Bridging the Gap: Precision Modelling Reveals Optimal 5-FU Dose Reduction for Dihydropyrimidine Dehydrogenase (DPD)-deficient patients

The study is aimed to evaluate the impact of Dihydropyrimidine dehydrogenase (DPD) deficiency on the PK of 5-fluorouracil (5-FU) by using pharmacometric simulations to propose an optimal 5-FU dosage regimen.

The pharmacokinetic model 5-FU following one-compartment open model- intravenous infusion administration was constructed using clearance (Cl) and volume of distribution (Vd) values obtained from the literature. A total of 1000 virtual patients, in each group such as normal DPD activity and DPD deficient activity populations groups were simulated for time vs plasma concentration data and using the time vs plasma concentration data, area under the curve (AUC) were calculated and the AUC (0-∞) were compared with the established therapeutic range and subsequent dose adjustments were made.

Dose of 400 mg/m ², followed by 2400 mg/m ² was given prior to dose adjustment, DPD-deficient population exhibited a significantly higher AUC (0-∞) compared to the normal DPD activity population, necessitating a dose reduction of 37.25% to achieve target AUC (0-∞) of 20-30 mg.h/l. Following dose adjustment, both populations achieved AUC values within the therapeutic range, with the adjusted dose of 400 mg/m ², followed by 1500 mg/m ² (2410mg) for DPD-deficient patients.

DPD-deficient patients had significantly higher AUC (0-∞) than those with normal DPD activity and different dosing–37.25 % reduction. Following dose individuation, both populations reached targeted levels of therapeutic AUC and encouraged individualized dosing for those patients who are DPD-deficient.