. This review emphasizes interesting and important new findings, and provides an updated overview, on the subject of therapeutic drug monitoring. While exploring the hypothesis that “one size does not fit all”, we focused on the first prospective studies investigating the novel approach in IBD of ‘target concentration adjusted dosing’ and personalized medicine.


Adalimumab Anti-drug antibodies Anti-TNF Biologics Crohn’s disease Immunogenicity Infliximab Trough concentrations Ulcerative colitis 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132(1):52–65.PubMedCrossRefGoogle Scholar
  2. 2.
    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(9317):1541–9.PubMedCrossRefGoogle Scholar
  3. 3.
    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(23):2462–76.PubMedCrossRefGoogle Scholar
  4. 4.
    Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D’Haens G, Wolf DC, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142(2):257–65.PubMedCrossRefGoogle Scholar
  5. 5.
    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(1):85–95.PubMedCrossRefGoogle Scholar
  6. 6.
    Allez M, Karmiris K, Louis E, Van Assche G, Ben-Horin S, Klein A, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects. J Crohns Colitis. 2010;4(4):355–66.PubMedCrossRefGoogle Scholar
  7. 7.
    D’Haens GR, Panaccione R, Higgins PDR, Vermeire S, Gassull M, Chowers Y, et al. The London position statement of the world congress of gastroenterology on biological therapy for IBD with the European Crohn’s and colitis organization: when to start, when to stop, which drug to choose, and how to predict response[quest]. Am J Gastroenterol. 2011;106(2):199–212.PubMedCrossRefGoogle Scholar
  8. 8.
    Gisbert JP, Panes J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009;104(3):760–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Billioud V, Sandborn WJ, Peyrin-Biroulet L. Loss of response and need for adalimumab dose intensification in Crohn’s disease: a systematic review. Am J Gastroenterol. 2011;106(4):674–84.PubMedCrossRefGoogle Scholar
  10. 10.
    Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Van Assche G, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut. 2009;58(4):492–500.PubMedCrossRefGoogle Scholar
  11. 11.
    • 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(4):635–46. Review of pharmacological aspects associated with the use of anti-TNF monoclonal antibodies in IBD. PubMedCrossRefGoogle Scholar
  12. 12.
    Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004;93(11):2645–68.PubMedCrossRefGoogle Scholar
  13. 13.
    Nestorov I. Clinical pharmacokinetics of tumor necrosis factor antagonists. J Rheumatol Suppl. 2005;74:13–8.PubMedGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    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.PubMedCrossRefGoogle Scholar
  16. 16.
    Van Moerkercke W, Compernolle G, Ackaert C, Gils A, Vermeire S, Jürgens M, et al. S31 Mucosal healing in Crohn’s disease is associated with high infliximab trough levels. J Crohn’s Colitis Suppl. 2010;4(1):30–1.CrossRefGoogle Scholar
  17. 17.
    Karmiris K, Paintaud G, Noman M, Magdelaine-Beuzelin C, Ferrante M, Degenne D, 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.PubMedCrossRefGoogle Scholar
  18. 18.
    • Steenholdt C, Ainsworth MA, Tovey M, Klausen TW, Thomsen OO, Brynskov J, et al. Comparison of techniques for monitoring infliximab and antibodies against infliximab in Crohn’s disease. Ther Drug Monit. 2013;35(4):530–8. Comparative study of different assays used for therapeutic drug monitoring. PubMedCrossRefGoogle Scholar
  19. 19.
    • Vande Casteele N, Buurman DJ, Sturkenboom MGG, Kleibeuker JH, Vermeire S, Rispens T, et al. Detection of infliximab levels and anti-infliximab antibodies: a comparison of three different assays. Aliment Pharmacol Ther. 2012;36(8):765–71. Comparative study of different assays used for therapeutic drug monitoring. PubMedCrossRefGoogle Scholar
  20. 20.
    Wang SL, Ohrmund L, Hauenstein S, Salbato J, Reddy R, Monk P, 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.PubMedCrossRefGoogle Scholar
  21. 21.
    Imaeda H, Andoh A, Fujiyama Y. Development of a new immunoassay for the accurate determination of anti-infliximab antibodies in inflammatory bowel disease. J Gastroenterol. 2012;47(2):136–43.PubMedCrossRefGoogle Scholar
  22. 22.
