Capecitabine in the Treatment of Advanced Gastric Cancer

Jae-Lyun Lee; Yoon-Koo Kang


Future Oncol. 2008;4(2):179-198. 

In This Article

Pharmacokinetics & Metabolism

After oral administration, capecitabine is rapidly and extensively absorbed from the gastrointestinal tract and converted to its first two metabolites, 5´-DFCR and 5´-DFUR. The median Tmax for capecitabine and its metabolites is 1.5-2 h.[33,34] Plasma concentrations then decline exponentially, with an elimination half-life (T1/2) of 0.66-1.11 h for capecitabine and its metabolites. Plasma concentrations of the cytotoxic moiety 5-FU are very low. After 14 days of treatment with capecitabine 1255 mg/m2 twice a day, the AUC of 5-FU was approximately 13-times lower than the systemic exposure to 5´-DFUR.[33] Comparison of 5-FU concentrations in primary colorectal tumors and adjacent healthy tissues after capecitabine administration showed that capecitabine was preferentially activated to 5-FU in the tumors, which had an average 5-FU concentration 3.2-fold higher than in adjacent healthy tissue (p = 0.002), which can not be recapitulated by the intravenous infusion of 5-FU.[35,36] Following repeated administration, capecitabine and its metabolites do not accumulate significantly in plasma.[34] Capecitabine metabolites are primarily recovered in the urine (approximately 95% of administered capecitabine dose is recovered in urine), and fecal excretion is minimal. The major metabolite excreted in urine is α-fluoro-β-alanine (FBAL) (Figure 2).[34,37]

Pharmacokinetic Considerations in Selected Patient Populations

Gastrectomized Patients. There are limited pharmacokinetic data on the use of capecitabine in patients following gastric surgery.[34] A Phase I study of capecitabine-based combination chemotherapy found no significant differences in pharmacokinetic parameters between patients with an intact stomach and those who had previously undergone esophagogastric resection.[38] In addition, the aggregate of previous studies of capecitabine, which included prior gastrectomized patients, found that previous surgery had no impact on the efficacy of this agent.[39,40]

Patients With Renal or Hepatic Function Impairment. Capecitabine and its metabolites are excreted primarily via the kidneys, with more than 90% of the administered dose recovered in urine as inactive FBAL. Patients with impaired renal function (creatinine clearance ≤50 ml/min) who received capecitabine showed increased exposure to the drug and its metabolites (FBAL and 5´-DFUR) when compared with patients with normal renal function. Therefore, physicians should be cautious about prescribing capecitabine to patients with mild or moderate renal impairment, and a 25% dose reduction is recommended for patients with moderate renal impairment (creatinine clearance: 30-50 ml/min). Capecitabine is contraindicated when creatinine clearance is less than 30 ml/min.[41] No dosage adjustments for patients with hepatic dysfunction are currently recommended. However, this was based on the results of a small study, which also excluded patients with hepatic impairment caused by cirrhosis or hepatitis.[42] To date, there have been no additional studies on this population; thus, caution is advised in administering capecitabine to patients with hepatic impairment.

Patients Receiving Warfarin. A clinically significant pharmacokinetic and pharmacodynamic interaction has been observed between capecitabine and warfarin, which could result in enhanced anticoagulation activity. In four capecitabine-treated patients who received a single dose of warfarin 20 mg, the mean AUC of warfarin was increased by 57%, its elimination half-life was prolonged by 51%, and the maximum observed mean International Normalized Ratio value increased by 91%.[43] Therefore, physicians should be cautious about prescribing capecitabine to patients receiving warfarin anticoagulation therapy and should monitor their International Normalized Ratios closely or consider changing anticoagulation treatment to low-molecular-weight heparin.


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