Therapeutic Drug Monitoring in Inflammatory Bowel Disease: Optimising Therapeutic Effectiveness of Thiopurines

  • Ashish Srinivasan
  • Peter De Cruz
  • Daniel van Langenberg


Azathioprine (AZA) and 6-mercaptopurine (6-MP) remain important therapeutics in the management of Crohn’s disease (CD) and ulcerative colitis (UC). Despite their clinical effectiveness, thiopurines present clinicians with several challenges including their narrow therapeutic index and risk of adverse reactions. These factors account for high rates of discontinuation, underscoring the importance of optimal dosing strategies geared towards maximising clinical effectiveness and minimising intolerances.

There are a number of methods to optimise therapy including measuring thiopurine-S-methyltransferase (TPMT) genotype or phenotype, manipulating metabolism through the addition of allopurinol in shunters, and splitting the thiopurine dose to reduce adverse effects. Furthermore, 6-MP has been established as a safe and effective alternative to AZA intolerance, while thioguanine presents an alternative in patients intolerant of either AZA or 6-MP.

Understanding their pharmacokinetic profile and acknowledging inter-patient variations also remain important, particularly given thiopurine metabolite levels have been shown to correlate poorly with dose. Despite the lack of high-quality, supportive data, there is sufficient evidence to suggest that targeting therapeutic 6-thioguanine nucleotide (6-TGN) levels in the setting of active disease is worthwhile, particularly given that subtherapeutic levels expose patients to side effects without comparative effectiveness. However, based on current evidence, recommending proactive thiopurine metabolite monitoring and optimisation relative to standard weight-based dosing remains uncertain. Thiopurines have also been shown to be useful when used in combination with antitumour necrosis factor-α (anti-TNF) agents, although optimal dosing and 6-TGN in this context remain to be clearly defined. Metabolite testing also plays an important role in evaluating suboptimal response, poor adherence, and/or identifying the cause of suspected toxicities, all of which provide valuable information to direct clinical decision-making.

This chapter will concentrate on thiopurine optimisation in inflammatory bowel disease (IBD), with a particular focus on aspects of thiopurine metabolite monitoring to guide clinical decision-making.


Therapeutic drug monitoring Thiopurine Azathioprine Mercaptopurine Inflammatory bowel disease Ulcerative colitis Crohn’s disease 


