Clinical Pharmacokinetics of Capecitabine

Abstract

Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps. After oral administration of 1250 mg/m2, capecitabine is rapidly and extensively absorbed from the gastrointestinal tract [with a time to reach peak concentration (tmax) of 2 hours and peak plasma drug concentration (Cmax) of 3 to 4 mg/L] and has a relatively short elimination half-life (t(1/2)) [0.55 to 0.89 h]. Recovery of drug-related material in urine and faeces is nearly 100%. Plasma concentrations of the cytotoxic moiety fluorouracil are very low [with a Cmax of 0.22 to 0.31 mg/L and area under the concentration-time curve (AUC) of 0.461 to 0.698 mg x h/L]. The apparent t(1/2) of fluorouracil after capecitabine administration is similar to that of the parent compound. Comparison of fluorouracil concentrations in primary colorectal tumour and adjacent healthy tissues after capecitabine administration demonstrates that capecitabine is preferentially activated to fluorouracil in colorectal tumour, with the average concentration of fluorouracil being 3.2-fold higher than in adjacent healthy tissue (p = 0.002). This tissue concentration differential does not hold for liver metastasis, although concentrations of fluorouracil in liver metastases are sufficient for antitumour activity to occur. The tumour-preferential activation of capecitabine to fluorouracil is explained by tissue differences in the activity of cytidine deaminase and thymidine phosphorylase, key enzymes in the conversion process. As with other cytotoxic drugs, the interpatient variability of the pharmacokinetic parameters of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine and fluorouracil, is high (27 to 89%) and is likely to be primarily due to variability in the activity of the enzymes involved in capecitabine metabolism. Capecitabine and the fluorouracil precursors 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine do not accumulate significantly in plasma after repeated administration. Plasma concentrations of fluorouracil increase by 10 to 60% during long term administration, but this time-dependency is assumed to be not clinically relevant. A potential drug interaction of capecitabine with warfarin has been observed. There is no evidence of pharmacokinetic interactions between capecitabine and leucovorin, docetaxel or paclitaxel.

Comparative pharmacology of oral fluoropyrimidines: a focus on pharmacokinetics, pharmacodynamics and pharmacomodulation

“…Since capecitabine generates 5-FU directly at cellular level, it can be anticipated that the variability in plasma pharmacokinetics of capecitabine and metabolite will be of little concern for pharmacodynamics. This opinion has been confirmed by clinical pharmacokinetic investigations (Reigner et al, 2001).…”

“…The clinical pharmacokinetics of capecitabine have been recently reviewed by Reigner et al (2001). The preferential delivery of 5-FU into the tissues through the intermediary of thymidine phosphorylase (TP) is responsible for its much lower presence (approximately 10 times lower) in plasma than its prodrugs capecitabine, 5 0 DFCR, 5 0 DFUR or its catabolites FUH2 and FBAL (Reigner et al, 2001).…”

“…The preferential delivery of 5-FU into the tissues through the intermediary of thymidine phosphorylase (TP) is responsible for its much lower presence (approximately 10 times lower) in plasma than its prodrugs capecitabine, 5 0 DFCR, 5 0 DFUR or its catabolites FUH2 and FBAL (Reigner et al, 2001). Reigner et al (2001) noted that the AUC of capecitabine, 5 0 -DFCR and 5 0 -DFUR did not accumulate in plasma after long-term administration.…”

“…The preferential delivery of 5-FU into the tissues through the intermediary of thymidine phosphorylase (TP) is responsible for its much lower presence (approximately 10 times lower) in plasma than its prodrugs capecitabine, 5 0 DFCR, 5 0 DFUR or its catabolites FUH2 and FBAL (Reigner et al, 2001). Reigner et al (2001) noted that the AUC of capecitabine, 5 0 -DFCR and 5 0 -DFUR did not accumulate in plasma after long-term administration. We recently conducted a phase I and pharmacokinetic study of the association of capecitabinecisplatin in head and neck cancer patients (Pivot et al, 2003) and found that there was a significant but moderate increase in postdose (capecitabine, 1000 mg m À2 ) AUC values for 5 0 DFUR and 5-FU between day 2 and day 15.…”

Chemotherapy for pancreatic cancer

“…Cytidine deaminase in the liver and tumour cells converts 5-DFCR into 5¢-deoxy-5-fluorouradine (5-DFUR). [40][41][42] The final step in the conversion of 5¢-deoxy-5-fluorouridine to active 5-FU is regulated by tumour thymidine phosphorylase ( Figure 1). Tumours express thymidine phosphorylase in higher concentrations than surrounding normal tissues.…”