Clinical Pharmacokinetics

, Volume 4, Issue 5, pp 380–394 | Cite as

Clinical Pharmacokinetics of Cyclophosphamide

  • Louise B. Grochow
  • Michael Colvin
Article

Summary

Cyclosphosphamide is widely used for cancer chemotherapy and for immunosuppression. The parent compound is inactive in vitro and exerts its biological activities through metabolites generated by hepatic microsomal enzymes. The drug may be administered either parenterally or orally. Systemic availability after oral administration is greater than 75% at the low doses which have been studied. Cyclophosphamide is minimally protein bound but some of its metabolites are more than 60% protein bound.

A linear 2-compartment model for the disposition of the parent compound has been formulated, but characteristics of the kinetics of disposition of the active metabolites have been delayed by analytical difficulties. Parameters vary widely between patients. Vc for this polar compound ranges from 0.32 to 0.34L/kg. Vd ranges from 0.60 to 0.64L/kg. T½β ranges from 3 to 12 hours.

Modelling of the time course of specific cytotoxic metabolites (aldophosphamide, 4-hydroxycyclophosphamide and phosphoramide mustard) has not been systematically performed. When measured by various nonspecific techniques, the serum concentration of metabolites was found to be maximal about 2 hours after an intravenous dose and declined by only 25% during the next 6 hours. Mean t½ was 7.7 hours in 1 study. Alkylating metabolites have been measured in the cerebrospinal fluid, but only a small fraction crosses the blood brain barrier.

At least 80% of an administered dose of cyclophosphamide is eliminated by metabolism. Both cyclophosphamide and metabolites are principally excreted by the kidney. Renal clearance has been measured at 5 to 11 ml/min, suggesting extensive tubular resorption; up to 25% of the administered dose is excreted unchanged in the first 24 hours. Only 60% of radiolabet can be recovered in the urine over 24 to 48 hours. An additional 1 to 4% can be collected as expired CO2 or in the stool. Although elevated levels of metabolites have been described in patients with renal failure, a recent study did not demonstrate excess clinical toxicity in such patients. Unchanged cyclophosphamide has been shown to be extensively cleared by haemodialysis (78ml/min).

Complex interactions are to be expected with agents modifying hepatic microsomal activation, and conflicting data have been obtained in several animal studies. No clear alteration of the effects of cyclophosphamide has been observed in patients after phenobarbitone administration. Synergistic haematopoietic toxicity may occur with concomitant use of allopurinol.

