Select the genetic phenotypes for TPMT and NUDT15 to visualize the safety-optimized initial dosing strategy.
Guidelines & Evidence
Clinical Details
Section 1
When to Use
When to Use
Prior to initiating Thiopurine therapy (Azathioprine or 6-Mercaptopurine) in patients with IBD
To identify patients at extreme risk of life-threatening myelosuppression (leukopenia/pancytopenia)
Standard of care in modern gastroenterology for preventing preventable drug toxicity
TPMT vs. NUDT15
TPMT variants are the primary driver of toxicity in Caucasian populations (~10%). NUDT15 variants are critical in East Asian and Hispanic populations (up to 20%), where it is the #1 predictor of early thiopurine-induced alopecia and leucopenia.
Section 2
Formula & Logic
Metabolizer Phenotypes
Normal (NM)
Two functional alleles. Normal risk.
Intermediate (IM)
One deficient allele. Moderate risk of toxicity.
Poor (PM)
Two deficient alleles. Extreme risk of fatal toxicity.
Dosing Adjustments (CPIC Guideline)
01
Normal TPMT/NUDT15: Start at standard dose (e.g., AZA 2.0–2.5 mg/kg).
02
Intermediate TPMT or NUDT15: Reduce starting dose to 30%–80% of normal (e.g., AZA 1.0–1.5 mg/kg).
03
Poor TPMT or NUDT15: Reduction by at least 10-fold OR use alternative therapy (High risk).
Section 3
Pearls/Pitfalls
The "Poor Metabolizer" Catastrophe
Patients with a TPMT "Poor" phenotype who are given standard doses will develop profound, prolonged marrow suppression within 4–6 weeks. This event carries a mortality risk of ~5–10% due to septic complications. Genotyping identifies these patients with > 90% sensitivity.
NUDT15 and Hair Loss
In Asian populations, early-onset severe alopecia (hair loss) is a hallmark sign of NUDT15 deficiency and impending leucopenia. If a patient reports rapid hair loss in the first month of AZA, therapy should be stopped and NUDT15 status checked immediately.
Clinical Pearls
Genotyping (DNA) is preferred over enzyme activity testing (EAT) if the patient has received a blood transfusion in the last 3 months
Normal genotype does not guarantee safety; all patients require weekly WBC/Liver monitoring for the first month
Low-dose Allopurinol (100mg) strategy can be used even in Intermediate metabolizers to shunt metabolism toward 6-TGN efficiently
Section 4
Next Steps
Treatment Strategy
01
PM Genotype: Switch to Biological (Infliximab/Ustekinumab) or JAK inhibitor (Tofacitinib); Avoid Thiopurines.
02
IM Genotype: Start low and slow; Check metabolites at 4 weeks.
Complementary Tools
Thiopurine Metabolite Interpreter (6-TGN/6-MMP)
Harvey-Bradshaw Index
Mayo Score for UC
Section 5
Evidence Appraisal
CPIC Guideline
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update.
Relling MV et al. • Clinical Pharmacology & Therapeutics. 2019;105(5):1095-1105. The global authority on dosing.
The TPMT/Thiopurine link was first described in the late 1970s. However, the NUDT15 link (2014) was a major breakthrough that explained why Asian patients were "intolerant" to what were previously considered "standard" Western doses.
