Prospective evaluation of a developed S-1 dosage formula based on renal function.

Abstract

86 Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP, inhibitor of dihydoropyrimidine dehydrogenase) and potassium oxonate. Because CDHP is excreted in urine, renal dysfunction increases incidence of severe adverse drug reactions due to higher exposure of 5-FU. As approved dose of S-1 is determined by body surface area (BSA) for patients with normal renal function, dose of S-1 is practically reduced according to renal function of creatinine clearance (CLcr) estimated by the Cockcroft-Gault equation. In a previous pharmacokinetic study (n = 16), we had developed an S-1 dosage formula based on renal function achieving the target area under the concentration-time curve (AUC) of 5-FU: Dose = target AUC x (21.9 + 0.375 x CLcr) x BSA. We conducted a prospective study to evaluate and refine this formula if necessary. Methods: Thirty patients with various renal function received S-1 at dose determined by our developed formula. A series of blood samples were obtained at predefined times after the first dose to calculate the AUC of 5-FU. Predictability of the formula was evaluated by comparison between the observed and the target AUCs. Results: The observed daily AUC was ranged from 712.6 to 2868.7 ng‧h/mL in 30 patients with BSA in the range of 1.14-1.84 m2 and CLcr in the range of 23.8-96.4 mL/min. Eighteen patients of them achieved the target AUC (1447.8 ± 545.4 ng‧h/mL). Since population pharmacokinetic analysis using combined pharmacokinetic data of 30 patients in this study and 16 patients in the previous study demonstrated that clearance of 5-FU is significantly lower in female than in male, the S-1 dosage formula was refined including gender as an additional factor: Dose = target AUC × (14.5 + 8.23 x GENDER [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms showing recommended daily dose of S-1 were proposed for males and females taking into account tablet strengths. Conclusions: The refined formula for determining S-1 dosage on the basis of renal function, BSA and gender can be applied to clinical practice to ensure efficacy and safety for cancer patients treated with S-1. Clinical trial information: UMIN 000023880.