Pharmacokinetic and pharmacogenetic study of S-1 in Korean patients with metastatic biliary cancer

Abstract

2505 Background: S-1 is an oral anticancer agent composed of tegafur (FT), CDHP, and oxonate. CYP2A6 is related to the biotransformation of FT to 5-FU. We evaluated associations of genetic variants of CYP2A6 with PK/PD of S-1 when combined with oxaliplatin in metastatic biliary cancer. Methods: This is a prospective study of patients with histologically confirmed metastatic adenocarcinoma of the biliary tract. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 14 days followed by a 7-day rest period. For PK study, S-1 was given only once at day 1 of cycle 1. From day 2, it was administered twice daily. Oxaliplatin was administered intravenously at a dose of 130 mg/m2 for 2 hours every 3 weeks. CYP2A6 polymorphism (*1, *4, *7, *9 or *10) were genotyped. Results: A total of 49 patients were enrolled. Median age was 52 years (range 23–68) and male accounted for 63%. Thirty patients (61%) had intrahepatic cholangiocarcinoma and 10 (20%) gallbladder cancer. Response rate was observed in 24.5%. The median PFS and OS were 3.7 months and 8.7 months . Grade 3–4 adverse events include vomiting (22%), diarrhea (4%) and neutropenia (14%). The allele frequencies of CYP2A6*4, *7, *9 and *10 were 10.2%, 8.2%, 19.4%, and 4.1%, respectively. AUC0–24hr of 5-FU was 1030±617.3 hr*ng/mL (range 249.5–3969, CV: 59.9%). Log- transformed AUC0–24hr were significantly different for FT and 5-FU in the *1/*1 group; metabolic ratio (AUC0- 24hr of 5-FU/AUC0–24hr of FT) of the *1/*1 group was 1.85-times higher than the other group (90% CI 1.37–2.49). AUC0–24hr of CDHP was not significantly associated with CYP2A6 genotype. Despite differences in exposure, CYP2A6 genotypes were not significantly associated with diarrhea (P=0.0740), neutropenia (P=0.396) and clinical efficacy (response rate: P=0.583, PFS: P=0.916). Conclusions: CYP2A6 genotypes was associated with transformation of FT to 5-FU; however, this association did not translate into different clinical efficacy or toxicity. [Table: see text] No significant financial relationships to disclose.