Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients

Purpose: The objective of the study was to assess the bioequivalence of two tablet formulations of capecitabine and to explore the effect of age, gend er, body surface area and creatinine clearance on the systemic exposure to capecitabine and its metabolites. Methods: The study was designed as an ope n, randomized two-way crossover trial. A single oral dose of 2000 mg capeci tabine was administered on two separate days to 25 patients with solid tumo rs. On one day, the patients received four 500-mg tablets of formulation B (test formulation) and on the other day, four 500-mg tablets of formulation A (reference formulation). The washout period between the two administrati ons was between 2 and 8 days. After each administration, serial blood and u rine samples were collected for up to 12 and 24 h, respectively. Unchanged capecitabine and its metabolites were determined in plasma using LC/MS-MS a nd in urine by NMRS. Results: Based on the primary pharmacokinetic paramete r, AUC(0-infinity) of 5'-DFUR, equivalence was concluded for the two formul ations, since the 90% confidence interval of the estimate of formulation B relative to formulation A of 97% to 107% was within the acceptance region 8 0% to 125%. There was no clinically significant difference between the t(ma x) for the two formulations (median 2.1 versus 2.0 h). The estimate for C-m ax was 111% for formulation B compared to formulation A and the 90% confide nce interval of 95% to 136% was within the reference region 70% to 143%. Ov erall, these results suggest no relevant difference between the two formula tions regarding the extent to which 5'-DFUR reached the systemic circulatio n and the rate at which 5'-DFUR appeared in the systemic circulation. The o verall urinary excretions were 86.0% and 86.5% of the dose, respectively, a nd the proportion recovered as each metabolite was similar for the two form ulations. The majority of the dose was excreted as FBAL (61.5% and 60.3%), all other chemical species making a minor contribution. Univariate and mult ivariate regression analysis to explore the influence of age, gender, body surface area and creatinine clearance on the log-transformed pharmacokineti c parameters AUC(0-infinity) and C-max of capecitabine and its metabolites revealed no clinically significant effects. The only statistically signific ant results were obtained for AUC(0-infinity) and C-max of intact drug and for C-max of FBAL, which were higher in females than in males. Conclusion: The bioavailability of 5'-DFUR in the systemic circulation was practically identical after administration of the two tablet formulations. Therefore, t he two formulations can be regarded as bioequivalent. The variables investi gated (age, gender, body surface area, and creatinine clearance) had no cli nically significant effect on the pharmacokinetics of capecitabine or its m etabolites.