Long-term pharmacokinetics of doxorubicin HCl stealth liposomes in patients after polychemotherapy with vinorelbine, cyclophosphamide and prednisone (CCVP)

  • W. Linkesch
  • M. Weger
  • I. Eder
  • H. W. Auner
  • C. Pernegg
  • C. Kraule
  • M. J. Czejka


The concentration-time profiles of Doxorubicin (DOXO) from day 0 to day 21 after i.v. infusion of 25 or 30 mg/m2 doxorubicin HCl stealth liposomes (Caelyx®) were investigated in 9 patients receiving combination polychemotherapy with cyclophosphamide, vinorelbine and prednisone. Peak serum concentrations occurred from 0.04 to 4.0 days after infusion (mean tmax=1.79±1.55 d) with a mean cmax of 4595±2849 ng/ml. A total amount of 12.84±2.47 mg liposomal DOXO in the plasma volume (Vp=2794+537 ml) could be estimated at tmax (=27% of the mean dose of 47.6 mg). Stealth liposomes were eliminated slowly from the blood with a mean t1/2el of 1.9+0.5 days (MRT was 4.6+2.5 days).

AUClast values ranged from 8070 to 33446 ng/ml*d (mean 10987±9339 ng/ml*d). The low plasma clearance (Cltot=4681±2835 ml/day) and the small volume of distribution (Vz=11.7±6.3 l) suggested that stealth-liposomes were stable in the blood at least for 14 days. Polychemotherapy with Hyper-CCVP schedule did not alter the stability of stealth liposomes, but peak levels of DOXO seemed to be somewhat lower compared to regression analysis of literature data (cmax versus dosage range from 20 to 60 mg/m2). Due to clast occurring between day 12 to 18, no indices for an accumulation of the drug in the blood could be found, when liposomes were given every four weeks.