Dose related efficacy has been demonstrated in animal models. Human data are available on dose related toxicity. One study demonstrated a direct relationship between metabolite AUC and depth of white blood count nadir. Clinical correlation between kinetic data and efficacy and/or toxicity awaits studies evaluating the time course of specific cytotoxic metabolites.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alberts, D.S.; Peng, Y.M.; Chen, H.S. and Struck, R.F.: Effect of phenobarbital on plasma levels of cyclophosphamide and its metabolites in the mouse. British Journal of Cancer 38: 316–324 (1978).PubMedCrossRefGoogle Scholar
  2. Alberts, D.S. and van Daalen Wetters, T.: The effect of phenobarbital on cyclophosphamide antitumor activity. Cancer Research 36: 2785–2789 (1976a).PubMedGoogle Scholar
  3. Alberts, D.S. and van Daalen Wetters, T.: The effect of allopurinol on cyclophosphamide antitumor activity. Cancer Research 36: 2790–2794 (1976b).PubMedGoogle Scholar
  4. Allen, L.M. and Creaven, P.J.: In vitro activation of isophosphamide (NSC-109724), a new oxazaphosphorine, by rat liver microsomes. Cancer Chemotherapy Reports, Part 1, 56: 603–610 (1972).Google Scholar
  5. Bagley, C.M., Jr.; Bostick, F.W. and DeVita, V.T., Jr.: Clinical pharmacology of cyclophosphamide. Cancer Research 33: 226–233 (1973).PubMedGoogle Scholar
  6. Bakke, J.E.; Feil, V.J.; Fjelstul, C.E. and Thacker, E.J.: Metabolism of cyclophosphamide in sheep. Journal of Agricultural and Food Chemistry 20: 384–388 (1972).PubMedCrossRefGoogle Scholar
  7. Bending, M.R. and Finch, R.E.: Haemodialysis during cyclophosphamide treatment. British Medical Journal 1: 1145–1146 (1978).PubMedCrossRefGoogle Scholar
  8. Bergsagel, D.E.; Robertson, G.L. and Hasselbach, R.: Effect of cyclophosphamide on advanced lung cancer and the hematological toxicity of large, intermittent doses. Canadian Medical Association Journal 98: 532–538 (1968).PubMedGoogle Scholar
  9. Boston Collaborative Drug Surveillance Program. Allopurinol and cytotoxic drugs. Interaction and relation to bone marrow suppression. Journal of the American Medical Association 227: 1036–1040 (1974).CrossRefGoogle Scholar
  10. Brock, N.: Comparative pharmacologic study in vitro and in vivo with cyclophosphamide (NSC-26271), cyclophosphamide metabolites, and plain nitrogen mustard compounds. Cancer Treatment Reports 60: 301–308 (1976).PubMedGoogle Scholar
  11. Brock, N.; Gross, R.; Hohorst, H.-J.; Klein, H.O. and Schneider, B.: Activation of cyclophosphamide in man and animals. Cancer 27: 1512–1529 (1971).PubMedCrossRefGoogle Scholar
  12. Brock, N. and Hohorst, H.-J.: Uber die aktivierung von cyclophosphamid in vivo und in vitro. Arzneimittel-Forschung 13: 1021–1031 (1963).PubMedGoogle Scholar
  13. Buckner, C.D.; Rudolph, R.H.; Fefer, A.; Clift, R.A.; Epstein, R.B.; Funk, D.D.; Neiman, P.E.; Slichter, S.J.; Starb, R. and Thomas, E.D.: High dose cyclophosphamide therapy for malignant disease. Cancer 29: 357–365 (1972).CrossRefGoogle Scholar
  14. Bus, J.S.; Short, R.D. and Gibson, J.E.: Effect of phenobarbital and SKF-525A on the toxicity, elimination, and metabolism of cyclophosphamide in new born mice. Journal of Pharmacology and Experimental Therapeutics 184: 749–756 (1973).PubMedGoogle Scholar
  15. Cohen, J.L. and Jao, J.Y.: Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat. Journal of Pharmacology and Experimental Therapeutics 174: 206–210 (1970).PubMedGoogle Scholar
  16. Cohen, J.L.; Jao, J.Y. and Jusko, W.J.: Pharmacokinetics of cyclophosphamide in man. British Journal of Pharmacology 43: 677–680 (1971).PubMedCrossRefGoogle Scholar
  17. Colvin, M.: A review of the pharmacology and clinical use of cyclophosphamide; in Pinedo (Ed) Clinical Pharmacology of Anti-Neoplastic Drugs, p. 245–261 (Elsevier/North-Holland Biomedical Press, Amsterdam 1978).Google Scholar
  18. Colvin, M.; Brundrett, R.B.; Kan, M.-N.N.; Jardine, I. and Fenselau, C.: Alkylating properties of phosphoramide mustard. Cancer Research 36: 1121–1126 (1976).PubMedGoogle Scholar
  19. Colvin, M.; Padgett, C.A. and Fenselau, C.: A biologically active metabolite of cyclophosphamide. Cancer Research 33: 915–918 (1973).PubMedGoogle Scholar
  20. Connors, T.A.; Cox, P.J.; Farmer, P.B.; Foster, A.B. and Jarman, M.: Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochemical Pharmacology 23: 115–129 (1974).PubMedCrossRefGoogle Scholar