    •• Reinisch W, Feagan BG, Rutgeerts PJ, Adedokun OJ, Cornillie FJ, Diamond R, et al. 566 Infliximab concentration and clinical outcome in patients with ulcerative colitis. Gastroenterology. 2012;142(5, Supplement 1):S-114. Abstract of post hoc analysis of ACT 1 and ACT 2 trials investigating the correlation between infliximab trough concentrations and clinical outcomes. Google Scholar
  23. 23.
    Murthy S, Kevans D, Seow CH, Newman A, Steinhart AH, Silverberg MS, et al. Sa2047 Association of serum infliximab and antibodies to Infliximab to long-term clinical outcome in acute ulcerative colitis. Gastroenterology. 2012;142(5, Supplement 1):S-388.Google Scholar
  24. 24.
    Feagan BG, Singh S, Lockton S, Hauenstein S, Ohrmund L, Croner LJ, et al. 565 Novel Infliximab (IFX) and Antibody-to-Infliximab (ATI) Assays are Predictive of Disease Activity in Patients With Crohn’s Disease (CD). Gastroenterology. 2012;142(5):S-114.Google Scholar
  25. 25.
    Bortlik M, Duricova D, Malickova K, Machkova N, Bouzkova E, Hrdlicka L, et al. Infliximab trough levels may predict sustained response to infliximab in patients with Crohn’s disease. J Crohns Colitis. 2013;7(9):736–43.PubMedCrossRefGoogle Scholar
  26. 26.
    •• Chiu YL, Rubin DT, Vermeire S, Louis E, Robinson AM, Lomax KG, et al. Serum adalimumab concentration and clinical remission in patients with Crohn’s disease. Inflamm Bowel Dis. 2013;19(6):1112–22. Post hoc analysis of CLASSIC 1 and CLASSIC 2 trials investigating the correlation between adalimumab trough concentration and clinical remission. PubMedCrossRefGoogle Scholar
  27. 27.
    •• Mostafa NM, Eckert D, Pradhan RS, Mensing S, Robinson AM, Sandborn WJ, et al. P333 Exposure-efficacy relationship (ER) for adalimumab during induction phase of treatment of adult patients with moderate to severe ulcerative colitis (UC). U Eur Gastroenterol J. 2013;1(1 suppl):A221–2. Abstract of post hoc analysis of ULTRA 2 trial investigating the exposure–response relationship for adalimumab. Google Scholar
  28. 28.
    Velayos FS, Sheibani S, Lockton S, Hauenstein S, Singh S, Terdiman JP, et al. 490 Prevalence of Antibodies to Adalimumab (ATA) and correlation between ata and low serum drug concentration on CRP and clinical symptoms in a prospective sample of IBD Patients. Gastroenterology. 2013;144(5):S-91.Google Scholar
  29. 29.
    Yarur AJ, Deshpande AR, Sussman DA, Hauenstein S, Lockton S, Barkin JS, et al. Tu1147 Serum adalimumab levels and antibodies correlate with endoscopic intestinal inflammation and inflammatory markers in patients with inflammatory bowel disease. Gastroenterology. 2013;144(5):S-774–5.Google Scholar
  30. 30.
    Imaeda H, Takahashi K, Fujimoto T, Bamba S, Tsujikawa T, Sasaki M, 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.PubMedCrossRefGoogle Scholar
  31. 31.
    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(1):80–4.PubMedCrossRefGoogle Scholar
  32. 32.
    • 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. Simulated model evaluating the cost-effectiveness of a TDM based approach for the treatment of secondary loss of response. PubMedCrossRefGoogle Scholar
  33. 33.
    •• 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. 2013 Jul 22. [Epub ahead of print]. First randomized controlled trial evaluating a TDM based approach for the treatment of secondary loss of response.Google Scholar
  34. 34.
    • Paul S, Del Tedesco E, Marotte H, Rinaudo-Gaujous M, Moreau A, Phelip JM, et al. Therapeutic drug monitoring of infliximab and mucosal healing in inflammatory bowel disease: a prospective study. Inflamm Bowel Dis. 2013;19(12):2568–76. Prospective observational study investigating the correlation between mucosal healing and serum adalimumab concentration before and after dose escalation at time of loss of response. PubMedCrossRefGoogle Scholar
  35. 35.
    Vermeire S, Gils A. Value of drug level testing and antibody assays in optimising biological therapy. Front Gastroenterol. 2012;4(1):41–3.CrossRefGoogle Scholar
  36. 36.
    Cleynen I, Vermeire S. Paradoxical inflammation induced by anti-TNF agents in patients with IBD. Nat Rev Gastroenterol Hepatol. 2012;9(9):496–503.PubMedCrossRefGoogle Scholar
  37. 37.
