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Pharmacotherapeutic Group: Cytostatic (antimetabolite). ATC Code: L01BC06.
Pharmacology: Pharmacodynamics: Capecitabine is relatively noncytotoxic in vitro. This drug is enzymatically converted to 5-fluorouracil in vivo.
With normal and tumor cells metabolize 5-fluorouracil to 5-fluoro-2-deoxyuridine monophosphate and 5-fluorouridine triphosphate. These metabolites cause cell injury by 2 different mechanisms. First, 5-fluoro-2-deoxyuridine monophosphate and the folate cofactor, N-ethylenetetrahydrofolate, bind to thymidylate synthase to form a valently bound ternary complex. This binding inhibits the formation of thymidylate from 2-deoxy-uridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of deoxynucleic acid (DNA), so that a deficiency of this compound can inhibit cell vision. Second, nuclear transcriptional enzymes can mistakenly incorporate 5-fluorouridine triphosphate in place of uridine triphosphate during the synthesis of ribonucleic acid (RNA). This metabolic error can interfere with DNA processing and protein synthesis.
Pharmacokinetics: Absorption: Capecitabine is readily absorbed from the GI tract. Capecitabine reached peak blood in about 1.5 hour (Tmax) with peak 5-fluorouracil levels occurring slightly later, at 2 hours. Food reduced both of rate and extent of absorption of capecitabine with mean maximum plasma concentration (Cmax) and area under the curve (AUC0-ᾳ) decreased 60% and 35%, respectively. The Cmax and AUC0-ᾳ of 5-fluorouracil were also reduced by food by 43% and 21%, respectively. Food delayed Tmax of both parent and 5-fluorouracil by 1.5 hours.
The pharmacokinetics of capecitabine and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m2/day. Over this range, the pharmacokinetics of capecitabine and its metabolite, 5-deoxy-5-fluorocytidine were dose proportional and did not change over time. The increases in the AUCs of 5-deoxy-5-fluorouracil and 5-fluorouracil, however, were greater than proportional to the increase in dose, and the AUC of 5-fluorouracil was 34% higher on day 14 than on day 1.
The interpatient variability in the Cmax and AUC of 5-fluorouracil was greater than 85%.
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%).
Metabolism: Capecitabine is extensively metabolized enzymatically to 5-fluorouracil. The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-fluorouracil, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5,6-dihydro-fluorouracil. Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid. Finally, beta-ureido-propionase cleaves 5-fluoro-ureido-propionic acid to alpha-fluoro-beta-alanine, which is cleared in the urine.
Excretion: Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is alpha-fluoro-beta-alanine, which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-fluorouracil was about three fourths of an hour.
Protein binding: in vitro human plasma studies have determined that capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 54%, 10%, 62% and 10% protein bound, mainly to albumin.
Special populations: Renal function impairment: Following oral administration of 1250 mg/m2 capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance less than 30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to alpha-fluoro-beta-alanine on day 1 compared with healthy renal function patients (creatinine clearance greater than 80 mL/min). Systemic exposure to 5'-deoxy-5-fluorouridine was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in healthy patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients. Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min).
Hepatic function impairment: Capecitabine has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score, including bilirubin, AST/ALT, and alkaline phosphatase following a single 1255 mg/m2 dose of capecitabine. Both AUC0-ᾳ and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared with patients with healthy hepatic function (n=14). The AUC0-ᾳ and Cmax of 5-fluorouracil were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, exercise caution when capecitabine is administered. The effect of severe hepatic dysfunction on capecitabine is not known.
Toxicology: Preclinical safety data: In repeat-dose toxicity studies, daily oral administration of capecitabine to cynomolgus monkeys and mice produced toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical for fluoropyrimidines. These toxicities were reversible. Skin toxicity, characterised by degenerative/regressive changes, was observed with capecitabine. Capecitabine was devoid of hepatic and CNS toxicities. Cardiovascular toxicity (e.g. PR- and QT-interval prolongation) was detectable in cynomolgus monkeys after intravenous administration (100 mg/kg) but not after repeated oral dosing (1379 mg/m2/day).
A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine.
During standard fertility studies, impairment of fertility was observed in female mice receiving capecitabine; however, this effect was reversible after a drug-free period. In addition, during a 13-week study, atrophic and degenerative changes occurred in reproductive organs of male mice; however these effects were reversible after a drug-free period.
In embryotoxicity and teratogenicity studies in mice, dose-related increases in foetal resorption and teratogenicity were observed. In monkeys, abortion and embryolethality were observed at high doses, but there was no evidence of teratogenicity.
Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). However, similar to other nucleoside analogues (ie, 5-FU), capecitabine was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse bone marrow micronucleus tests (in vivo).