  1. 1.
    Gisbert JP, Gomollón F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103:1783.CrossRefGoogle Scholar
  2. 2.
    Ardizzone S, Maconi G, Russo A, et al. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut. 2006;55:47–53.CrossRefGoogle Scholar
  3. 3.
    Lopez-Sanroman A, Bermejo F, Carrera E, Garcia-Plaza A. Efficacy and safety of thiopurinic immunomodulators (azathioprine and mercaptopurine) in steroid-dependent ulcerative colitis. Aliment Pharmacol Ther. 2004;20:161–6.CrossRefGoogle Scholar
  4. 4.
    Lim W-C, Hanauer S. Aminosalicylates for induction of remission or response in Crohn’s disease. Cochrane Database Syst Rev. 2010;12:CD008870.Google Scholar
  5. 5.
    Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.CrossRefGoogle Scholar
  6. 6.
    Chevaux JB, Peyrin-Biroulet L, Sparrow MP. Optimizing thiopurine therapy in inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:1428–35.CrossRefGoogle Scholar
  7. 7.
    Cosnes J, Nion-Larmurier I, Beaugerie L, et al. Impact of the increasing use of immunosuppressants in Crohn’s disease on the need for intestinal surgery. Gut. 2005;54:237–41.CrossRefGoogle Scholar
  8. 8.
    Jharap B, Seinen ML, De Boer N, et al. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis. 2010;16:1541–9.CrossRefGoogle Scholar
  9. 9.
    Yatscoff RW, Aspeslet LJ, Gallant HL. Pharmacodynamic monitoring of immunosuppressive drugs. Clin Chem. 1998;44:428–32.PubMedGoogle Scholar
  10. 10.
    Elion G. The George Hitchings and Gertrude Elion lecture: the pharmacology of azathioprine. Ann N Y Acad Sci. 1990;685:1239–56.Google Scholar
  11. 11.
    Aarbakke J, Janka-Schaub G, Elion GB. Thiopurine biology and pharmacology. Trends Pharmacol Sci. 1997;18:3–7.CrossRefGoogle Scholar
  12. 12.
    Sandborn W. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol. 1996;91:423–33.PubMedGoogle Scholar
  13. 13.
    Moreau AC, Paul S, Del Tedesco E, et al. Association between 6-thioguanine nucleotides levels and clinical remission in inflammatory disease: a meta-analysis. Inflamm Bowel Dis. 2014;20:464–71.CrossRefGoogle Scholar
  14. 14.
    Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980;32:651.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Ansari A, Hassan C, Duley J, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther. 2002;16:1743–50.CrossRefGoogle Scholar
  16. 16.
    Chocair PR, Duley JA, Simmonds HA, Cameron JS. The importance of thiopurine methyltransferase activity for the use of azathioprine in transplant recipients. Transplantation. 1992;53:1051–6.CrossRefGoogle Scholar
  17. 17.
    Soria-Royer C, Legendre C, Mircheva J, et al. Thiopurine-methyl-transferase activity to assess azathioprine myelotoxicity in renal transplant recipients. Lancet. 1993;341:1593–4.CrossRefGoogle Scholar
  18. 18.
    Dubinsky MC, Yang H, Hassard PV, et al. 6-mp metabolite profiles provide a biochemical explanation for 6-mp resistance in patients with inflammatory bowel disease. Gastroenterology. 2002;122:904–15.CrossRefGoogle Scholar
  19. 19.
    Coenen MJ, de Jong DJ, van Marrewijk CJ, et al. Identification of patients with variants in tpmt and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology. 2015;149:907–17. e7.CrossRefGoogle Scholar
  20. 20.
    Newman WG, Payne K, Tricker K, et al. A pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to azathioprine treatment: the target study. Pharmacogenomics. 2011;12:815–26.CrossRefGoogle Scholar
  21. 21.
    Sayani FA, Prosser C, Bailey RJ, Jacobs P, Fedorak RN. Thiopurine methyltransferase enzyme activity determination before treatment of inflammatory bowel disease with azathioprine: effect on cost and adverse events. Can J Gastroenterol Hepatol. 2005;19:147–51.Google Scholar
  22. 22.
    Colombel JF, Ferrari N, Debuysere H, et al. Genotypic analysis of thiopurine s-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology. 2000;118:1025–30.CrossRefGoogle Scholar
  23. 23.
    Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118:705–13.CrossRefGoogle Scholar
  24. 24.
    Yang S-K, Hong M, Baek J, et al. A common missense variant in nudt15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014;46:1017.CrossRefGoogle Scholar
