Most recent guideline publication:
Clinical Pharmacogenetics Implementation Consortium Guidelines for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 Update (November 2018)
Updates since publication:
March 2024: At the time of guideline publication, the extent of dosage reduction for thiopurines recommended for patients with intermediate metabolism for both TPMT and NUDT15 was unclear. A recent publication (PMID: 38230823) found that these individuals need a substantial dose reduction to mitigate toxicity in TPMT/NUDT15 IM/IM patients. The recommendation for a TPMT intermediate metabolizer/NUDT15 intermediate metabolizer has been updated for all thiopurines to recommend a starting dose at 20%-50% of normal dosages, depending on the starting dose. See here for updated recommendation tables (azathioprine, mercaptopurine, thioguanine). The pre- and post-tests alert tables have been updated accordingly.
April 2020: The authors of this guideline have added recommendations for TPMT and NUDT15 indeterminate phenotypes (i.e. combination of uncertain and/or unknown function alleles). TPMT indeterminate: Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. NUDT15 indeterminate: If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity. See here for updated recommendation tables (azathioprine, mercaptopurine, thioguanine). The diplotype-phenotype tables and pre- and post-tests alert tables have been updated accordingly below.
February 2019: Based on a recent publication confirming NUDT15*9 function and association with toxicity to thiopurines, NUDT15*9 function has been changed from “uncertain function” to “no function” (PMID: 30728528). The NUDT15 allele definition table, NUDT15 allele functionality table, NUDT15 diplotype-phenotype table and NUDT15 frequency table have been updated accordingly.
Tables and figures provided in the main manuscript of the guideline:
| Figure 1. Metabolism of azathioprine, thioguanine, and mercaptopurine |
| Table 1. Assignment of likely TPMT and NUDT15 phenotypes based on genotypes |
| Table 2. Recommended Dosing of Thiopurines by TPMT phenotype |
| Table 3. Recommended Dosing of Thiopurines by NUDT15 phenotype |
| Figure 2. Recommended Starting Doses of Thiopurines by TPMT and NUDT15 phenotype |
Supplement to: Clinical Pharmacogenetics Implementation Consortium Guidelines for thiopurine dosing based on TPMT and NUDT15 genotpes: 2018 Update (November 2018)
Tables and figure included in the supplement or referenced in the guidelinea:
| Figure S1. Idealized depictions of TPMT activity in erythrocytes from a normal, healthy, non-transfused population |
| Supplemental Table S1. Evidence linking TPMT genotype with Thiopurine phenotype |
| Supplemental Table S2. Evidence linking NUDT15 genotype with Thiopurine phenotype |
| TPMT allele definition table |
| TPMT allele functionality table |
| TPMT frequency table |
| TPMT diplotype-phenotype table |
| NUDT15 allele definition table |
| NUDT15 allele functionality table |
| NUDT15 frequency table |
| NUDT15 diplotype-phenotype table |
| Gene resource mapping |
| Drug resource mapping |
| Clinical decision support:b
Azathioprine pre- and post-test alerts and flow chart |
aSome of the tables included in the guideline may have been updated online, particularly to reflect newly described or newly characterized alleles. These include the gene-specific information tables (https://www.pharmgkb.org/page/pgxGeneRef) that support CPIC guidelines by providing information regarding star (*) allele definitions, allele function, allele frequency by major ethnic groups, translations of diplotype to phenotype, and gene resource mappings.
bThese resources support the adoption of CPIC guidelines into the electronic health record with clinical decision support and provide information that clinical implementers find helpful.
Older versions of this guideline:
Update (April 2013):
- Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing: 2013 Update
- 2013 supplement
Original publication (March 2011):
- Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing
- 2011 supplement
This guideline has been endorsed by the American Society of Health-System Pharmacists (ASHP).