Results: Patient with a known TPMT and/or NUDT15 genotype requiring thiopurines for non-malignant indications

A 50-year-old woman has been diagnosed with inflammatory bowel disease and the clinician would like to prescribe azathioprine. The patient has previously had pharmacogenomic testing as part of a clinical trial, and the genotype results indicate that she has two no-function TPMT variants, making her a TMPT poor metaboliser. This means that she is expected to have high levels of azathioprine-active metabolites (called thioguanine nucleotides) and is significantly more likely to experience severe side effects, such as haematological toxicity.

• Azathioprine and 6-mercaptopurine are types of thiopurines used as immunosuppressant therapy for a range of clinical indications. Azathioprine is a pro-drug of 6-mercaptopurine.
• Active metabolites of 6-mercaptopurine are transformed to inactive metabolites by the TPMT and NUDT15 enzymes.
• Genetic variants in the TPMT and NUDT15 genes increase an individual’s levels of active thiopurine metabolites, thereby increasing their risk of experiencing serious side effects from these drugs.
• Though frequencies vary across ethnic groups, up to 1 in 300 people have two no-function variants in TMPT, making them TMPT poor metabolisers, while up to 1 in 100 individuals have two no-function NUDT15 variants.
• Up to one-third of patients have to stop thiopurine treatment due to side effects, the main concerns being myelosuppression, hepatotoxicity, pancreatitis and gastric intolerance. Some patients with a poor metaboliser phenotype may even experience life-threatening myelotoxicity toxicity unless a reduced dose is prescribed.
• At the time of writing, TPMT and NUDT15 genotype testing for patients receiving azathioprine or 6-mercaptopurine for non-malignant indications is not routinely available and there is no NHS guidance on altering thiopurine prescriptions for non-malignant indications according to TPMT or NUDT15 status. Nevertheless, patients may present with TPMT and/or NUDT15 genotyping results provided by clinical trials, private testing or other healthcare systems, and this data can be used to inform choice of therapy or dosing of thiopurines (caution should be exercised when interpreting results from non-validated genomic tests).
• This article deals exclusively with thiopurine treatment in non-malignant indications. For information about malignant indications in patients with TPMP and NUDT15 variants, see Patient requiring 6-mercaptopruine for acute lymphoblastic leukaemia.

• Both the Clinical Pharmacogenetic Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have published pharmacogenetic prescribing recommendations for patients with TPMT or NUDT15 genetic variants who are receiving thiopurine treatment (see the resources list below).
• Neither guideline is for or against pharmacogenomic testing, but both provide dosing recommendations that include how to use pharmacogenetic information if it is already known.
• Pharmacogenetic dosing guidance for thiopurines is complex and you should review the latest, most up-to-date version of the relevant guidelines prior to adjusting any prescription.
• Ensure that the rationale for using a genotype- or phenotype-guided thiopurine prescription is clearly stated in the patient’s medical notes and on the prescription, and is also explained to the patient.
• In addition, consider adding the information about the TPMT or NUDT15 genotype to the patient’s medical summary, to help ensure that it will be passed on to other prescribers (for example, in secondary care).
• There are many other factors that can influence thiopurine efficacy and adverse effects, including drug interactions and co-morbidities. As with all pharmacogenomic results, dosing should take these other clinical factors into account.

For clinicians

• CPIC: Guideline for thiopurines and TPMT and NUDT15
• PharmGKB: Annotation of CPIC guideline for azathioprine and NUDT15, TPMT
• PharmGKB: Annotation of CPIC guideline for mercaptopurine and NUDT15, TPMT
• PharmGKB: Annotation of DPWG guidance for azathioprine and TPMT
• UK Clinical Pharmacy Association: Guideline for 6-mercaptopurine dosing based on TPMT and NUDT15 genotypes

References:

• Hindorf U and Lindqvist Appell M. ‘Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function’. Journal of Crohn’s and Colitis 2012: volume 6, issue 6, pages 655–659. DOI: 10.1016/j.crohns.2011.11.014
• Warner B, Johnston E, Arenas-Hernandez M and others. ‘A practical guide to thiopurine prescribing and monitoring in IBD’. Frontline Gastroenterology 2018: volume 9, issue 1, pages 10–15. DOI: 10.1136/flgastro-2016-100738