UGT1A1 Irinotecan Toxicity Simulator

UGT1A1 Genotype

Genotype sets glucuronidation activity — how fast the liver clears SN-38 via UGT1A1.

Dosing

Irinotecan dose 180 mg/m²

Simulation speed 1.0×

Live Readouts

SN-38 plasma conc.0.0 ng/mL

Cumulative AUC0.0 ng·h/mL

Grade 0 — Minimal risk Predicted ANC nadir: 100% of baseline

How it works

Irinotecan is a prodrug: carboxylesterases convert it to SN-38, the active (and toxic) metabolite. SN-38 is cleared almost entirely by UGT1A1, which glucuronidates it to inert SN-38G for excretion. A one-compartment model with first-order absorption and elimination (the Bateman function) describes the plasma curve:

C(t) = Dose·kA / [V·(kA − kE)] · (e^(−kE·t) − e^(−kA·t))

kA  = 0.90 /h    (conversion rate, genotype-independent)
kE  = kE0 · AS   (SN-38 clearance rate via UGT1A1)
AS  = activity score: NM 1.00 · IM 0.55 · PM 0.22
AUC(∞) = Dose / (V·kE)

The *28 allele adds a TA repeat in the UGT1A1 promoter, lowering enzyme expression. Fewer functional alleles → smaller kE → the same dose produces a higher peak and a much larger area under the SN-38 curve (AUC), which drives dose-limiting neutropenia. Predicted ANC (absolute neutrophil count) nadir uses an E_max pharmacodynamic model:

Nadir% = 100 · [1 − Emax·AUC / (EC50 + AUC)]
Emax = 0.85,  EC50 = 40 ng·h/mL

Genotype buttons — set UGT1A1 activity score (AS), i.e. how many functional alleles the patient carries.
Dose slider — total irinotecan dose per body-surface area; scales the whole SN-38 curve linearly.
Administer Dose — restarts the infusion clock at t = 0 and resets the running AUC integral.
Orbiting particles are SN-38 molecules; their number tracks C(t) live, and each one is pulled into the glowing UGT1A1 enzyme cluster and cleared at a rate set by kE — visibly slower for poor metabolizers.

Clinically, CPIC guidelines recommend a reduced starting dose for UGT1A1 poor metabolizers (*28/*28, and some *6/*6 or *6/*28 genotypes in East Asian patients) to avoid severe neutropenia and diarrhea.

t = 0.0 h

SN-38 molecule UGT1A1 enzyme cluster

⚠ Couldn't load the 3D engineThree.js failed to load from the CDN. Check your connection and reload.