CPIC Guideline: TPMT and NUDT15 Genotyping Essential for Safe Thiopurine Dosing Across Ancestries
This updated CPIC guideline provides dosing recommendations for azathioprine, mercaptopurine, and thioguanine based on both TPMT and NUDT15 genotypes, the latter being particularly relevant for patients of Asian and Hispanic descent. Loss-of-function variants in either gene predispose to severe myelosuppression, and preemptive testing can prevent potentially fatal toxicity. Laboratories offering pharmacogenomic panels should include both genes to ensure equitable, ancestry-informed thiopurine safety across diverse patient populations.
The original study
Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update.
- Authors
- Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM, et al.
- Journal
- Clinical pharmacology and therapeutics
- Type
- Journal Article, Practice Guideline, Research Support, N.I.H., Extramural
- PMID
- 30447069
Original abstract
Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).