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The Oncologist, Vol. 12, No. 2, 152-155, February 2007; doi:10.1634/theoncologist.12-2-152
© 2007 AlphaMed Press
Clinical Pharmacology: Concise Drug Reviews |
Capecitabine
Jan H.M. Schellens
The Netherlands Cancer Institute, Amsterdam, The Netherlands, and Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Section of Biomedical Analysis, Division of Drug Toxicology, Utrecht, The Netherlands
Correspondence:
Jan H.M. Shellens, M.D., Ph.D., Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. e-mail: jhm{at}nki.nl
Received September 19, 2006;
accepted for publication November 15, 2006.
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:- Identify the main toxicity profile associated with capecitabine therapy.
- Identify the main clinical indications for capecitabine therapy.
- Identify the populations at risk for severe toxicity from capecitabine therapy.
Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com
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INTRODUCTION
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Capecitabine (Xeloda®; Hoffmann-LaRoche Inc., Nutley, NJ) is currently registered for four indications: (a) monotherapy in the first line of treatment of advanced colorectal cancer, (b) adjuvant treatment of patients with stage III (Duke’s stage C) colon cancer, (c) in combination with docetaxel in the treatment of locally advanced or metastatic breast cancer, and (d) as monotherapy in advanced breast cancer after failure of a taxane- and anthracycline-containing chemotherapy or for patients for whom an anthracycline is contraindicated [1].
Capecitabine is becoming increasingly popular and has largely replaced 5-fluorouracil (5-FU) in several indications, including gastric cancer. Clinical activity of a 14-day schedule of capecitabine given every 21 days is therapeutically equivalent to bolus 5-FU with low-dose leucovorin given every 4 weeks in colorectal cancer [1].
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CLINICAL USE
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Capecitabine is available in tablets of 150 and 500 mg. The recommended dose as a single agent is 1,250 mg/m2 b.i.d. for 14 days repeated on day 22. At this dose level, approximately one third of patients need a dose reduction due to toxicity, and many physicians start, therefore, at the lower dose of 1,000 mg/m2 b.i.d. Proof of the usefulness of dosing per unit of body surface area has never been provided. In combination with docetaxel, the dose is 1,250 mg/m2 b.i.d. for 14 days plus 75 mg/m2 docetaxel intravenously repeated on day 22.
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MECHANISM OF ACTION
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Capecitabine is a pre-prodrug of 5-FU and is rapidly converted to 5-FU in tumor tissue. Thymidylate synthase inhibition and incorporation into RNA and DNA are the most important mechanisms of action of capecitabine.
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ANALYTICAL METHODOLOGY
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The bioanalysis of capecitabine and its nucleoside metabolites can be exerted by high-performance liquid chromatography with tandem mass spectrometry detection [2].
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PHARMACOKINETICS
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Absorption
After oral administration, capecitabine is rapidly taken up from the gut and converted into its main metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluoro-uridine (5'-DFUR). Systemic levels of 5-FU are low. Concomitant food intake significantly reduces the systemic exposure to capecitabine. It is recommended to take the drug after a meal because this has also been done in the clinical trials. The time to reach the maximal plasma concentration after food ingestion is around 2 hours. Oral pharmacokinetics are linear. The absolute bioavailability is estimated to be 40%–45% [3].
Protein Binding
Binding is mainly to albumin and is 54% for capecitabine and 10%, 62%, and 10% for its metabolites 5'-DFCR, 5'-DFUR, and 5-FU, respectively [2]. No relevant interactions at this level are to be expected.
Metabolism
After oral uptake, capecitabine is first metabolized to 5'-DFCR, which takes place mainly in the liver by carboxyl-esterase. The metabolite is converted to 5'-DFUR by cytidine deaminase in liver and tumor tissue and converted to 5-FU intracellularly by thymidine phosphorylase, an enzyme that is often expressed in tumor tissue (Fig. 1
). Catalytic inactivation of 5-FU proceeds by dihydropyrimidine dehydrogenase (DPD), which is polymorphically expressed.
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Figure 1. Chemical structure of capecitabine and its main metabolites. Abbreviations: 5'-DFCR, 5'-deoxy-5-fluorocytidine; 5'-DFUR, 5'-deoxy-5-fluorouridine; 5-FU, 5-fluoro uracil; 5-FUH2, 5-fluorodihydrouracil; FdUMP, 5-fluoro-2'-deoxyuridine-monophosphate; FUTP, 5-fluorouridine-5'-triphosphate.
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Elimination
Capecitabine is largely eliminated as metabolites (> 95% of the dose). The terminal half-life of the parent drug and its metabolites is short (< 1 hour). Excretion proceeds via the urine. No clinically relevant demographic factors or ethnic differences affecting the pharmacokinetics have been found to date.
Drug and Complementary and Alternative Medicine Interactions
Clinically, the most important interaction between capecitabine and other drugs is with coumarins [4]. Capecitabine inhibits CYP2C9, which isozyme is the main oxidizing enzyme for coumarins. Patients on coumarins should be monitored frequently or changed to low-molecular weight heparin anticoagulation during therapy with capecitabine. Phenytoin levels can increase; therefore, plasma levels should be monitored during capecitabine therapy. Combination with inhibitors of DPD could induce severe toxicity, as seen for the combination of 5-FU and sorivudine, an antiviral drug that is converted in the gut to a uracil analogue and irreversible DPD inhibitor. No controlled study data are available about complementary and alternative medicine use and capecitabine.
