Warfarin Pharmacogenomic Dosing Simulator

CYP2C9 Metabolizer

VKORC1 Sensitivity

Daily warfarin dose 5.00 mg/day

Simulation speed 0.75 days/s

Genotype-Guided Algorithm

Predicted dose

5.00 mg/day

Day

0.0

Current INR

1.00

Time in range 2–3

How it works

Two genes explain most of the person-to-person variation in warfarin maintenance dose. CYP2C9 is the liver enzyme that clears warfarin from plasma — reduced-function alleles (*2, *3) slow clearance and raise the drug's half-life. VKORC1 encodes the enzyme warfarin actually inhibits (vitamin K epoxide reductase) — the -1639G>A promoter variant lowers VKORC1 expression, so an A-carrier needs less drug to hit the same anticoagulant effect.

Elimination:      dC/dt = −k_el · C            k_el = ln2 / t½(CYP2C9)
Clotting factor:  dR/dt = k_in·(1 − I_max·C/(IC50+C)) − k_out·R
INR:              INR ≈ R^(−1.3)                 (R = 1 at baseline)

C is the plasma warfarin level (an indirect-response "turnover" model, the standard way warfarin PK/PD is described in the literature). Daily dosing adds a bolus to C at each day boundary; C then decays exponentially between doses at a rate set by the CYP2C9 half-life. R is the fraction of normal vitamin-K-dependent clotting factor activity — inhibition of its synthesis is an Emax function of C, with IC50 set by the VKORC1 genotype (a G-carrier needs a high C to inhibit synthesis; an AA homozygote is inhibited at a much lower C). INR rises as R falls.

The predicted dose box applies a simplified genotype-guided starting-dose rule modeled on published CYP2C9/VKORC1 dosing algorithms: it scales a 5 mg/day reference dose down for slower CYP2C9 clearance (less drug needed to reach the same level) and down again for higher VKORC1 sensitivity (less level needed to reach the same effect) — which is exactly why poor-metabolizer + AA patients land near 0.7 mg/day while normal + GG patients land near 5 mg/day, matching the direction (not the exact numbers) of real clinical dosing tables. Manually overshooting or undershooting that dose for a given genotype is the point of the sliders: it shows why fixed-dose warfarin initiation is dangerous in outlier metabolizers.

Green band on the chart — the therapeutic INR window (2.0–3.0) used for most indications.
Below the band — under-anticoagulated, clot risk. Above the band — over-anticoagulated, bleeding risk.

Educational model only — illustrative constants, not a clinical dosing tool.

Warfarin molecules Clotting factor activity

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