CAPEMAX 500

Indications

• Stage III colon cancer, adjuvant following surgery
• Locally advanced or metastatic breast cancer, as second-line treatment after failure of taxane and anthracycline regimens

Dosage

Adults: 1.25 g/m2 twice daily for 14 days, subsequent courses repeated after a 7

Mechanism of action

Capecitabine is metabolized to 5-fluorouracil in vivo through a series of enzymatic reactions involving carboxylesterases, cytidine deaminase, and thymidine phosphorylase. The active metabolites of 5-FU, including FdUMP, interact with thymidylate synthase, inhibiting its activity and leading to the depletion of dTMP necessary for DNA synthesis. This mechanism of action disrupts cell proliferation and induces apoptosis in cancer cells, providing an effective treatment for tumors.

Pharmacodynamics

Capecitabine exerts its antitumor effects by interfering with DNA synthesis and function. As an antimetabolite, its primary action is through inhibition of thymidylate synthase, which is crucial for DNA replication. The selective conversion of capecitabine to 5-FU within tumor tissues enhances its therapeutic index, reducing gastrointestinal toxicity while maintaining efficacy. This drug leads to cell cycle arrest and eventual cancer cell death, primarily affecting rapidly dividing cells.

Pharmacokinetics

Capecitabine is absorbed well from the gastrointestinal tract, with peak plasma concentrations occurring approximately 1-2 hours after oral administration. It is extensively metabolized by the liver and other tissues, with a half-life of about 0.5 to 2 hours. The drug's metabolites are primarily excreted through urine. Dosage adjustments may be necessary in patients with hepatic or renal impairment, and monitoring of liver function and renal parameters is essential during treatment.

Contra-indications

• Complete dihydropyrimidine dehydrogenase deficiency

Adverse effects

• Severe and fatal toxicity
• Diarrhea
• Dehydration
• Bleeding

Interactions

• Capecitabine + coumarins: Moderate (increases effects)
• Allopurinol + capecitabine: Unknown (decreases effects)
• Capecitabine + antiepileptics: Unknown (increases concentration)
• Capecitabine + fosphenytoin: Unknown (increases concentration)
• Capecitabine + phenytoin: Unknown (increases concentration)
• Live vaccines + capecitabine: Unknown (increases risk of generalized infection, possibly life-threatening)
• Metronidazole + capecitabine: Unknown (increases risk of capecitabine toxicity)
• Cimetidine + capecitabine: Unknown (increases exposure)

Precautions

• Monitor liver function tests, serum creatinine, and serum bicarbonate before initiation and before each treatment cycle
• Monitor full blood count before initiation and before each treatment cycle
• Caution in patients with diabetes mellitus

Pregnancy

Use in pregnancy only if the potential benefit justifies the potential risk to the fetus. There is a risk of fetal harm.

Breast-feeding

Capecitabine is not recommended during breastfeeding due to potential risk to the infant.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Capecitabine 500 mg tablet
• Capecitabine 150 mg tablet

