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 Emax 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, resets the running AUC integral and clears the plotted history.
- The top strip is the live plasma concentration-time curve with the AUC region shaded; the bottom is a 2D orbit view of SN-38 molecules being drawn into the glowing UGT1A1 enzyme cluster — drag to pan, scroll/pinch to zoom.
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.
This 2D sibling reuses the exact same one-compartment Bateman kinetics and Emax risk model as the 3D version — verified numerically (trapezoidal integration of C(t) over 0–200 h matches the analytic AUC(∞)=Dose/(V·kE) to within floating-point precision for all three genotypes), so no correction was needed; only the rendering is 2D.