Caxeta Mechanism of Action

Pharmacotherapeutic group: Cytostatic agent. ATC code: L01BC06.
PHARMACOLOGY: Pharmacodynamics: Mechanism of action: Capecitabine is a fluoropyrimidine carbamate derivative that was designed as an orally administered, tumour-activated and tumour-selective cytotoxic agent.
Capecitabine is non-cytotoxic in vitro. However, in vivo, it is sequentially converted to the cytotoxic moiety 5-fluorouracil (5-FU), which is further metabolised.
Formation of 5-FU is catalysed preferentially at the tumour site by the tumour-associated angiogenic factor thymidine phosphorylase (dThdPase), thereby minimising the exposure of healthy tissues to systemic 5-FU.
The sequential enzymatic biotransformation of capecitabine to 5-FU leads to higher concentrations of 5-FU within tumour tissues. Following oral administration report of capecitabine to patients with colorectal cancer (N=8), the ratio of 5-FU concentration in colorectal tumours vs adjacent tissues was 3.2 (range 0.9 to 8.0). The ratio of 5-FU concentration in tumour vs plasma was 21.4 (range 3.9 to 59.9) whereas the ratio in healthy tissues to plasma was 8.9 (range 3.0 to 25.8). Thymidine phosphorylase activity was 4 times greater in primary colorectal tumour than in adjacent normal tissue.
Several human tumours, such as breast, gastric, colorectal, cervical and ovarian cancers, have a higher level of thymidine phosphorylase (capable of converting 5'-DFUR [5'-deoxy-5-fluorouridine] to 5-FU) than corresponding normal tissues.
Normal cells and tumour cells metabolise 5-FU to 5-fluoro-2-deoxyuridine mono-phosphate (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 uracil. 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.
Pharmacokinetics: Absorption: After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive conversion to the metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR. Administration with food decreases the rate of capecitabine absorption but has only a minor effect on the areas under the curve (AUC) of 5'-DFUR and the subsequent metabolite 5-FU. At the dose of 1250 mg/m² on day 14 with administration after food intake, the peak plasma concentrations (C_max in ug/mL) for capecitabine, 5'-DFCR. 5'-DFUR, 5-FU and FBAL were 4.47, 3.05, 12.1, 0.95 and 5.46, respectively. The times to peak plasma concentrations (T_max in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC values in ug·h/mL were 7.75, 7.24, 24.6, 2.03 and 36.3.
Distribution: Protein binding: In vitro human plasma studies have reported that capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 54%, 10%, 62% and 10% protein bound, mainly to albumin.
Metabolism: Capecitabine is first metabolised by hepatic carboxylesterase to 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, principally located in the liver and tumour tissues.
Formation of 5-FU occurs preferentially at the tumour site by the tumours-associated angiogenic factor dThdPase, thereby minimising the exposure of healthy body tissues to systemic 5-FU.
The plasma AUC of 5-FU is 6 to 22 times lower than that following an i.v. bolus of 5-FU (dose of 600 mg/m²). The metabolites of capecitabine become cytotoxic only after conversion to 5-FU and anabolites of 5-FU (see Mechanism of action as previously mentioned).
5-FU is further catabolized to the inactive metabolites of dihydro-5-fluorouracil (FUH₂), 5-fluoro-ureidopropionic acid (FUPA) and a-fluoro-B-alanine (FBAL) via dihydro-pyrimidine dehydrogenase (DPD), which is rate limiting.
Elimination: The elimination half-lives (t_½ in hours) of capecitabine, 5'-DFCR, 5-DFUR, 5-FU and FBAL were 0.85, 1.11, 0.66, 0.76 and 3.23 respectively. The pharmacokinetics of capecitabine have been evaluated over a dose range of 502-3514 mg/m²/day. The parameters of capecitabine, 5-DFCR and 5'-DFUR measured on days and 14 were similar. The AUC of 5-FU was 30%-35% higher on day 14 but did not increase subsequently (day 22). At therapeutic doses, the pharmacokinetics of capecitabine and its metabolites were dose proportional, except 5-FU.
After oral administration, capecitabine metabolites are primarily recovered in urine. Most (95.5%) of administered capecitabine dose is recovered in urine. Faecal excretion minimal (2.6%). The major metabolite excreted in urine is FBAL, which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug.
Combination therapy: Phase reported studies evaluating the effect of capecitabine on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel or paclitaxel (C_max and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR (the most important metabolite of capecitabine).
Pharmacokinetics in Special Populations: A population pharmacokinetic analysis was reported after capecitabine treatment of 505 patients with colorectal cancer dosed at 1250 mg/m² twice daily. Gender, presence or absence of liver metastasis at baseline, Kamofsky Performance Status, total bilirubin, serum albumin, ASAT and ALAT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.
Hepatic impairment due to liver metastases: No clinically significant effect on the bioactivation and pharmacokinetics of capecitabine was reported in cancer patients with mildly to moderately impaired liver function due to liver metastases (see RECOMMENDED DOSE under Dosage & Administration).
No formal pharmacokinetic study has been reported and no population pharmacokinetic data was reported in patients with severe hepatic impairment.
Renal impairment: Based on a reported pharmacokinetic study in cancer patients with mild to severe renal impairment, there is no evidence for an effect of creatinine clearance on the pharmacokinetics of intact drug and 5-FU. Creatinine clearance was found to influence the systemic exposure to 5'-DFUR (35% increase in AUC when creatinine clearance decreases by 50%) and to FBAL (114% increase in AUC when creatinine clearance decreases by 50%) FBAL is a metabolite without antiproliferative activity: 5'DFUR is the direct precursor of 5-FU (see RECOMMENDED DOSE under Dosage & Administration).
Geriatric Population: Based on a reported population pharmacokinetic analysis that included patients with a wide range of ages (27 to 86 years) and included 234 (46%) patients greater than or equal to 65 years, age has no influence on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (20% increase in age results in a 15% increase in the AUC of FBAL). This increase is likely due to a change in renal function (see RECOMMENDED DOSE under Dosage & Administration and previous text).
Race: In a reported population pharmacokinetic analysis of 455 white patients (90.1%) 22 black patients (4.4%) and 28 patients of other race or ethnicity (5.5%), the pharmacokinetics of capecitabine in black patients were not different from those in white patients.