Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 6, pp 1285–1293

Pharmacokinetics and exposure–effect relationships of capecitabine in elderly patients with breast or colorectal cancer

  • Z. Daher Abdi
  • S. Lavau-Denes
  • A. Prémaud
  • S. Urien
  • F. L. Sauvage
  • J. Martin
  • S. Leobon
  • P. Marquet
  • N. Tubiana-Mathieu
  • A. Rousseau
Original Article



The aims of the present study were (1) to investigate the impact of great age on pharmacokinetics of capecitabine and its metabolites and (2) to evaluate the exposure–effect relationship of capecitabine in elderly patients.


Data collected from 20 elderly patients (75–92 years old) with breast or colorectal cancer who received oral capecitabine were analyzed. In order to study the old age effect on pharmacokinetics, data collected from two phase I studies involving 40 younger adults (<75 years old) with metastatic cancer who received oral capecitabine were added in the database. The population pharmacokinetic analysis was based on a four-compartment model describing the sequence of capecitabine and three of its metabolites.


The absorption rate constant was found lower in the oldest patient group (≥75 years) compared with the youngest group, and the constant rate elimination of the 5-fluorouracil metabolite was found decreased over time (i.e., after 2 consecutive weeks of capecitabine administration). This time effect was not found different between the two age groups. In elderly patients, the exposure-safety analysis showed, from the second cycle of chemotherapy, significantly higher median exposures of capecitabine and its metabolites (5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine and 5-fluorouracil) in patients who experienced hand-foot syndrome compared with patients who did not.


This study puts forward new arguments for the treatment of elderly cancer patients who could benefit from capecitabine chemotherapy with acceptable toxicity.


