Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Antimetabolites

  • Pyrimidine Analogues continued

    • Capecitabine (Xeloda)

      • 5-fluorouracil (Adrucil) may be administered directly as 5-FU or can be made available by administration of the prodrug, capecitabine (Xeloda).¹

        • Capecitabine is converted to 5-FU.

        • Capecitabine (Xeloda)

    • Introduction:

      • Capecitabine (Xeloda) is a fluoropyrimidine carbamate the may be taken orally.⁶ 

        • Following significant and rapid gut mucosal absorption, capecitabine is associated with high oral bioavailability (about 80%).⁶  

        • The parent form of the drug is inactive in requires 3 subsequent activating step facilitated by enzyme catalysis.

          • The last step (the 3rd step) occurs in tumor tissue thus allowing selective 5-FU activation in the target tissue.

          • This 3rd step is the conversion of 5'-deoxy-5-fluorouridine (5'-dFdU) to 5-fluorouracil (5-FU), a step catalyzed by thymidine phosphorylase (TP).

          • This enzyme (TP) is found at notably higher levels in tumors, compared to corresponding normal tissue.⁶  

        • The two preceding steps involves deesterification (1st step) followed by deamination (2nd step).¹

          • Capecitabine Metabolism⁷ 

            Attribution (figure modified from) Desmoulin F Gilard V Malet-Martino M Martino R Metabolism of Capecitabine, an Oral Fluorouracil Prodrug:  19F NMR Studies in Animal Models and Human Urine ASPET Drug Metabolism and Dispositon November 2002, 30(11) 1221-1229. http://dmd.aspetjournals.org/content/30/11/1221

           

          • Capecitabine (Xeloda) was initially introduced and approved for breast cancer shown anthracycline-and taxane-resistant.⁶ 

            • In a combination protocol with docetaxel, capecitabine was approved as second-line treatment for metastatic breast cancer.⁶ 

            • Capecitabine in combination with lapatinib (Tykerb),may be an appropriate option for treating HER2-positive metastatic breast cancer, if disease progression had been noted on trastuzumab (Herceptin)-based protocols.⁶

              • Lopatinib (Tykerb) is a tyrosine-kinase inhibitor of human epidermal growth factor receptor type II (HER2) and epidermal growth factor receptor (EGFR).

            • Capecitabine is also approved for:

              • First-line treatment of metastatic colorectal cancer (mCRC)⁶  and as

              • Adjuvant treatment for stage III colon cancer for those cases in which fluoropyrimidine monotherapy is desirable.⁶ 

            • In many countries, capecitabine in combination with oxaliplatin (Xelox) is viewed appropriate for treating mCRC and as adjuvant treatment in stage III colon cancer.

        • Absorption, Distribution, Biotransformation, Excretion:

          • Usually, capecitabine is given orally in two divided doses with food for 2 weeks followed by a one-week rest period.¹ 

            • As noted earlier capecitabine is well absorbed following oral administration (about 80%).

              • Following rapid deesterification and deamination (see chart above) a high plasma level of an inactive prodrug 5'-dFdU is noted, exhibiting a t_1/2 of about one hour.¹ 

                • Thymidine phosphorylase catalyzes conversion of 5'-dFdU to the active drug, 5-FU with conversion occurring in peripheral tissues, liver, and tumors.

                  • Thymidine Phosphorylase Dimer

                    Attribution:  Wangj2013 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons https://commons.wikimedia.org/wiki/File:Thymidine_phosphorylase_dimer.png

                  • Liver dysfunction may delay conversion of the parent compound (capecitabine) to the prodrug 5'-dFdU and 5-FU, although no reproducible effect on toxicity has been reported.¹

          • Excretion:  Capecitabine and its metabolites are excreted mainly by the kidneys.

            • As a consequence, renal dysfunction interfering with drug excretion may require dosage adjustment.

              • In patients exhibiting creatinine clearance <30 mL/min, the use of capecitabine is contraindicated.

              • There is, in addition, an important drug-drug interaction that has been identified between warfarin and capecitabine-based anticancer therapy.

                • Weekly monitoring of coagulation parameters for patients receiving warfarin and capecitabine concurrently is recommended along with warfarin dose adjustments as appropriate.

          • Toxicity:³

            • The primary toxicities of capecitabine include:³

              • Diarrhea along with

              • Hand-foot syndrome (HFS).

            • Myelosuppression, mucositis, alopecia, and nausea and vomiting although observed following capecitabine administration occur less frequently than following intravenous 5-FU administration.³

    • Clinical Uses:¹

      •  Capecitabine (5-FU pro-drug) has been approved for treatment of several cancers including:¹

        • Metastatic breast cancer not responsive to a protocol including paclitaxel and an anthracycline

        • Metastatic breast cancer when used along with docetaxel in those patients who have previously received an anthracycline-containing protocol and for

        • Metastatic colorectal cancer¹

          • Capecitabine in Metastatic ER⁺ Breast Cancer⁹

            Attribution: Kimmick GG Capecitabine for Metastatic ER+ Breast Cancer (9/2018) https://www.youtube.com/watch?v=qDlicCUwboY Targeted Oncology Youtube Channel:  https://www.youtube.com/channel/UCE-5JpR_HFBQXgG0dH5DYPg

      • Capecitabine has been frequently used in combination with other drugs.¹ 

        • One example is a combination with cisplatin for treating head and neck cancer.

        • Another example is combination of 5-FU and oxaliplatin or irinotecan for treating metastatic colorectal cancer (first-line treatment).¹ 

        • The use of 5-FU in combination protocols confers improved survival as adjuvant breast cancer treatment and similarly in combination with oxaliplatin and leucovorin in colorectal cancer.

        • 5-FU is an important and significant radiation sensitizer.

          • Beneficial effects have been noted when 5-FU is combined with radiation in primary patient treatment with:

            • Locally advanced esophageal cancer

            • Stomach cancer

            • Pancreatic cancer

            • Head and neck cancer

            • Cervical cancer and

            • Anal cancer ¹

        • 5-FU is also effective topically in treating premalignant skin keratoses and in treating multiple superficial basal cell carcinomas.¹

    • Toxicity:

      • Side effects associated with capecitabine administration are similar to those described for 5-FU infusion.

        • Major side effects include diarrhea and hand-foot syndrome (HFS).⁶ 

        • Likelihood of certain side effects including myelosuppression, mucositis, neutropenic fever, alopecia as well as nausea/vomiting is reduced with capecitabine compared to 5-FU.⁶

      • Capecitabine in addition to 5-FU and tegafur administration has been associated with a relatively high rate (20%-50%) of alimentary tract mucositis.¹⁰