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

  • Ashish Srinivasan
  • Peter De Cruz
  • Daniel van Langenberg
Chapter

Abstract

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.

Keywords

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

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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

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