  25. 25.
    Zabala-Fernández W, Barreiro-de Acosta M, Echarri A, et al. A pharmacogenetics study of tpmt and itpa genes detects a relationship with side effects and clinical response in patients with inflammatory bowel disease receiving azathioprine. J Gastrointestin Liver Dis. 2011;20:247–53.PubMedGoogle Scholar
  26. 26.
    Nielsen O, Vainer B, Rask-Madsen J. The treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther. 2001;15:1699–708.CrossRefGoogle Scholar
  27. 27.
    Cuffari C, Hunt S, Bayless T. Enhanced bioavailability of azathioprine compared to 6-mercaptopurine therapy in inflammatory bowel disease: correlation with treatment efficacy. Aliment Pharmacol Ther. 2000;14:1009–14.CrossRefGoogle Scholar
  28. 28.
    Sandborn WJ, Tremaine WJ, Wolf DC, et al. Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn’s disease. Gastroenterology. 1999;117:527–35.CrossRefGoogle Scholar
  29. 29.
    Dubinsky MC, Reyes E, Ofman J, et al. A cost-effectiveness analysis of alternative disease management strategies in patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Am J Gastroenterol. 2005;100:2239.CrossRefGoogle Scholar
  30. 30.
    Cuffari C, Theoret Y, Latour S, Seidman G. 6-mercaptopurine metabolism in Crohn’s disease: correlation with efficacy and toxicity. Gut. 1996;39:401–6.CrossRefGoogle Scholar
  31. 31.
    Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut. 2001;48:642–6.CrossRefGoogle Scholar
  32. 32.
    Gupta P, Gokhale R, Kirschner BS. 6-mercaptopurine metabolite levels in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2001;33:450–4.CrossRefGoogle Scholar
  33. 33.
    Wright S, Sanders D, Lobo A, Lennard L. Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease. Gut. 2004;53:1123–8.CrossRefGoogle Scholar
  34. 34.
    Seidman EG. Clinical use and practical application of tpmt enzyme and 6-mercaptopurine metabolite monitoring in ibd. Rev Gastroenterol Disord. 2003;3:S30–S7.PubMedGoogle Scholar
  35. 35.
    Haines ML, Ajlouni Y, Irving PM, et al. Clinical usefulness of therapeutic drug monitoring of thiopurines in patients with inadequately controlled inflammatory bowel disease. Inflamm Bowel Dis. 2010;17:1301–7.CrossRefGoogle Scholar
  36. 36.
    Gomollon F, Dignass A, Annese V, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 1: diagnosis and medical management. J Crohns Colitis. 2017;11:3–25.CrossRefGoogle Scholar
  37. 37.
    Reinshagen M, Schütz E, Armstrong VW, et al. 6-thioguanine nucleotide–adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active Crohn disease: results from a randomized, controlled, open trial. Clin Chem. 2007;53:1306–14.CrossRefGoogle Scholar
  38. 38.
    Dassopoulos T, Dubinsky MC, Bentsen JL, et al. Randomised clinical trial: individualised vs weight-based dosing of azathioprine in Crohn’s disease. Aliment Pharmacol Ther. 2014;39:163–75.CrossRefGoogle Scholar
  39. 39.
    Casteele NV, 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(3):835–57.CrossRefGoogle Scholar
  40. 40.
    Roblin X, Boschetti G, Williet N, et al. Azathioprine dose reduction in inflammatory bowel disease patients on combination therapy: an open-label, prospective and randomised clinical trial. Aliment Pharmacol Ther. 2017;46:142–9.CrossRefGoogle Scholar
  41. 41.
    Osterman MT, Kundu R, Lichtenstein GR, Lewis JD. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology. 2006;130:1047–53.CrossRefGoogle Scholar
  42. 42.
    Chouchana L, Narjoz C, Beaune P, Loriot MA, Roblin X. The benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2012;35:15–36.CrossRefGoogle Scholar
  43. 43.
    Bouguen G, Sninsky C, Tang KL, et al. Change in erythrocyte mean corpuscular volume during combination therapy with azathioprine and infliximab is associated with mucosal healing: a post hoc analysis from sonic. Inflamm Bowel Dis. 2015;21:606–14.CrossRefGoogle Scholar
  44. 44.
    Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol. 2007;5:209–14.CrossRefGoogle Scholar
  45. 45.
    Ansari A, Patel N, Sanderson J, et al. Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2010;31:640–7.CrossRefGoogle Scholar
  46. 46.
    Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol. 1995;39:456–9.CrossRefGoogle Scholar
  47. 47.
    Hande S, Wilson-Rich N, Bousvaros A, et al. 5-aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine. Inflamm Bowel Dis. 2006;12:251–7.CrossRefGoogle Scholar
  48. 48.
    De Boer NK, Wong DR, Jharap B, et al. Dose-dependent influence of 5-aminosalicylates on thiopurine metabolism. Am J Gastroenterol. 2007;102:2747.CrossRefGoogle Scholar
  49. 49.
    Andrews J, Travis S, Gibson P, Gasche C. Systematic review: does concurrent therapy with 5-asa and immunomodulators in inflammatory bowel disease improve outcomes? Aliment Pharmacol Ther. 2009;29:459–69.CrossRefGoogle Scholar
  50. 50.
    Shih D, Nguyen M, Zheng L, et al. Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-mmp metabolism. Aliment Pharmacol Ther. 2012;36:449–58.CrossRefGoogle Scholar
  51. 51.
    Kennedy N, Rhatigan E, Arnott I, et al. A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis. Aliment Pharmacol Ther. 2013;38:1255–66.CrossRefGoogle Scholar
  52. 52.
    Mulder C, van Sorge A. Why measure thiopurine methyltransferase activity? Direct administration of 6-thioguanine might be the alternative for 6-mercaptopurine or azathioprine. Gut. 2001;49:874–5.CrossRefGoogle Scholar
  53. 53.
    Dubinsky MC, Vasiliauskas EA, Singh H, et al. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology. 2003;125:298–303.CrossRefGoogle Scholar
  54. 54.
    De Boer N, Reinisch W, Teml A, et al. 6-thioguanine treatment in inflammatory bowel disease: a critical appraisal by a european 6-tg working party. Digestion. 2006;73:25–31.CrossRefGoogle Scholar
  55. 55.
    Lémann M, Mary J-Y, Colombel J-F, et al. A randomized, double-blind, controlled withdrawal trial in Crohn’s disease patients in long-term remission on azathioprine. Gastroenterology. 2005;128:1812–8.CrossRefGoogle Scholar
  56. 56.
    O’Donoghue D, Dawson A, Powell-Tuck J, Bown R, Lennard-Jones J. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease. Lancet. 1978;312:955–7.CrossRefGoogle Scholar
  57. 57.
    Wenzl HH, Primas C, Novacek G, et al. Withdrawal of long-term maintenance treatment with azathioprine tends to increase relapse risk in patients with Crohn’s disease. Dig Dis Sci. 2015;60:1414–23.CrossRefGoogle Scholar
  58. 58.
    Vilien M, Dahlerup J, Munck L, et al. Randomized controlled azathioprine withdrawal after more than two years treatment in Crohn’s disease: increased relapse rate the following year. Aliment Pharmacol Ther. 2004;19:1147–52.CrossRefGoogle Scholar
  59. 59.
    Hawthorne A, Logan R, Hawkey C, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ. 1992;305:20–2.CrossRefGoogle Scholar
  60. 60.
    Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the classic ii trial. Gut. 2007;56:1232–9.CrossRefGoogle Scholar
  61. 61.
    Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the charm trial. Gastroenterology. 2007;132:52–65.CrossRefGoogle Scholar
  62. 62.
    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;146:392–400. e3.CrossRefGoogle Scholar
  63. 63.
    Kotlyar DS, Lewis JD, Beaugerie L, et al. Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: a meta-analysis. Clin Gastroenterol Hepatol. 2015;13:847–58. e4.CrossRefGoogle Scholar
  64. 64.
    Kirchgesner J, Lemaitre M, Carrat F, et al. Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases. Gastroenterology. 2018;155:337–46.e10.CrossRefGoogle Scholar
  65. 65.
    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;11:444–7.CrossRefGoogle Scholar
  66. 66.
    Strik A, Brink G, Ponsioen C, et al. Suppression of anti-drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1128–34.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ashish Srinivasan
    • 1
    • 2
    • 3
  • Peter De Cruz
    • 1
    • 4
  • Daniel van Langenberg
    • 2
    • 3
  1. 1.Department of GastroenterologyAustin HealthMelbourneAustralia
  2. 2.Department of GastroenterologyEastern HealthMelbourneAustralia
  3. 3.Monash University, Department of MedicineMelbourneAustralia
  4. 4.Department of MedicineThe University of MelbourneMelbourneAustralia

Personalised recommendations