  21. Creaven, P.J.; Allen, L.M.; Alford, D.A. and Cohen, M.H.: Clinical pharmacology of isophosphamide. Clinical Pharmacology and Therapeutics 16: 77–86 (1974).PubMedGoogle Scholar
  22. DeFronzo, R.A.; Braine, H.; Colvin, M. and Davis, P.J.: Water intoxication in man after cyclophosphamide therapy. Time course and relationship to drug activation. Annals of Internal Medicine 78: 861–869 (1973).PubMedGoogle Scholar
  23. D’Incalci, M.; Bolis, G.; Facchinetti, T.; Mangioni, C.; Morasca, L.; Morazzoni, P. and Salmona, M.: Decreased half life of cyclophosphamide in patients under continual treatment. European Journal of Cancer 19: 7–10 (1979).Google Scholar
  24. Donelli, M.G.; Vecchi, A.; Bossi, A.; Colombo, T.; Sironi, M.; Pantarotto, C.; Garattini, S. and Spreafico, F.: Effect of phenobarbital on cyclophosphamide cytotoxic activity and pharmacokinetics in mice. Tumori 63: 137–146 (1977).PubMedGoogle Scholar
  25. Facchinetti, T.; D’Incalci, M.; Martelli, G.; Cantoni, L.; Belvedere, G. and Salmona, M.: A simple and sensitive method for the determination of cyclophosphamide by means of a nitrogen phosphorus selective detector (NPSD). Journal of Chromatography 145: 315–318 (1978).PubMedCrossRefGoogle Scholar
  26. Feil, V.J. and Lamoureux, C.J.H.: Alopecia activity of cyclophosphamide metabolites and related compounds in sheep. Cancer Research 34: 2596–2598 (1974).PubMedGoogle Scholar
  27. Fenselau, C.; Kan, M.-N.N.; Subba Rao, S.; Myles, A.; Friedman, O.M. and Colvin, M.: Identification of aldophosphamide as a metabolite of cyclophosphamide in vitro and in vivo in humans. Cancer Research 37: 2538–2543 (1977).PubMedGoogle Scholar
  28. Field, R.B.; Gang, M.; Kline, I.; Venditti, J.M. and Waravdekar, V.S.: The effect of phenobarbital or 2-diethylaminoethyl-2,2-diphenylvalerate on the activation of cyclophosphamide in vivo. Journal of Pharmacology and Experimental Therapeutics 180: 475–483 (1972).PubMedGoogle Scholar
  29. Friedman, O.M. and Boger, E.: Colorimetric estimation of nitrogen mustards in aqueous media. Analytical Chemistry 33: 906–910 (1961).CrossRefGoogle Scholar
  30. Friedman, C.M.; Myles, A. and Colvin, M.: Cyclophosphamide and related phosphoramide mustards: current status and future prospects; in Rosowsky (Ed) Advances in Cancer Chemotherapy, Vol. 1 (Marcel Dekker, New York, in press 1979).Google Scholar
  31. Grochow, L.B.; Humphrey, R.L. and Colvin, M.: The influence of renal insufficiency on cyclophosphamide induced hematopoietic depression and recovery. In preparation (1979).Google Scholar
  32. Hill, D.L.: A Review of Cyclophosphamide (Charles C. Thomas, Springfield, Illinois 1975).Google Scholar
  33. Hohorst, H.-J.; Draeger, U.; Voelcker, G. and Brock, N.: Metabolic activation and inactivation of cyclophosphamide as the cause of its oncostatic activity; in Becalossi, Veronesi and Cascinelli (Eds) Proceedings of the 11th Cancer Congress, Florence, Italy, Vol. 4. p. 729 (Excerpta Medica, Amsterdam 1975).Google Scholar
  34. Humphrey, R.L. and Kvols, L.K.: The influence of renal insufficiency on cyclophosphamide induced hematopoietic depression and recovery. Proceedings of the American Association of Cancer Research 15: 84 (1974).Google Scholar
  35. Jao, J.Y.; Jusko, W.J. and Cohen, J.L.: Phenobarbital effects on cyclophosphamide pharmacokinetics in man. Cancer Research 32: 2761–2764 (1972).PubMedGoogle Scholar
  36. Jardine, I.; Fenselau, C.; Appier, M.; Kan, M.-N.; Brundrett, R.B. and Colvin, M.: Quantitation by gas chromatography-chemical ionization mass spectrometry of cyclophosphamide, phosphoramide mustard, and nornitrogen mustard in the plasma and urine of patients receiving cyclophosphamide therapy. Cancer Research 38: 408–415 (1978).PubMedGoogle Scholar
  37. Juma, F.D.; Rogers, H.J. and Trounce, J.R.: Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration. British Journal of Clinical Pharmacology, in press (1979).Google Scholar
  38. Mellett, L.B.: Chemistry and metabolism of cyclophosphamide; in Vancil (Ed) Immunosuppressive Properties of Cyclophosphamide, pp.6–34 (Mead Johnson & Company, Evansville, Indiana 1971).Google Scholar
  39. Mellett, L.B.; El Dareer, S.M.; Rall, D.P. and Adamson, R.H.: Metabolism of cyclophosphamide-C14 by various marine species. Archives Internationales de Pharmacodynamic et de Therapie 177: 59–70 (1969).Google Scholar
  40. Millar, J.L.; Phelps, T.A.; Carter, R.L. and McElwain, T.J.: Cyclophosphamide pretreatment reduces the toxic effect of high dose melphalan on intestinal epithelium in sheep. European Journal of Cancer 14: 1283–1285 (1978).PubMedCrossRefGoogle Scholar