Capecitabine Elderly Pharmacokinetics Response 


  1. 1.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics. CA Cancer J Clin 60(5):277–300PubMedCrossRefGoogle Scholar
  2. 2.
    Wydra J, Kruszewski W, Jasiński W, Szajewski M, Ciesielski M, Szefel J et al (2013) Is age a risk factor of postoperative complications in colorectal cancer? Pol Przegl Chir 85:491–495PubMedGoogle Scholar
  3. 3.
    Wildiers H, Kunkler I, Biganzoli L, Fracheboud J, Vlastos G, Bernard-Marty C et al (2007) Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology. Lancet Oncol 8:1101–1115PubMedCrossRefGoogle Scholar
  4. 4.
    Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS (1999) Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061–2067PubMedCrossRefGoogle Scholar
  5. 5.
    Lewis JH, Kilgore ML, Goldman DP, Trimble EL, Kaplan R, Montello MJ et al (2003) Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 21:1383–1389PubMedCrossRefGoogle Scholar
  6. 6.
    Woodhouse KW (1994) Pharmacokinetics of drugs in the elderly. J R Soc Med 87:2–4PubMedCentralPubMedGoogle Scholar
  7. 7.
    Turnheim K (2003) When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 38:843–853PubMedCrossRefGoogle Scholar
  8. 8.
    Twelves C (2001) Vision of the future: capecitabine. Oncologist 6:35–39PubMedCrossRefGoogle Scholar
  9. 9.
    Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K et al (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274–1281PubMedCrossRefGoogle Scholar
  10. 10.
    Gieschke R, Burger H-U, Reigner B, Blesch KS, Steimer J-L (2003) Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients. Br J Clin Pharmacol 55:252–263PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Judson IR, Beale PJ, Trigo JM, Aherne W, Crompton T, Jones D et al (1999) A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug. Invest New Drugs 17:49–56PubMedCrossRefGoogle Scholar
  12. 12.
    Reigner B, Blesch K, Weidekamm E (2001) Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet 40:85–104PubMedCrossRefGoogle Scholar
  13. 13.
    Louie SG, Ely B, Lenz H-J, Albain KS, Gotay C, Coleman D et al (2013) Higher capecitabine AUC in elderly patients with advanced colorectal cancer (SWOGS0030). Br J Cancer 109:1744–1749PubMedCrossRefGoogle Scholar
  14. 14.
    Gieschke R, Reigner B, Blesch KS, Steimer JL (2002) Population pharmacokinetic analysis of the major metabolites of capecitabine. J Pharmacokinet Pharmacodyn 29:25–47PubMedCrossRefGoogle Scholar
  15. 15.
    Urien S, Rezaí K, Lokiec F (2005) Pharmacokinetic modelling of 5-FU production from capecitabine—a population study in 40 adult patients with metastatic cancer. J Pharmacokinet Pharmacodyn 32:817–833PubMedCrossRefGoogle Scholar
  16. 16.
    Grande C, Quintero G, Candamio S, París Bouzas L, Villanueva MJ, Campos B et al (2013) Biweekly XELOX (capecitabine and oxaliplatin) as first-line treatment in elderly patients with metastatic colorectal cancer. J Geriatr Oncol 4:114–121PubMedCrossRefGoogle Scholar
  17. 17.
    Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB et al (2013) Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol 14:1077–1085PubMedCrossRefGoogle Scholar
  18. 18.
    Freedman RA, Pitcher B, Keating NL, Ballman KV, Mandelblatt J, Kornblith AB et al (2013) Cognitive function in older women with breast cancer treated with standard chemotherapy and capecitabine on Cancer and Leukemia Group B 49907. Breast Cancer Res Treat 139:607–616PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Zandvliet AS, Siegel-Lakhai WS, Beijnen JH, Copalu W, Etienne-Grimaldi M-C, Milano G et al (2008) PK/PD model of indisulam and capecitabine: interaction causes excessive myelosuppression. Clin Pharmacol Ther 83:829–839PubMedCrossRefGoogle Scholar
  20. 20.
    Beal SL, Sheiner LB, Boeckmann A, Bauer RJ (1998) NONMEM User’s Guide; NONMEM project group. University of California, San FranciscoGoogle Scholar
  21. 21.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41PubMedCrossRefGoogle Scholar
  22. 22.
    Etienne MC, Chatelut E, Pivot X, Lavit M, Pujol A, Canal P et al (1998) Co-variables influencing 5-fluorouracil clearance during continuous venous infusion. A NONMEM analysis. Eur J Cancer 34:92–97PubMedCrossRefGoogle Scholar
  23. 23.
    Parke J, Holford NH, Charles BG (1999) A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Programs Biomed 59:19–29PubMedCrossRefGoogle Scholar
  24. 24.
    Terret C, Erdociain E, Guimbaud R, Boisdron-Celle M, McLeod HL, Féty-Deporte R et al (2000) Dose and time dependencies of 5-fluorouracil pharmacokinetics. Clin Pharmacol Ther 68:270–279PubMedCrossRefGoogle Scholar
  25. 25.
    Fety R, Rolland F, Barberi-Heyob M, Hardoin A, Campion L, Conroy T et al (1998) Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinoma. Clin Cancer Res 4:2039–2045PubMedGoogle Scholar
  26. 26.
    Poole C, Gardiner J, Twelves C, Johnston P, Harper P, Cassidy J et al (2002) Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients. Cancer Chemother Pharmacol 49:225–234PubMedCrossRefGoogle Scholar
  27. 27.
    Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C et al (1999) Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 7:485–493Google Scholar
  28. 28.
    Abushullaih S, Saad ED, Munsell M, Hoff PM (2002) Incidence and severity of hand-foot syndrome in colorectal cancer patients treated with capecitabine: a single-institution experience. Cancer Invest 20:3–10PubMedCrossRefGoogle Scholar
  29. 29.
    Bruno R, Hille D, Riva A, Vivier N, ten Bokkel Huinnink WW, van Oosterom AT et al (1998) Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187–196PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Z. Daher Abdi
    • 1
    • 2
  • S. Lavau-Denes
    • 3
  • A. Prémaud
    • 1
    • 2
  • S. Urien
    • 4
  • F. L. Sauvage
    • 1
    • 5
  • J. Martin
    • 3
  • S. Leobon
    • 3
  • P. Marquet
    • 1
    • 2
    • 5
  • N. Tubiana-Mathieu
    • 3
  • A. Rousseau
    • 1
    • 2
  1. 1.UMR-S850, Faculty of PharmacyInsermLimoges CedexFrance
  2. 2.Laboratoire de Pharmacologie médicaleUniv LimogesLimogesFrance
  3. 3.CHU LimogesService oncologie médicaleLimogesFrance
  4. 4.EA 3620Univ Paris DescartesSorbonne Paris CitéFrance
  5. 5.CHU LimogesService de pharmacologie, toxicologie et pharmacovigilanceLimogesFrance

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