Thiopurines are widely used drugs whose activity depends on cellular metabolism. Here, the authors develop chemical tools to remove NUDT5 and show that protein loss, but not inhibition, alters drug re...

Thiopurine toxicity and dose adjustment · Clin Pharmacol Ther 2026

We are excited to announce our latest release! This update is highly recommended. It fixes an issue with pharmcat_pipeline where it uses the original input VCF instead of the preprocessed VCF if it is given a directory instead of a file. Data highlights * PharmVar: new alleles were released for CYP2C9, CYP2D6, CYP3A4, CYP3A5, NUDT15 * ClinPGx: * updates released/published for the CPIC Guideline for RYR1, CACNA1S and Volatile anesthetic agents and Succinylcholine and the CPIC Guideline f

A correction to Table 1 of the "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update" was published in Clinical Pharmacology and Therapeutics. An individual carrying one no function allele plus one decreased function allele is an Intermediate Metabolizer (IM), not a Possible Intermediate Metabolizer as shown in the original table. The therapeutic recommendations for TPMT IMs and Possible IMs are the same. The

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update has been published in Clinical Pharmacology and Therapeutics (PMID:41618934). The guideline contains multiple updates to the previous recommendations for adjusting the starting doses of azathioprine, mercaptopurine and thioguanine according to the combination of TPMT and NUDT15 phenotypes derived from genotypes and the specific indication (i.e. malignant

Purine nucleotides are critical for nucleic acid synthesis, signaling, and cellular metabolism. Thiopurines (TPs), including 6-mercaptopurine and 6-thioguanine, are cornerstone agents for the treatment of acute lymphoblastic leukemia (ALL). TP efficacy and cytotoxicity depend on the metabolism and intracellular activation of TPs, a process influenced by pharmacogenes such as thiopurine-S methyltransferase (TPMT) and NUDIX (nucleoside diphosphates linked to moiety-X) hydrolase 15 (NUDT15). In this issue of the JCI, Maillard et al. identified NUDT5 as a determinant of TP pharmacology. They demonstrated that loss of NUDT5 conferred TP resistance by impairing drug activation and DNA damage responses. Metabolomics studies by Maillard and others revealed that NUDT5 may regulate the balance between the de novo purine synthesis and salvage pathways. Clinically, NUDT5 expression variants were associated with altered TP tolerance. These findings position NUDT5 as a key modulator of nucleotide metabolism and TP efficacy, with potential implications for pharmacogenomics-guided therapy optimization in ALL.

Thiopurines are anticancer agents used for the treatment of leukemia and autoimmune diseases. These purine analogs are characterized by a narrow therapeutic index because of the risk of myelosuppression. With the discovery of NUDIX hydrolase 15 (NUDT15) as a major modulator of thiopurine metabolism and toxicity, we sought to comprehensively examine all members of the NUDIX hydrolase family for their effect on the pharmacologic effects of thiopurine. By performing a NUDIX-targeted CRISPR/Cas9 screen in leukemia cells, we identified NUDT5, whose depletion led to drastic thiopurine resistance. NUDT5 deficiency resulted in a nearly complete depletion of active metabolites of thiopurine and the loss of thioguanine incorporation into DNA. Mechanistically, NUDT5 deletion resulted in substantial alteration in purine nucleotide biosynthesis, as determined by steady-state metabolomics profiling. Stable isotope tracing demonstrated that the loss of NUDT5 was linked to a marked suppression of the purine salvage pathway but with minimal effects on purine de novo synthesis. Finally, we comprehensively identified germline genetic variants in NUDT5 associated with thiopurine-induced myelosuppression in 582 children with acute lymphoblastic leukemia. Collectively, these results pointed to NUDT5 as a key regulator of the thiopurine response primarily through its effects on purine homeostasis, highlighting its potential to inform individualized thiopurine therapy.

This secondary analysis of a randomized clinical trial examines the use of pharmacogenetic-informed prescribing of fluoropyrimidines and/or irinotecan in patients with gastrointestinal cancer.

A New Blueprint for Safer Thiopurine Therapy The Clinical Pharmacogenetics Implementation Consortium (CPIC) has released its 2025 update to the guideline for dosing thiopurine drugs—including azathioprine, mercaptopurine, and thioguanine—based on genetic testing. The guideline details how specific genetic variants in the TPMT and NUDT15 enzymes, which are critical for metabolizing these drugs, can predict a patient's risk of severe adverse effects like myelosuppression.

A New Guideline for Safer Emergency Prescribing The Clinical Pharmacogenetics Implementation Consortium (CPIC) has released a crucial 2025 update to its guideline for thiopurine dosing. These drugs, including azathioprine, are used in acute and chronic inflammatory conditions. The guideline provides specific recommendations for adjusting starting doses based on genetic testing for two key enzymes, TPMT and NUDT15. Individuals with genetic variants that reduce or eliminate the function of these enzymes are at a significantly higher risk of severe, life-threatening myelosuppression when given standard doses.

The Genetic Key to Safer Pediatric Immunosuppression The Clinical Pharmacogenetics Implementation Consortium (CPIC) has released a critical 2025 update to its guideline for thiopurine dosing. These immunosuppressant drugs, including mercaptopurine, thioguanine, and azathioprine, are used to treat conditions like childhood leukemia and autoimmune disorders. The guideline provides specific recommendations for adjusting starting doses based on a patient's genetic profile for the TPMT and NUDT15 enzymes.

Updated genetic roadmap for safer thiopurine dosing in autoimmune care The Clinical Pharmacogenetics Implementation Consortium (CPIC) has released its 2025 update on thiopurine dosing, solidifying the role of genetic testing for TPMT and NUDT15 enzymes. This guideline provides specific recommendations for adjusting starting doses of drugs like azathioprine and mercaptopurine based on a patient's genotype to mitigate the risk of severe adverse effects, including life-threatening myelosuppression.

A Pharmacogenetic Roadmap for Safer Thiopurine Dosing The Clinical Pharmacogenetics Implementation Consortium (CPIC) has issued a crucial 2025 update to its guideline for thiopurine dosing, focusing on the enzymes TPMT and NUDT15. These enzymes are responsible for metabolizing drugs like azathioprine, mercaptopurine, and thioguanine, which are used in conditions ranging from autoimmune diseases to post-transplant immunosuppression. The guideline provides specific, genotype-based recommendations for adjusting starting doses to mitigate the risk of severe, potentially life-threatening myelosuppression, a known adverse effect in patients with reduced-function genetic variants.

A Genomic Blueprint for Safer Thiopurine Dosing The Clinical Pharmacogenetics Implementation Consortium (CPIC) has released a crucial 2025 update to its guideline for thiopurine dosing, a cornerstone of personalized medicine in pharmacology. This update refines recommendations for adjusting starting doses of drugs like azathioprine, mercaptopurine, and thioguanine based on genetic testing for two key enzymes: thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15).