TPMT/NUDT15 Thiopurine Dosing Simulator

Patient Genotype

TPMT phenotype

NUDT15 phenotype

Dosing Strategy

Standard dose (mg/kg/day) 2.5

Live Status

Pre-treatment

Actual dose given

0.0 mg/kg/d

Combined activity

100%

6-TGN metabolite

0 pmol/8×10⁸ RBC

ANC

4500 /µL

How it works

TPMT and NUDT15 are two independent enzymes that detoxify thiopurine drugs (azathioprine, 6-mercaptopurine). Low activity in either one lets more drug convert into the active, cytotoxic metabolite 6-thioguanine nucleotide (6-TGN), which suppresses bone-marrow neutrophil production. CPIC guidelines classify patients by a combined phenotype and cut the starting dose accordingly.

Combined activity  A = min(A_TPMT, A_NUDT15)
Genotype-guided dose  D = D_standard × clamp(A, 0.1, 1)
6-TGN steady state  C_ss = k × D / A   (low A ⇒ metabolite piles up per mg)
Myelosuppression (Emax model):
  ANC_target = ANC_base × [ 1 − Emax·C^γ / (EC50^γ + C^γ) ]
  dANC/dt = (ANC_target − ANC) / τ

TPMT / NUDT15 phenotype — sets each enzyme's relative activity (1.0 = normal, 0.1 = poor); the drug-inactivation bottleneck is whichever enzyme is weaker.
Fixed dose — every patient receives the same mg/kg/day regardless of genotype, the pre-genomic standard of care.
Genotype-guided — CPIC-style dose reduction scales the prescribed dose down for reduced-activity patients before therapy starts.
ANC (absolute neutrophil count) — the clinically monitored safety marker; below ~1500/µL is neutropenia, below ~500/µL is severe and infection-risk life-threatening.

Real-world relevance: CPIC and FDA labeling require TPMT/NUDT15 testing before thiopurine therapy — a poor metabolizer on a standard dose can develop fatal myelosuppression within 2–4 weeks, entirely preventable by pre-emptive genotyping.

Day 0 of 28

Healthy neutrophil Suppressed marrow

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