A phase I study evaluating the pharmacokinetics of components of S-1 in pts with varying degrees of renal function.

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e13089 Background: S‐1 is an oral fluoropyrimidine that combines tegafur with two modulators, gimeracil and oteracil potassium. This study was designed to evaluate the PK of S-1 components (FT, CDHP, and Oxo) and the metabolites (5-FU, FBAL, CA) after single and multiple doses of S-1 administered to pts with renal impairment. Methods: This phase I study was conducted in 2 parts (PK Phase and Extension Phase). During the PK Phase, pts were stratified into 4 cohorts: Normal (CrCL >80 mL/min); Mild (CrCL of 51 to 80 mL/min); Moderate (CrCL of 30 to 50 mL/min); Severe (CrCL <30 mL/min). S-1 dosing was determined by degree of renal impairment: 20 mg/m2 QD (severe); 20 mg/m2 BID (moderate); 30 mg/m2 BID (mild), and 30 mg/m2 BID (normal) for 14 days followed by a 1‐week off period. 6 pts were enrolled into each cohort. Plasma and urine were collected to measure the concentrations of S-1 components and its metabolites on day -2 through 48 hrs after the first administration of a single dose of S-1, day 7 and 14. Results: There was no DLTs in the normal (n=7) or moderate(n=6) cohorts. One of 6 pts in the mild cohort experienced 4 DLTs: Gr 3 diarrhea, Gr 3 mucosal inflammation, Gr 3 dehydration, and Gr 3 blood creatinine increased. For the single dose 5-FU and CDHP data, there was statistically significant increase in AUC0-inf value for the mild cohort relative to the normal cohort. For the multiple dose 5-FU, CDHP, Oxo, FBAL, CA, and uracil data, there were no statistically significant differences in Cmax or AUC 0-12 values for the mild or moderate cohort relative to the normal cohort. As compared to normal cohort, there was no evidence of increased accumulation of S-1 components or metabolites following multiple-dose administration in mild or moderate cohort. Conclusions: Based on the results from the single dose PK, a dose reduction from 30 mg/m2 BID to 25 mg/m2 BID for pts with mild renal impairment, 20 mg/m2 BID for pts with moderate renal impairment should be considered for S-1 monotherapy. Data on the severe cohort will be presented at the meeting. S-1 was generally well tolerated in this population with normal renal function, and mild or moderate renal impairment.