Enzyme testing

Pre-therapy testing can identify patients at risk for bone marrow suppression or organ toxicity from thiopurines due to low TPMT activity and a diminished ability to rid the body of the medication’s active form. Enzyme activity testing can detect both deficient and hyperactive TPMT activity and identify individuals at risk for therapeutic resistance.

Key testing

• TPMT3 | Thiopurine Methyltransferase Activity Profile, Erythrocytes

Advantages

• Measures enzyme activity in patient's blood to determine thiopurine metabolization.
• Measures TPMT activity using three enzyme substrates in separate reactions, which do not interfere with each other and compete for TPMT.
• Reduces inconclusive results obtained when using only one substrate to measure TPMT activity.
• Integrates results from the three enzyme reactions into a likelihood score of having reduced, deficient, or hyperactive TPMT activity determined through bioinformatic analysis using Collaborative Laboratory Integrated Reports (CLIR).

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Genotype testing

Enzyme and genotype testing can be used together to assess patient risk prior to therapy initiation. TPMT3 enzyme testing can detect individuals with increased metabolism and rare variants not included in the genotyping test. However, genotyping is required to test for genetic variations in NUDT15, an enzyme that helps break down thiopurines in the body and has been shown to affect thiopurine toxicity.^1,2

Key testing

• TPNUQ | Thiopurine Methyltransferase (TPMT) and Nudix Hydrolase (NUDT15) Genotyping, Varies

Advantages

• Uses patients’ genetic information to determine thiopurine metabolism.
• Evaluates for nuances in TPMT and NUDT15, which can have genetic variants strongly associated with thiopurine-related toxicity.
• Key in detecting predictive decreased or no activity alleles know to be more prevalent in Asian, Hispanic, and some Native American populations.³
• Noninvasive, child-friendly specimen collection option — saliva sample.

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Testing after therapy initiation

Metabolite monitoring after initiation of therapy enables clinicians to optimize therapy and identify elevated metabolite concentrations that may result in toxicity. This testing is recommended at four weeks post-therapy initiation, 12–16 weeks after therapy initiation, and annually. It can also be ordered as needed for dose changes, flare-ups, signs of toxicity, and suspicion of noncompliance, and for patients who do not respond to therapy as expected.

Key testing

• THIO | Thiopurine Metabolites, Whole Blood

Advantages

• Monitors treatment efficacy.
• Supports dosage adjustments.
• Supports patient compliance.

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References

1. Moriyama T, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016;48(4):367-73.
2. Kakuta Y, et al. Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping. J Gastroenterol. 2018;53(2):172-80.
3. Tanaka Y, Saito Y. Importance of NUDT15 polymorphisms in thiopurine treatments. J Pers Med. 2021;11(8):778. Published 2021 Aug 10. Doi:10.3390/jpm11080778.