    Krieckaert C, Nair SC, Nurmohamed MT, van Dongen CJ, Lems WF, Lafeber FP, et al. Evaluating the cost-effectiveness of personalized treatment with adalimumab using serum drug level and anti-adalimumab antibodies in rheumatoid arthritis patients. Ann Rheum Dis. 2012;71(Suppl3):104.Google Scholar
  38. 38.
    Vande Casteele N, Compernolle G, Ballet V, Van Assche G, Gils A, Vermeire S, et al. 1159 Results on the optimisation phase of the prospective controlled Trough Level Adapted Infliximab Treatment (TAXIT) Trial. Gastroenterology. 2012;142(5):S-211–2.Google Scholar
  39. 39.
    •• Vande Casteele N, Gils A, Ballet V, Compernolle G, Peeters M, Van Steen K, et al. OP001 Randomised controlled trial of drug level versus clinically based dosing of infliximab maintenance therapy in IBD: final results of the TAXIT study. U Eur Gastroenterol J. 2013;1(1 suppl):A1. Abstract of final results of TAXIT trial. CrossRefGoogle Scholar
  40. 40.
    Vande Casteele N, Ballet V, Van Assche G, Rutgeerts P, Vermeire S, Gils A. Early serial trough and antidrug antibody level measurements predict clinical outcome of infliximab and adalimumab treatment. Gut. 2012;61(2):321.PubMedCrossRefGoogle Scholar
  41. 41.
    •• Cornillie F, Hanauer S, Diamond R, Wang J, Zelinger D, Xu Z, et al. Early serum infliximab trough level, clinical disease activity and CRP as markers of sustained benefit of infliximab treatment in Crohn’s disease: a post-hoc analysis of the ACCENT1 trial. Am J Gastroenterol. 2011;106:S462–3. Abstract of post hoc analysis of ACCENT 1 trial investigating serum infliximab trough concentration as a marker of sustained benefit. Google Scholar
  42. 42.
    • Baert FJ, Drobne D, Ballet V, Gils A, Vande Casteele N, Hauenstein S, et al. 492 Trough levels and antidrug antibodies predict safety and success of restarting Infliximab after a long drug holiday. Gastroenterology. 2013;144(5, Supplement 1):S-91–2. Retrospective cohort study evaluating the use of TDM when restarting infliximab after a drug holiday. Google Scholar
  43. 43.
    •• Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. 2013;108(1):40–7. Meta-analysis of the impact of antibodies to infliximab on serum infliximab concentrations and clinical outcomes. PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    • 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(6):962–71. Transient versus sustained antibodies to infliximab and their impact on infliximab pharmarcokinetics and clinical outcomes. PubMedCrossRefGoogle Scholar
  45. 45.
    Ungar B, Chowers Y, Yavzori M, Picard O, Fudim E, Har-Noy O, et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut. 2013 Sep 16. [Epub ahead of print]Google Scholar
  46. 46.
    • Ben-Horin S, Waterman M, Kopylov U, Yavzori M, Picard O, Fudim E, 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. Preliminary results suggesting that adding an immunosuppressant can eliminate anti-drug antibodies. PubMedCrossRefGoogle Scholar
  47. 47.
    Smith M, Blaker P, Patel C, Marinaki A, Arenas M, Escuredo E, et al. The impact of introducing thioguanine nucleotide monitoring into an inflammatory bowel disease clinic. Int J Clin Pract. 2013;67(2):161–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Vermeire S, Ferrante M, Rutgeerts P. Recent advances: personalised use of current Crohn’s disease therapeutic options. Gut. 2013;62(10):1511–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Fasanmade AA, Adedokun OJ, Olson A, Strauss R, Davis HM. Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis. Int J Clin Pharmacol Ther. 2010;48(5):297–308.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Niels Vande Casteele
    • 1
    • 2
    • 3
  • Brian G. Feagan
    • 3
  • Ann Gils
    • 2
  • Séverine Vermeire
    • 4
  • Reena Khanna
    • 3
  • William J. Sandborn
    • 1
    • 3
  • Barrett G. Levesque
    • 1
    • 3
  1. 1.Division of GastroenterologyUniversity of California San DiegoLa JollaUSA
  2. 2.KU Leuven Department of Pharmaceutical and Pharmacological SciencesLaboratory for Therapeutic and Diagnostic AntibodiesLeuvenBelgium
  3. 3.Robarts Clinical TrialsWestern UniversityLondonCanada
  4. 4.Department of GastroenterologyUniversity Hospitals LeuvenLeuvenBelgium

Personalised recommendations