Mechanism of action

Capecitabine is metabolized to 5-fluorouracil in vivo by carboxylesterases, cytidine deaminase, and thymidine phosphorylase/uridine phosphorylase sequentially. 5-fluorouracil is further metabolized through a series of enzymatic reactions into 3 main active metabolites: 5-fluorouridine triphosphate (5-FUTP), 5-fluoro-2’-deoxyuridine monophosphate (5-FdUMP), and 5-fluorodeoxyuridine triphosphate (5-FdUTP).. These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate (CH₂THF), bind to thymidylate synthase (TS) to form a covalently bound ternary complex. TS is an enzyme that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Under normal physiological conditions, dUMP binds to TS first before CH₂THF, followed by a 1,4 or Michael addition from the pyrimidine C (6)atom to the Cys146 nucleophile. If correctly positioned, dUMP, CH₂THF, and TS would form a ternary complex to facilitate the donation of the methyl group from CH₂THF to dUMP. However, the substitution of dUMP with FdUMP results in a new time-dependent TS–FdUMP–CH2THF complex. Since the fluorine group prevents dissociation of FdUMP from the pyrimidine ring, the whole complex is rendered irreversibly deactivated, terming this reaction "suicide inhibition". TS inhibition prevents the conversion of dUMP to dTMP, depleting the pool of dTMP that could be phosphorylated into dTTP to be incorporated as DNA nucleotides. This disrupts the nucleotides balance, particularly the the ATP/dTTP ratio, thus impairing DNA synthesis and repair and causing apoptosis. 5-FdUMP can also be phosphorylated into 5-FdUTP, further increasing the pool of dUTP base to potentially overwhelm the activity of dUTPase. Coupled with the decrease in dTTP, 5-FdUMP, and 5-FdUTP increase the probability of mistakenly incorporating a uracil base into DNA strands in place of thymine. Although this mistake can often be resolved by the nucleotide excision repair enzyme uracil-DNA-glycosylase (UDG), the high (F)dUTP/dTTP ratio would result in re-incorporation of uracil into DNA, leading to a futile cycle of misincorporation, excision, and repair. Repeated base excision repair can result in abasic sites, which can lead to DNA mutagenesis and thus protein miscoding, replication forks collapse, and DNA fragmentation through single or double strand breaks However, several reports have found that the incorporation of uracil in genomic DNA does not significantly affect the cytotoxicity of 5-FU, suggesting that the cytotoxic effect of 5-FU is dominated by the perturbation of RNA through 5-FUTP. Similar to 5-dFUTP, 5-FUTP can be mistakenly incorporated into RNA in place of regular UTP and disrupt regular RNA biology through various mechanisms. 5-FUTP can be incorporated into the spliceosomal U2 snRNA at pseudouridylated sites to prevent further pseudouridylation and thus pre-mrNA splicing. 5-FUTP can also change the structure of U4 and U6 snRNA and reduce the turnover rate of U1 snrNA once incorporated. For tRNA, 5-FUTP can affect tRNA's post-transcriptional RNA modifications activity, particularly by inhbiting pseudouridine synthase through formation of covalent complex. Recently, the effect of 5-FUTP on miRNAs and lncRNA was also observed through profound changes in expression, although the precise mechanism is still unknown. Although the main mechanism of 5-FU cytotoxicity was thought to be attributed to DNA damages, recent reports have shown that the majority of 5-FU pharmacological action is mediated through RNA, since 5-FU is accumulated ~3000- to 15 000-fold more in RNA compared to that of DNA. Capecitabine is a prodrug and has little pharmacologic activity until it is converted to fluorouracil, an antimetabolite. Because capecitabine is converted to fluorouracil by enzymes that are expressed at higher concentrations in many tumors than in adjac

Pharmacodynamics

Capecitabine is a fluoropyrimidine carbamate belonging to a group of antineoplastic agents called antimetabolites, which kill cancerous cells by interfering with DNA synthesis. It is an orally administered systemic prodrug that has little pharmacologic activity until it is converted to 5-fluorouracil (5-FU) by enzymes that are expressed in higher concentrations in many tumors. Capecitabine was designed specifically to overcome the disadvantages of 5-FU and to mimic the infusional pharmacokinetics of 5-FU without the associated complexity and complications of central venous access and infusion pumps. Particularly, since the enzymes converting 5-FU into active metabolites exist in the gastrointestinal tract, infusion of 5-FU can have gastrointestinal toxicity while also losing efficacy. Since capecitabine can be transported intact across the intestinal mucosa, it can be selectively delivered 5-FU to tumor tissues through enzymatic conversion preferentially inside tumor cells. 5-FU exerts its pharmacological action through the inhibition and interference of 3 main targets: thymidylate synthase, DNA, and RNA, leading through protein synthesis disruption and apoptosis. Population-based exposure-effect analyses demonstrated a positive association between AUC of 5-FU and grade 3-4 hyperbilirubinemia.