Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT
Summary
Consider an alternate agent or extreme dose reduction of mercaptopurine for patients who are TPMT or NUDT15 poor metabolizers. Start at 30-80% of target dose for patients who are intermediate metabolizers of either TPMT or NUDT15. Start at 20-50% of target dose for patients who are intermediate metabolizers of both TPMT and NUDT15.
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Alleles not present in the above pull-down menus have no recommendation.
Annotation
This annotation is based on the CPIC® guideline for thiopurines and TPMT and NUDT15.
February 2024 Update
CPIC have updated the recommendations for patients who are intermediate metabolizers of both TPMT and NUDT15. Patients who are intermediate metabolizers or possible intermediate metabolizers for both genes are recommended to begin with a starting dose of 20-50% of the normal dosage. The recommendations in the genotype picker tool and on this annotation page have been updated accordingly.
October 2018 Update
Advance online publication November 2018.
- The 2018 update of CPIC guidelines regarding azathioprine, thioguanine and mercaptopurine, have been published in Clinical Pharmacology and Therapeutics. Literature published between October 2012 to June 2017 was reviewed, recommendations and supplemental information was updated.
- These guidelines are applicable to:
- pediatric patients
- adult patients
- Excerpt from the 2018 thiopurine dosing guideline update:
- "TPMT activity exhibits a monogenic co-dominant 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 reduces the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression."
- Download and read:
- Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 Update
- 2018 supplement
- TPMT Gene-Specific Information Tables
- NUDT15 Gene-Specific Information Tables
- Mercaptopurine Drug Resource Mappings
- Mercaptopurine Pre and Post Test Alerts
- Mercaptopurine Clinical Decision Support Flow Chart
Table 1: Recommended dosing of mercaptopurine by TPMT phenotype
Adapted from Tables 1 and 2 of the 2018 guideline update.
Table 2: Recommended dosing of mercaptopurine by NUDT15 phenotype
Adapted from Tables 1 and 2 of the 2018 guideline update.
Table 3: Recommended dosing of mercaptopurine by TPMT and NUDT15 phenotypes
Adapted from Figure 2 and Table 2 of the 2018 guideline update.
May 2016 Update on PharmGKB
Several studies have reported that individuals who carry low-function alleles for NUDT15 are unable to tolerate usual doses of thiopurines. [Articles:25108385, 25624441, 26033531, 26076924, 26405151, 26503813, 26590936, 26735160, 26878724] These alleles are more common among those of Asian ancestry and Hispanic ethnicity than others. [Articles:25624441, 26878724] The dose tolerated by those with two low-function alleles is only ~ 10% that tolerated by those with no low-function NUDT15 or TPMT alleles. [Articles:25624441, 26878724] CPIC is planning a guideline to address NUDT15 variants and possible dosing recommendations for thiopurines.
April 2013 Update
Advance online publication January 2013
- The 2013 update of CPIC guidelines regarding azathioprine, thioguanine and mercaptopurine, have been published in Clinical Pharmacology and Therapeutics. Literature published between June 2010-November 2012 was reviewed and there is no new evidence that would change the original guidelines. Therefore, the dosing recommendations in the original publication remain clinically current.
- These guidelines are applicable to:
- pediatric patients
- adult patients
- Download and read:
March 2011
Advance online publication January 2011.
- Guidelines regarding the use of pharmacogenomic tests in dosing for azathioprine, thioguanine and mercaptopurine were published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
- Excerpt from the 2011 thiopurine dosing guidelines:
- "Thiopurines are most commonly used to treat nonmalignant conditions but are also critical anticancer agents. The approach to dosing adjustments based on TPMT status may differ depending on the clinical indication and the propensity to initiate therapy at higher vs. lower starting doses. We and others advocate testing for TPMT status prior to initiating thiopurine therapy, so that starting dosages can be adjusted accordingly."
- Download and read: