Capecitabine - How It Works
Clinical pharmacology details from the US FDA-approved label: how Capecitabine works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Capecitabine is metabolized to fluorouracil in vivo. Both normal and tumor cells metabolize fluorouracil to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N 5-10 -methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2’-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Capecitabine is metabolized to fluorouracil in vivo.
Both normal and tumor cells metabolize fluorouracil to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP).
These metabolites cause cell injury by two different mechanisms.
First, FdUMP and the folate cofactor, N 5-10 -methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex.
This binding inhibits the formation of thymidylate from 2’-deoxyuridylate.
Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division.
Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA.
This metabolic error can interfere with RNA processing and protein synthesis.
12.2 Pharmacodynamics Population-based exposure-effect analyses demonstrated a positive association between AUC of fluorouracil and grade 3-4 hyperbilirubinemia.
12.3 Pharmacokinetics The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage range of 500 mg/m 2 /day to 3,500 mg/m 2 /day (0.2 to 1.4 times the approved recommended dosage).
The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greater than proportional to the dose.
The interpatient variability in the Cmax and AUC of fluorouracil was greater than 85%.
Absorption Following oral administration of capecitabine tablets 1,255 mg/m 2 orally twice daily (the recommended dosage when used as single agent), the median Tmax of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and 2 hours, respectively.
Effect of Food Following administration of a meal (breakfast medium-rich in fat and carbohydrates), the mean Cmax and AUC0-INF of capecitabine was decreased by 60% and 34%, respectively.
The mean Cmax and AUC0-INF of fluorouracil were also decreased by 37 % and 12%, respectively.
The Tmax of both capecitabine and fluorouracil was delayed by 1.5 hours.
Distribution Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent.
Capecitabine was primarily bound to human albumin (approximately 35%).
Following oral administration of capecitabine tablets 7 days before surgery in patients with colorectal cancer, the median ratio of concentration for the active metabolite fluorouracil in colorectal tumors to adjacent tissues was 2.9 (range: 0.9 to 8.0).
Elimination The elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hour.
Pharmacokinetics
12.3 Pharmacokinetics The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage range of 500 mg/m 2 /day to 3,500 mg/m 2 /day (0.2 to 1.4 times the approved recommended dosage). The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the Cmax and AUC of fluorouracil was greater than 85%. Absorption Following oral administration of capecitabine tablets 1,255 mg/m 2 orally twice daily (the recommended dosage when used as single agent), the median Tmax of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and 2 hours, respectively. Effect of Food Following administration of a meal (breakfast medium-rich in fat and carbohydrates), the mean Cmax and AUC0-INF of capecitabine was decreased by 60% and 34%, respectively. The mean Cmax and AUC0-INF of fluorouracil were also decreased by 37 % and 12%, respectively. The Tmax of both capecitabine and fluorouracil was delayed by 1.5 hours. Distribution Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Following oral administration of capecitabine tablets 7 days before surgery in patients with colorectal cancer, the median ratio of concentration for the active metabolite fluorouracil in colorectal tumors to adjacent tissues was 2.9 (range: 0.9 to 8.0). Elimination The el