Doxorubicin Caelyx stealth liposomes pharmacokinetics polychemotherapy 


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  1. 1.
    Bielack S.S., Ertmann R., & Kempf-Bielack G. (1996): Impact of scheduling of toxicity and clinical efficacy of doxorubicin: what do we know in the mid-nineties? Eur. J. Cancer, 32A, 1652CrossRefPubMedGoogle Scholar
  2. 2.
    SEQUUS Pharmaceutical Inc. Investigators Brochure (1997): “Doxorubicin encapsulated in stealth liposomes”, pp. 65–70Google Scholar
  3. 3.
    Allen T.M., Hansen C., Martin F., Redemann C., Yau-Yong A. (1991): Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half lives in-vivo. Biochim. Biophys. Acta, 1066, 29–36.CrossRefPubMedGoogle Scholar
  4. 4.
    Huang S.K., Lee K.D., Hong K., Friend D.S., Papahadjopoulos D. (1992): Microscopic localisation of sterically stabilised liposomes in colon carcinoma bearing mice. Cancer Res., 52, 5135–43.PubMedGoogle Scholar
  5. 5.
    Huang S.K., Martin F.J., Jay G. (1993): Extravasation and transcytosis of liposomes in Kaposi’s sarcoma-like dermal lesions of transgenic mice bearing the HIC tat gene. Am. J. Pathol. 143, 10–14PubMedGoogle Scholar
  6. 6.
    Northfelt D.W., Kaplan L., Russell J., Volberding P.A., Martin F.J. Pharmacokinetics and tumour localisation of DOX-SL (STEALTH” liposomal doxorubicin) by comparison with Adriamycin in patients with AIDS and Kaposi’s sarcoma. In: Stealth Liposomes (Lasic D and Martin F, eds). Boca Raton, FL: CRC Press 1995: pp 257–66Google Scholar
  7. 7.
    Amantea M., Newman M.S., Sullivan T.M., Forrest A., Working P.K. (1999): Relationship of dose intensity to the induction of palmar-plantar erythro-dysesthia by pegylated liposomal doxorubicin in dogs. Human Exp. Toxicol., 18, 17–26.CrossRefGoogle Scholar
  8. 8.
    Shipp M.A. (1993): A predictive model for aggressive Non-Hodgkin’s Lymphoma. New Engl. J. Med., 329, 987–994.CrossRefGoogle Scholar
  9. 9.
    Czejka M.J., Georgopoulos A. (1988): High performance liquid chromato-graphic determination of adriblastin in human plasma, urine, saliva and liver punctuate by column switching for drug monitoring studies. J. Chromatogr. Biomed. Appl., 424, 182–188CrossRefGoogle Scholar
  10. 10.
    Scientific Tables Geigy, Vol. III, Haematology and Human Genetics (Ciba Geigy Limited AG, Basle, Switzerland) 1983: pp 66–67Google Scholar
  11. 11.
    Czejka M.J., Schueller J., Linkesch W., Eder I., Zeleny U., Kraule C., Pernegg, C. Serum and tissue concentrations of doxorubicin in patients receiving i.v. mono- and polychemotherapy of encapsulated doxorubicin (stealth liposomes, Caelyx”). 28th Annual Symposium European Society of Clinical Pharmacy, Oct. 1999, Berlin, Abstract No. 60Google Scholar
  12. 12.
    Dinnendahl V., Tricke, U. (1996): Arzneistoffprofile, Basisinformation über arzneiliche Wirkstoffe, 11. Ergänzung, GOVI Verlag GmbH. Pharmazeutischer Verlag, Frankfurt, GermanyGoogle Scholar
  13. 13.
    Schuler U., Ehninger G., Wagner, T. (1987): Repeated high dose cyclophosphamide administration in bone marrow transplantation; exposure to active metabolites. Cancer Chemother. Pharmacol., 3, 248CrossRefGoogle Scholar
  14. 14.
    Evans, W.E., Crom, W.R. & Yee, G.C. (1980): Adriamycin pharmacokinetics in children. Proc. Am. Assoc. Cancer Res., 21, 176Google Scholar
  15. 15.
    Dodion, P., Riggs, C.E., Akman, S.R., Tamburini, J.M., Colvin, O.M. & Bachur N.R. (1984): Interactions between cyclophosphamide and adriamycin in rats. J. Pharmac. Exp. Ther., 229, 51–57Google Scholar
  16. 16.
    Dodion P., Akman S.R., Tamburini J.M., Riggs C.E., Colvin, O.M., Bachur N.R. (1986): Interaction between cyclophosphamide and doxorubicin. Meta-bolism in rat, effect of cyclophosphamide aldoketoreductase system. J. Pharmac. Exp. Ther., 237, 271–74Google Scholar
  17. 17.
    Urien S., Bree F., Breillout F. (1993): Vinorelbine high affinity binding to human platelets and lymphocytes: distribution in human blood. Cancer Chemother. Pharmacol., 32, 231CrossRefPubMedGoogle Scholar
  18. 18.
    Jehl F., Quoix E., Leveque D. (1991): Pharmacokinetic and preliminary metabolic fate of navelbine in humans as determined by high performance liquid chromatography. Cancer Res., 51, 2073PubMedGoogle Scholar
  19. 19.
    Allen T.M. (1997) Liposomes: opportunities in drug delivery. Drugs 54, 8–14CrossRefPubMedGoogle Scholar
  20. 20.
    Amantea M. Gabizon A. (1998): Pharmacokinetics of Caelyx®, Doxil® (Stealth® liposomal doxorubicin) in patients with breast or prostate cancer. Proc. NCI-EORTC (Amsterdam) Abstract No. 653Google Scholar
  21. 21.
    Gabizon A., Catane R., Uziely B. (1994) Prolonged circulation-time and enhanced accumulation in malignant exsudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54, 987–992PubMedGoogle Scholar
  22. 22.
    Northfelt D.W., Francis J.M., Working P., et al. (1996) Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumour localization and safety in patients with AIDS related Kaposi sarcoma. J. Clin. Pharmacol., 36, 55–63.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • W. Linkesch
    • 1
  • M. Weger
    • 1
  • I. Eder
    • 2
  • H. W. Auner
    • 1
  • C. Pernegg
    • 2
  • C. Kraule
    • 2
  • M. J. Czejka
    • 2
  1. 1.Div. of Haematology, Dep. of MedicineUniversity Clinic of GrazAustria
  2. 2.Pharmacokinetic and Drug Metabolism Unit Department of Pharmaceutical ChemistryUniversity of ViennaViennaAustria

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