Population pharmacokinetic analysis of S-1 including the CYP2A6 genotype in patients with advanced cancer

Abstract

2507 Background: S-1 is an oral anticancer agent composed of tegafur, CDHP, and potassium oxonate. Tegafur is a prodrug of fluorouracil (5-FU), and CDHP prevents degradation of 5-FU by inhibiting dihydropyrimidine dehydrogenase and enhances the anticancer activity of 5-FU. The biotransformation of tegafur to 5-FU is demonstrated to be catalyzed by CYP2A6. CYP2A6 polymorphisms are seen more frequently in Japanese people than Caucasian. Therefore, we performed a population pharmacokinetic (PPK) analysis of S-1 including the CYP2A6 genotype in Japanese patients with advanced cancer and developed a model describing the disposition kinetics of tegafur, CDHP, and 5-FU after oral administration of S-1. Methods: Fifty-eight patients with advanced cancer were eligible if they had a performance status of 0 to 3 and had adequate organ function. A dose of 80 mg/m2 of S-1 was given orally twice daily for 28 consecutive days, followed by 14 days of rest. The PPK analysis was performed with plasma concentration data for tegafur, CDHP, and 5-FU. The CYP2A6 genotype was analyzed with the polymerase chain reaction-restriction fragment length polymorphism method or an allele-specific polymerase chain reaction-based method. On the basis of the CYP2A6 genotype, all patients were classified into 1 of 3 groups: wild type, 1 variant allele, and 2 variant alleles. Results: Creatinine clearance correlated with the individual clearance of CDHP. Body surface area correlated with the individual clearance and volumes of CDHP and tegafur. In patients with 2 variant alleles of CYP2A6, tegafur clearance was 58% less than that in patients with wild type or 1 variant allele of CYP2A6. In addition, in patients with a history of gastrectomy, the absorption rate constant of tegafur was 66% higher than that in patients with no history of gastrectomy. The time-varying concentration of CDHP was the most appropriate model component describing the inhibitory effect on 5-FU catabolism. The individual Bayesian predictions of CDHP, tegafur, and 5-FU concentrations based on the present PPK model were in good agreement with the observed data. Conclusions: This is the first PPK model of S-1 including the CYP2A6 genotype. No significant financial relationships to disclose.