  41. Milsted, R.A.V. and Jarman, M.: Haemodialysis during cyclophosphamide treatment. British Medical Journal 1: 820–821 (1978).PubMedCrossRefGoogle Scholar
  42. Mouridsen, H.T.; Faber, O. and Skovsted, L.: The biotransformation of cyclophosphamide in man: Analysis of the variation in normal subjects. Acta Pharmacologica et Toxicologica 35: 98–106 (1974).PubMedCrossRefGoogle Scholar
  43. Mouridsen, H.T.; Faber, O. and Skovsted, L.: The metabolism of cyclophosphamide. Dose dependency and the effect of long term treatment with cyclophosphamide. Cancer 37: 665–670 (1976).PubMedCrossRefGoogle Scholar
  44. Mouridsen, H.T. and Jacobsen, E.: Pharmacokinetics of cyclophosphamide in renal failure. Acta Pharmacologica et Toxicologica 36: 409–414 (1975).PubMedCrossRefGoogle Scholar
  45. Mouridsen, H.T.; Witten, J.; Frederiksen, P.L. and Hulsbaek, I.: Studies on the correlation between rate of biotransformation and haematological toxicity of cyclophosphamide. Acta Pharmacologica et Toxicologica 43: 328–330 (1978).PubMedCrossRefGoogle Scholar
  46. Mullins, C.M. and Colvin, M.: Intensive cyclophosphamide (NSC-26271) therapy in solid tumors. Cancer Chemotherapy Reports 59: 411–419 (1975).Google Scholar
  47. Pantarotto, C.; Bossi, A.; Belvedere, G.; Martini, A.; Donelli, M.G. and Frigerio, A.: Quantitative GLC determination of cyclophosphamide and isophosphamide in biological specimens. Journal of Pharmaceutical Sciences 63: 1554–1558 (1974).PubMedCrossRefGoogle Scholar
  48. Sensenbrenner, L.L.; Marini, J.J. and Colvin, M.: Comparative effects of cyclophosphamide, isophosphamide, 4-methyl-cyclophosphamide, and phosphoramide mustard on murine hematopoietic and immunocompetent cells. Journal of the National Cancer Institute 62: 975–981 (1979).PubMedGoogle Scholar
  49. Sladek, N.E.: Metabolism of cyclophosphamide by rat hepatic microsomes. Cancer Research 31: 901–908 (1971).PubMedGoogle Scholar
  50. Sladek, N.E.: Therapeutic efficacy of cyclophosphamide as a function of its metabolism. Cancer Research 32: 535–542 (1972).PubMedGoogle Scholar
  51. Sladek, N.E.: Bioassay and relative cytotoxic potency of cyclophosphamide metabolites generated in vitro and in vivo. Cancer Research 33: 1150–1158 (1973).PubMedGoogle Scholar
  52. Slavin, R.E.; Millan, J.C. and Mullins, G.M.: Pathology of high dose intermittent cyclophosphamide therapy. Human Pathology 6: 693–709 (1975).PubMedCrossRefGoogle Scholar
  53. Struck, R.F.; Kirk, M.C.; Mellett, L.B.; El Dareer, S. and Hill, D.L.: Urinary metabolites of the antitumor agent cyclophosphamide. Molecular Pharmacology 7: 519–529 (1971).PubMedGoogle Scholar
  54. Struck, R.F.; Kirk, M.C.; Witt, M.H. and Laster, W.R., Jr.: Isolation and mass spectral identification of blood metabolites of cyclophosphamide: Evidence for phosphoramide mustard as the biologically active metabolite. Biomedical Mass Spectrometry 2: 46–52 (1975).PubMedCrossRefGoogle Scholar
  55. Takamizawa, A.; Matsumoto, S.; Iwata, T.; Katagiri, K.; Tochino, Y. and Yamaguchi, K.: Studies on cyclophosphamide metabolites and their compounds. II. Preparation of an active species of cyclophosphamide and some related compounds. J. Amer. Chem. Soc. 95: 985–986 (1973).CrossRefGoogle Scholar
  56. Voelcker, G.; Wagner, T. and Hohorst, H.-J.: Identification and pharmacokinetics of cyclophosphamide (NSC-26271) metabolites in vivo. Cancer Treatment Reports 60: 415–422 (1976).PubMedGoogle Scholar
  57. Wagner, T.; Peter, G.; Voelcker, G. and Hohorst, H.-J.: Characterization and quantitative estimation of activated cyclophosphamide in blood and urine. Cancer Research 37: 2592–2596 (1977).PubMedGoogle Scholar
  58. Weaver, F.A.; Torkelson, A.R.; Zygmunt, W.A. and Browder, H.P.: Tissue culture cytotoxicity assay for cyclophosphamide metabolites in rat body fluids. Journal of Pharmaceutical Sciences 67: 1009–1012 (1978).PubMedCrossRefGoogle Scholar
  59. Whiting, B.; Miller, S.H.K. and Caddy, B.: A procedure for monitoring cyclophosphamide and isophosphamide in biological samples. British Journal of Clinical Pharmacology 6: 373–376 (1978).PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press Australasia Pty Ltd. 1979

Authors and Affiliations

  • Louise B. Grochow
    • 1
  • Michael Colvin
    • 1
  1. 1.Pharmacology LaboratoryJohns Hopkins Oncology CenterBaltimoreUSA

Personalised recommendations