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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 tumor-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 tumor tissues. Following oral administration of capecitabine to patients with colorectal cancer (N=8), the ratio of 5-FU concentration in colorectal tumors vs adjacent tissues was 3.2 (range 0.9 to 8.0). The ratio of 5-FU concentration in tumor 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 tumor than in adjacent normal tissue.
Several human tumors, 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 tumor cells metabolise 5-FU 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 N5-10-methylenetetrahydrofolate bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from uracil.
Thymidate is the necessary precursor of thymidate 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.
Clinical/Efficacy Studies: Colon and Colorectal Cancer: Monotherapy in adjuvant colon cancer: Data from one multicenter, randomized, controlled phase 3 clinical trial in patients with stage III (Dukes C) colon cancer supports the use of Capecitabine for the adjuvant treatment of patients with colon cancer (XACT Study: M66001). In this trial, 1987 patients were randomized to treatment with Capecitabine (1250 mg/m2 twice daily for 2 weeks by a 1-week rest period and given as 3-week cycles for 24 weeks) or 5-FU and leucovorin (Mayo regimen: 20 mg/m2 leucovorin i.v. followed by 425 mg/m2 i.v. bolus 5-FU, on days 1 to 5, every 28 days for 24 weeks).
Capecitabine was at least equivalent to i.v. 5-FU/LV in disease-free survival (p=0.0001, non-inferiority margin 1.2). In the all-randomized population, tests for difference of Capecitabine vs 5-FU/LV in disease-free survival and overall survival showed hazard ratios of 0.88 (95% Cl 0.77-1.01; p=0.068) and 0.86 (0.74-1.01; p=0.060), respectively. The median follow up at the time of the analysis was 6.9 years.
Combination therapy in adjuvant colon cancer: Data from one multicentre, randomised, controlled phase 3 clinical trial in patients with stage III (Dukes' C) colon cancer supports the use of Capecitabine in combination with oxaliplatin (XELOX) for the adjuvant treatment of patients with colon cancer (N016968 study). In this trial, 944 patients were randomised to 3-week cycles for 24 weeks with Capecitabine (1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period) in combination with oxaliplatin (130 mg/m2 intravenous infusion over 2-hours on day 1 every 3 weeks); 942 patients were randomized to bolus 5-FU and leucovorin. In the primary analysis for DFS, in the ITT population, XELOX was shown to be significantly superior to 5-FU/LV (HR=0.80, 95% Cl=[0.69; 0.93]; p=0.0045). The 3 year DFS rate was 71% for XELOX versus 67% for 5-FU/LV. The analysis for the secondary endpoint of relapse free survival (RFS) supports these results with a HR of 0.78 (95% Cl=[0.67; 0.92]; p=0.024) for XELOX vs. 5-FU/LV. XELOX showed a trend towards superior OS with a HR of 0.87 (95% Cl=[0.72; 1.05]; p=0.1486) which translates into a 13% reduction in risk of death. The 5 year OS rate was 78% for XELOX versus 74% for 5-FU/LV. The efficacy data provided is based on a median observation time of 59 months for OS and 57 months for DFS. The rate of withdrawal due to adverse events was higher in the XELOX combination therapy arm (21%) as compared with that of the 5-FU/LV monotherapy arm (9%) in the ITT population.
Monotherapy in metastatic colorectal cancer: Data from two identically multicenter, randomised, controlled, phase 3 clinical trials support the use of Capecitabine for first-line treatment of metastatic colorectal (S014695; S014796). In these trials, 603 patients were randomised to treatment with Capeciatbine (1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles) and 604 patients were randomised to treatment with 5-FU and leucovorin (Mayo regimen: 20 mg/m2 i.v. followed by 425 mg/m2 i.v. bolus 5-FU, on days 1 to 5, every 28 days).
The overall objective response rates in the all-randomised population (investigator assessment) were 25.7% (Capecitabine) vs 16.7% (Mayo regimen); p<0.0002. The median time to progression was 140 days (Capecitabine) vs 144 days (Mayo regimen). Median survival was 392 days (Capecitabine) vs 391 days (Mayo regimen).
Combination therapy - first-line treatment of colorectal cancer: Data from a multicenter, randomized, controlled phase 3 clinical study (N016966) support the use of Capecitabine in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab (BV) for the first-line treatment of metastastic colorectal cancer. The study contained two parts: an initial 2-arm part in which patients were randomized to two different treatment groups, including XELOX or FOLFOX-4, and a subsequent 2x2 factorial part with four different treatment groups, including XELOX+placebo(P), FOLFOX-4+P, XELOX+BV, and FOLFOX-4+ BV. The treatment regimens are summarized in the table as follows. (See Table 1.)
