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.

The task of estimating the starting dose is moving beyond empirical methods to those that are increasingly more systematic and theory based.

Aims To assess the relationship between systemic exposure to capecitabine metabolites and parameters of efficacy and safety in patients with advanced or metastatic colorectal cancer from two phase III studies. Methods Concentration-effect analyses were based on data from 481 patients (248 males, 193 females; age range 27-86 years) in two phase III studies. Plasma concentration-time data for 5 ¢ -deoxy-5-fluorouridine (5 ¢ -DFUR), 5-fluorouracil (5-FU) and a -fluoro-b -alanine (FBAL) were obtained from sparse blood samples collected within the time windows 0.5-1.5 h, 1.5-3.0 h, and 3.0-5.0 h after capecitabine administration (1250 mg m -2 ) on the first day of cycles 2 (day 22) and 4 (day 64), respectively. Systemic exposure based on plasma concentrations of capecitabine and its metabolites was determined using individual parameter estimates derived from a population pharmacokinetic model constructed for this purpose in NONMEM. Logistic regression analysis was conducted for selected safety parameters (all treatment-related grade 3-4 adverse events, treatment-related grade 3-4 diarrhoea, grade 3 hand-foot syndrome (HFS) and grade 3-4 hyperbilirubinaemia) and for tumour response. Cox regression analysis was used for the analysis of time-to-event data (time to disease progression and duration of survival). Results Statistically significant relationships between covariates and PK parameters were found as follows. A doubling of alkaline phosphatase activity was associated with a 11% decrease in 5-FU clearance and a 12% increase in its AUC. A 50% decrease in creatinine clearance was associated with a 35% decrease in FBAL clearance, a 53% increase in its AUC, a 24% decrease in its volume of distribution, and a 41% increase in its C max . A 30% increase in body surface was associated with a 24% increase in the volume of distribution of FBAL and a 19% decrease in its C max . There was a broad overlap in systemic drug exposure between patients regardless of the occurrence of treatment-related grade 3-4 adverse events or response to treatment, leading to weak relationships between systemic exposure to capecitabine metabolites and the safety and efficacy parameters. Of 42 concentration-effect relationships investigated, only five achieved statistical significance. Thus, we obtained a positive association between the AUC of FBAL and grade 3-4 diarrhoea ( P = 0.035), a positive association between the AUC of 5-FU and grade 3-4 hyperbilirubinaemia ( P = 0.025), a negative association between the C max of FBAL and grade 3-4 hyperbilirubinaemia ( P = 0.014), a negative association between the AUC of 5-FU (in plasma) and time to disease progression (hazard ratio (HR) = 1.626, P = 0.0056), and a positive association between the C max of 5 ¢ -DFUR and survival (HR = 0.938, P = 0.0048). Additionally, there were inconsistencies when concentration-effect relationships were compared across the two studies. cations for the use of capecitabine and argue against the value of therapeutic drug monitoring for dosage adjustment.

Capecitabine has been developed as an orally administered tumor selective fluoropyrimidine for use in the treatment of breast and colorectal cancer. The metabolic pathway for capecitabine includes 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), which is then converted to the pharmacologically active agent 5-fluorouracil (5-FU). A previous analysis showed that systemic exposure to 5'-DFUR and alpha-fluoro-beta-alanine (FBAL), a catabolite of 5-FU, was predictive of dose limiting toxicities. Therefore, a multi-response population pharmacokinetic (PK) model for the description of plasma concentrations of 5'-DFUR, 5-FU and FBAL following oral administration of capecitabine was developed using NONMEM. PK data from a bioequivalence study in 24 patients with various solid tumors were used to develop the PK structural part of the population PK model. The 5'-DFUR, 5-FU and FBAL plasma concentrations were described by a linear disposition PK model with first order absorption and lag time. Sparse plasma concentration data from 54 phase II breast cancer patients were added to the bioequivalence data and the influence of covariates on the apparent oral clearances of 5'-DFUR, 5-FU and FBAL and on the apparent volume of distribution of FBAL was investigated. This was conducted by including all significant (p < 0.05) single covariate-PK parameter pairs in the full PK model, followed by one by one deletion (p < 0.001) from the population model. Statistically significant effects were found for the influence of gender, body surface area and total bilirubin on 5'-DFUR clearance and the influence of creatinine clearance on FBAL clearance. However, none of these effects were considered to have clinical relevance.

No abstract