Thiopurine drug management

End-to-end thiopurine testing

Thiopurines are widely known as an effective treatment for patients with inflammatory bowel disease. However, a significant portion of these patients display individual variation in thiopurine metabolism, resulting in an increased risk for adverse reactions and/or a suboptimal therapeutic response.

Mayo Clinic Laboratories’ end-to-end thiopurine testing was thoughtfully developed to consider genetic variations, both in individuals and certain ethic groups, that impact metabolic response. Through special attention to diversity and equity in health care, our testing minimizes iatrogenic health care disparities in certain populations, such as Asians, Latin Americans, and Native Americans. This decreases the risk of adverse events related to medical mismanagement and medication-related toxicity.


Testing prior to therapy initiation

Before starting patients on therapy, testing enables clinicians to detect individuals with low thiopurine methyltransferase (TPMT) activity who are at risk for excessive myelosuppression or severe hematopoietic toxicity when taking thiopurine drugs such as azathioprine or 6-mercaptopurine.

Additionally, testing can detect individuals with hyperactive TPMT activity who have therapeutic resistance to thiopurine drugs and may develop hepatotoxicity if treated with these drugs.


A Test in Focus

Ann Moyer, M.D., Ph.D., gives an overview of TPMT testing. She discusses when this testing should be ordered, how this testing compares to previous testing approaches, and what clinical action can be taken due to the results of this testing.

Which test should I order?

There are currently two types of testing that can be ordered to assess a patient’s risk prior to initiation of therapy: enzyme testing and genotype testing.

While current literature does not clearly demonstrate one test to be superior to the other for TPMT testing, enzyme testing can detect individuals with increased metabolism and rare variants not included in genotype testing. Recent research demonstrates that genetic variants in Nudix hydrolase 15 (NUDT15) also affect thiopurine toxicity.1,2 NUDT15 can only be tested through the genotype test. Therefore, both the genotyping assay and the enzyme assay are considered complementary and are recommended.

Enzyme testing for metabolic activity

Enzyme testing measures enzyme activity in a patient’s blood to determine how they metabolize thiopurines. If enzyme activity testing determines a patient has a reduced ability to metabolize thiopurines, a clinician may adjust dosages or prescribe a different drug.

Our enzyme, or phenotyping, assay offers TPMT activity in three separate reactions, which do not interfere with one another and compete for TPMT. This approach offers greater specificity than measuring TPMT activity with only a single analyte analysis, enabling more conclusive results.

Additionally, we’ve developed a multivariate pattern recognition software (CLIR) that aids post-analytical interpretation to detect TPMT phenotype pattern differences, drive precise medicine, and reduce clinical uncertainty.

Genotype testing for thiopurine metabolization

Genotype testing uses a patient’s genetic information to determine how they metabolize thiopurines. If patients have genetic variants that reduce their ability to metabolize thiopurines, clinicians may adjust dosages or prescribe a different drug.

In addition to testing for variants in TPMT, our testing also evaluates Nudix hydrolase 15 (NUDT15), which can have genetic variants that are strongly associated with thiopurine-related toxicity.

Including NUDT15 as part of testing is especially important when clinicians are treating more diverse populations, as deficiency is most common among East Asian (22.6%), South Asian (13.6%), and Native American (12.5%–21.2%) populations.3


A Test in Focus

Ann Moyer, M.D., Ph.D., gives an overview of NUDT15. She discusses when this testing should be ordered, how this testing compares to previous testing approaches, and what clinical action can be taken due to the results of this testing.

Testing after therapy initiation

Testing after initiation of therapy enables clinicians to optimize therapy and identify elevated metabolite concentrations that may result in toxicity. Additionally, clinicians should order testing as needed for dose changes, flare-up, signs of toxicity, suspicion of noncompliance, as well as in patients who do not respond to therapy as expected.

Recommended time points for order:

  • 4 weeks after starting treatment to ensure patient compliance and to look for early risk of toxicity
  • 12-16 weeks (after TGN metabolites have reached steady-state)
  • Annually

Learn more about how to order these evaluations at your institution.


References

1. Levine, et al. Inflamm Bowel Dis. 2011 Jun;17(6):1314-21.

2. Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016 Apr;48(4):367-73.

3. Moyer, A. NUDIT15: A bench to bedside success story. Clinical Biochemistry. 2021;9211:1-8.