Alterations with Disease or Age
In mild-to-moderate liver disease, the absolute bioavailability of capecitabine was 62% versus 45% in patients without liver dysfunction [3]. It would be safe to reduce the dose to 75% in case of significant liver dysfunction. In case of renal dysfunction, dose reductions may also be necessary. Creatinine clearance of 30–50 ml/minute was associated with increased exposure and higher incidence of serious adverse events, and a reduction to 75% of the dose is recommended. In case of creatinine clearance of less than 30 ml/minute, capecitabine therapy is not recommended. No relevant effect of age was found on the disposition of 5-FU after capecitabine therapy, although wide variability in the pharmacokinetics may have masked a true relationship between age and 5-FU pharmacokinetics [5].
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PHARMACOGENETICS
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5-FU is enzymatically degraded by DPD, which enzyme is polymorphically expressed. The activity and genotype of DPD can be determined by several different assays. The single-nucleotide polymorphism in exon 14 of the DYPD gene (DYPD*2A [IVS14 + 1G > A]) probably has the greatest effect on DPD activity because it results in the absence of enzyme activity. In whites, the incidence of heterozygotes is 1%–2% [6]. It is not yet routine clinical practice to genotype patients prior to starting therapy with capecitabine or 5-FU and adapting the dose accordingly.
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PHARMACODYNAMICS
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Relationships between capecitabine dose and response are difficult to assess and have not been extensively explored. The key enzyme thymidylate synthase is correlated with 5-FU activity in preclinical models. There are no algorithms for adaptive dosing of capecitabine to prevent the development of significant toxicity.
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CONTRAINDICATIONS OR SPECIAL PRECAUTIONS
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Contraindications include severe liver dysfunction, severe renal impairment (creatinine clearance < 30 ml/minute), DPD deficiency, known hypersensitivity to 5-FU, capecitabine and excipients, thrombocytopenia (< 100 x 109/l), neutropenia (< 1.5 x 109/l), pregnancy, and milk lactation (or nursing). Caution is recommended in patients with is-chemic heart disease or coronary artery disease and/or in therapy with sorivudine and analogs, coumarins, and phenytoin. Elderly patients may experience a greater incidence of gastrointestinal grade 3/4 events (especially when capecitabine is used in combination with docetaxel).
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CLINICAL MONITORING
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Before every cycle.
Blood cell count, renal function test (serum creatinine), and liver function test (ASAT/ALAT, alkaline phosphatase, bilirubin).
During each cycle.
Clinical examination and grading of diarrhea, stomatitis, and hand–foot syndrome.
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PATIENT INSTRUCTIONS AND RECOMMENDATIONS FOR SUPPORTIVE CARE
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The tablets should be swallowed with water within 30 minutes after a meal.
Missed doses of capecitabine should not be replaced.
Hand–foot syndrome, when clinically relevant, necessitates dose reduction or shortening of the treatment period, for example, from 14 to 10 days.
Loperamide may be useful to alleviate symptoms of crampy diarrhea.
Pyridoxine (50 mg, t.i.d.) may be added to alleviate or prevent symptoms of hand–foot syndrome together with topical emollients (e.g., hand creams, udder balm).
It is recommended to keep the drug (tablets) at room temperature (below 30°C).
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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The author indicates no potential conflicts of interest.
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ACKNOWLEDGMENT
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I am indebted to Professor Jos H. Beijnen, hospital pharmacist, and Dr. Serena Marchetti, medical oncologist of the Netherlands Cancer Institute, for their critical comments.
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REFERENCES
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- Milano G, Schellens JHM. Pyrimidine antimetabolites. In: Schellens JHM, McLeod HL, Newell DR eds. Cancer Clinical Pharmacology. Oxford: University Press, 2005:51–62.
- Xu Y, Grem JL. Liquid chromatography-mass spectrometry method for the analysis of the anti-cancer agent capecitabine and its nucleoside metabolites in human plasma. J Chromatogr B Biomed Appl 2003; 783:273–285.
- Twelves C, Glynne-Jones R, Cassidy J et al. Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites. Clin Cancer Res 1998;4:941–948.[Abstract]
- Beijnen JH, Schellens JHM. Drug interactions in oncology. Lancet Oncology 2004; 5:689–696.
- Giescke R, Burger HU, Reigner B et al. Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients. Br J Clin Pharmacol 2003;55:252–263.[CrossRef][Medline]
- Raida M, Schwabe W, Hausler P, et al. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5'-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)-related toxicity compared with controls. Clin Cancer Res 2001;7:2832–2839.[Abstract/Free Full Text]
- Kuppens IE, Boot H, Beijnen JH et al. Capecitabine induces severe angina-like chest pain. Ann Intern Med 2004;140:494–495.[Free Full Text]
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Learning Objectives
Introduction
