Cancer Chemotherapy and Pharmacology

, Volume 33, Issue 6, pp 472–476 | Cite as

Variability in the pharmacokinetics of cyclophosphamide, methotrexate and 5-fluorouracil in women receiving adjuvant treatment for breast cancer

  • M. J. Moore
  • C. Erlichman
  • J. J. Thiessen
  • P. S. Bunting
  • R. Hardy
  • I. Kerr
  • S. Soldin
Original Articles Methotrexate, 5-Fluorouracil, Cylophosphamide, Variability, Pharmacokinetics, Breast Cancer


A total of 23 women with stage II breast cancer receiving adjuvant cyclophosphamide, methotrexate and 5-fluorouracil had detailed pharmacokinetic monitoring performed on the first and third courses of therapy. The area under the concentration time curve (AUC) of each of these three drugs varied by a factor of 3–4 among patients. No systematic change in pharmacokinetics between the first and third courses was seen for cyclophosphamide, methotrexate or 5-fluorouracil, and the mean AUC for each of the three drugs did not change. However, significant intrapatient variability in drug pharmacokinetics was observed for all three drugs such that the AUC, clearance and half-life in an individual on the third course could not be reliably predicted from data generated on the first course. On the basis of these results, cyclophosphamide, methotrexate, and 5-fluorouracil pharmacokinetic data from one treatment would not be useful information from which the doses for subsequent courses could be determined.


Breast Cancer Cancer Research Methotrexate Cyclophosphamide Adjuvant Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Bonadonna G, Valagussa P (1981) Dose response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 304: 10Google Scholar
  2. 2.
    Bonadonna G (1989) Conceptual and practical advances in the management of breast cancer. J Clin Oncol 7: 1380Google Scholar
  3. 3.
    Burkputt AR, Boyd MR (1980) Measurement of 5-fluorouracil in plasma by HPLC. Ann Biochem 106: 432Google Scholar
  4. 4.
    D'Argenio DZ, Schumitsky A (1979) A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Methods Programs Biomed 9: 115Google Scholar
  5. 5.
    Diasio RB, Harris BE (1989) Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16: 215Google Scholar
  6. 6.
    Egorin MJ, Forrest A, Belani CP, Ratain MJ, Abrams JS, Van Echo DA (1989) A limited sampling strategy for cyclophosphamide pharmacokinetics. Cancer Res 49: 3129Google Scholar
  7. 7.
    Egorin MJ, Van Echo DA, Olman EA, Whitacre MY, Forrest A, Aisner J (1985) Prospective validation of a pharmacologically based dosing scheme for the cisplatin analogue diamminecyclo-butanedicarboxylatoplatinum. Cancer Res 45: 6502Google Scholar
  8. 8.
    Gibaldi M, Perrier D (1982) Pharmacokinetics. Marcel Dekker, New YorkGoogle Scholar
  9. 9.
    Hardy RW, Erlichman C, Soldin SJ (1984) High-performance liquid chromatographic measurement of cyclophosphamide in plasma. Ther Drug Monit 6:313Google Scholar
  10. 10.
    Henderson IC, Hayes DF, Gelman R (1988) Dose response in the treatment of breast cancer: a critical review. J Clin Oncol 6: 1501Google Scholar
  11. 11.
    Hryniuk W, Levine L (1986) Dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4: 1162Google Scholar
  12. 12.
    Jolivet J, Cowan KH, Curt GA, Clendeninn NJ, Chabner BA (1983) The pharmacology and clinical use of methotrexate. N Engl J Med 309: 1094Google Scholar
  13. 13.
    Kerr IG, Jolivet J, Collins JM, Drake JC, Chabner BA (1983) Test dose for predicting high dose methotrexate infusions. Clin Pharmacol Ther 33: 44Google Scholar
  14. 14.
    Milano G, Roman P, Ishter R, Prenay M, Renee N, Namer M (1988) Dose versus pharmacokinetics for predicting tolerance to 5 day cotinuous infusion of 5-fluorouracil. Int J Cancer 41: 537Google Scholar
  15. 15.
    Moore M (1991) Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 20: 194Google Scholar
  16. 16.
    Moore MJ, Erlichman C (1987) Therapeutic drug monitoring in oncology. Clin Pharmacokinet 13: 205Google Scholar
  17. 17.
    Slee PH, DeBruijn EA, Dreissen OM, Oosterom AT van (1983) Pharmacokinetics of the cytostatic drugs used in the CMF regimen. Anticancer Res 3: 269Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • M. J. Moore
    • 1
    • 2
  • C. Erlichman
    • 1
    • 2
  • J. J. Thiessen
    • 4
  • P. S. Bunting
    • 5
  • R. Hardy
    • 5
  • I. Kerr
    • 3
  • S. Soldin
    • 5
  1. 1.Department of Medicine, Princess Margaret HospitalUniversity of TorontoTorontoCanada
  2. 2.Departments of Pharmacology, Princess Margaret HospitalUniversity of TorontoTorontoCanada
  3. 3.Departments of Medicine and PharmacologyToronto Bayview Regional Cancer CentreMississaugaCanada
  4. 4.Faculty of PharmacyUniversity of TorontoTorontoCanada
  5. 5.Department of Clinical BiochemistryUniversity of TorontoTorontoCanada

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