Click on icon to see table/diagram/imageNon-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall comparison was demonstrated in terms of progression-free survival in the eligible patient population and the intent-to-treat population (see table as follows). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of overall survival. A comparison of XELOX plus bevacizumab versus FOLFOX-4 plus bevacizumab was a pre-specified exploratory analysis. In this treatment subgroup comparison, XELOX plus bevacizumab was similar compared to FOLFOX-4 plus bevacizumab in terms of progression-free survival (hazard ratio 1.01 [97.5% CI 0.84, 1.22]). The median follow up at the time of the primary analyses in the intent-to-treat population was 1.5 years; data from analyses following an additional 1 year of follow up are also included in Table 2. (See Table 2.)
Click on icon to see table/diagram/imageCombination therapy - Second-line treatment of colorectal cancer: Data from a multicenter, randomized, controlled phase III clinical study (NO16967) support the use of Xeloda in combination with oxaliplatin for the second-line treatment of metastastic colorectal cancer. In this trial, 627 patients with metastatic colorectal carcinoma who have received prior treatment with irinotecan in combination with a fluoropyrimidine regimen as first-line therapy were randomized to treatment with XELOX or FOLFOX-4. For the dosing schedule of XELOX and FOLFOX-4 (without addition of placebo or bevacizumab), refer to Table 1. XELOX was demonstrated to be non-inferior to FOLFOX-4 in terms of progression-free survival in the per-protocol population and intent-to-treat population (see Table 3). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of overall survival. The median follow up at the time of the primary analyses in the intent-to-treat population was 2.1 years; data from analyses following an additional 6 months of follow up are also included in Table 3. (See Table 3.)
Click on icon to see table/diagram/imageA pooled analysis of the efficacy data from first-line (study NO16966; initial 2-arm part) and second-line treatment (study NO16967) further support the non-inferiority results of XELOX versus FOLFOX-4 as obtained in the individual studies: progression-free survival in the perprotocol population (hazard ratio 1.00 [95% CI: 0.88; 1.14]) with a median progression-free survival of 193 days (XELOX; 508 patients) versus 204 days (FOLFOX-4; 500 patients). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of overall survival (hazard ratio 1.01 [95% CI: 0.87; 1.17]) with a median overall survival of 468 days (XELOX) versus 478 days (FOLFOX-4).
Combination therapy - breast cancer: Data from one multicenter, randomised, controlled phase 3 clinical trial support the use of Xeloda in combination with docetaxel for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this trial, 255 patients were randomised to treatment with Xeloda (1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period) and docetaxel (75 mg/m2 as a 1-hour intravenous infusion every 3 weeks). A total of 256 patients were randomised to treatment with docetaxel alone (100 mg/m2 as a 1-hour intravenous infusion every 3 weeks). Survival was superior in the Xeloda+docetaxel combination arm (p=0.0126). Median survival was 442 days (Xeloda+docetaxel) vs 352 days (docetaxel alone). The overall objective response rates in the all-randomised population (investigator assessment) were 41.6% (Xeloda+docetaxel) vs 29.7% (docetaxel alone); p=0.0058. Time to disease progression or death was superior in the Xeloda+docetaxel combination arm (p<0.0001). The median time to progression was 186 days (Xeloda+docetaxel) vs 128 days (docetaxel alone).
Monotherapy-Breast carcinoma: Data from two multicenter phase 2 clinical trials support the use of Xeloda monotherapy for treatment of patients with locally advanced or metastatic breast cancer after failure of a taxane and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated. In these trials, a total of 236 patients were treated with Xeloda (1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period). The overall objective response rates (investigator assessment) were 20% (first trial) and 25% (second trial). The median time to progression was 93 and 98 days. Median survival was 384 and 373 days.
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 (Cmax in pg/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 (Tmax in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC0-8 values in µg·h/ml were 7.75, 7.24, 24.6, 2.03 and 36.3.
Distribution: 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.
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 tumor tissues.
Formation of 5-FU occurs preferentially at the tumor site by the tumor-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 previously mentioned in Pharmacology: Pharmacodynamics: Mechanism of Action). 5-FU is further catabolized to the inactive metabolites dihydro-5-fluorouracil (FUH2), 5-fluoro-ureidopropionic acid (FUPA) and a-fluoro-1-alanine (FBAL) via dihydropyrimidine dehydrogenase (DPD), which is rate limiting.
Elimination: The elimination half-lifes (t1/2 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 1 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 for 5-FU.
After oral administration, capecitabine metabolites are primarily recovered in the urine. Most (95.5%) of administered capecitabine dose is recovered in urine. Fecal excretion is 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 I 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 (Cmax 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 carried out 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, Karnofsky Performance Status, total bilirubin, serum albumin, ASAT and ALAT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.
Patients with hepatic impairment due to liver metastases: No clinically significant effect on the bioactivation and pharmacokinetics of capecitabine was observed in cancer patients with mildly to moderately impaired liver function due to liver metastases (see Dosage & Administration).
There are no pharmacokinetic data on patients with severe hepatic impairment.
Patients with renal impairment: Based on a 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 Dosage & Administration).
Elderly: Based on a 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 previously mentioned in Pharmacokinetics in Special Populations: Patients with renal impairment and Dosage & Administration).
Race: In a 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.
