Pharmacokinetics of capecitabine (Xeloda) in Japanese and Caucasian patients with breast cancer

Background-Capecitabine (Xeloda) is a novel, oral fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumor tissue via a three-step enzymatic cascade. Purpose: The objective of this study was to compare the pharmacokinetics of capecitabine and its metabolites in Japanese and Caucasian cancer patients. Methods: The study included 20 Japanese and 24 Caucasian patients with breast cancer. All patients received oral capecitabine 825 mg/m(2) twice daily for 14 days, except for study day 1 when only the morning dose was administered. On study days 1 and 14, blood and urine samples were collected after administration of the first dose and at steady state for the evaluation of the pharmacokinetics of capecitabine and its metabolites. The primary pharmacokinetic parameter was AUC(0-infinity) of 5'-deoxy-5-fluorouridine (5'-DFUR) on day 14. The pharmacokinetic parameters in Japanese and Caucasian patients were compared using an ANOVA with calculation of the 90% confidence interval (Cl) for the ratio of the geometric means. Results: Statistical analysis showed equivalence in the AUC of 5'-DFUR on day 14 with a ratio of 1.01 (90% CI 0.85-1.21). Similarly, no relevant influence of race on the pharmacokinetics of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), or 5-FU was observed. Systemic exposure to alpha-fluoro-beta-alanine (FBAL) was higher in Caucasian than in Japanese patients. On study day 14, both the AUC and the maximum plasma concentration (C-max) of FBAL were increased by 47% and 33% in Caucasian patients and Japanese patients, respectively. Conclusions: No clinically relevant differences in the pharmacokinetics of capecitabine and its key metabolites 5'-DFUR, 5'-DFCR, and 5-FU were found between Japanese and Caucasian patients. Plasma concentrations of FBAL were higher in Caucasian than in Japanese patients but this difference is not clinically relevant as FBAL has no antiproliferative activity and systemic exposure to FBAL does not correlate with the tolerability of capecitabine.