Skip to main content

Advertisement

SpringerLink
Log in

An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

There are no definitive data in humans on the dose dependence and/or cycle dependence of the pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD). This study examined the PK of PLD across a twofold dose variation and along 3 cycles.

Methods

Fifteen patients received PLD in successive doses of 60, 30, and 45 mg/m2 (Arm A) and 30, 60, and 45 mg/m2 (Arm B), every 4 weeks. Twelve patients, six on each arm, completed all three cycles and were fully evaluable. Plasma levels of doxorubicin were analyzed by HPLC and fluorimetry. PK analysis was done by non-compartmental method. Repeated measures ANOVA and paired tests were used for statistical analysis.

Results

There was no significant difference in the PK parameters examined when the dose was increased from 30 to 60 mg/m2. However, when we analyzed the effect of cycle number on the PK, we found a gradual and significant inhibition of clearance (P < 0.0001) from the 1st through the 3rd cycle of PLD, with a geometric mean increase of 43% in dose-normalized AUC (P = 0.0003). Dose-normalized Cmax and T½ mean values increased by 17 and 18%, respectively between the 1st and 3rd cycles, but only the increase in T½ was statistically significant (P = 0.0017).

Conclusions

While the PK of PLD is not dose-dependent within the dose range of 30–60 mg/m2, there is evidence of a cycle-dependent effect that results in inhibition of clearance when patients receive successive cycles of PLD. These results suggest the need for dose adjustments of PLD upon retreatment to minimize the risk of toxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Notes

  1. Marketed under the trade names of DOXIL® and CAELYX ®.

  2. The differences in AUC/mg dose between the 1st and 3rd cycle were also significant even if we would cancel the pairing of the data and compare the means with the unpaired t test (P = 0.0104; n = 12) or simply with the nonparametric Mann–Whitney test (P = 0.0142).

References

  1. Alberts DS, Muggia FM, Carmichael J et al (2004) Efficacy and safety of liposomal anthracyclines in phase I/II clinical trials. Semin Oncol 31:53

    Article  PubMed  CAS  Google Scholar 

  2. Allen TM, Hansen C (1991) Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim Biophys Acta 1068:133

    Article  PubMed  CAS  Google Scholar 

  3. Amantea M, Newman MS, Sullivan TM et al (1999) Relationship of dose intensity to the induction of palmar–plantar erythrodysesthia by pegylated liposomal doxorubicin in dogs. Hum Exp Toxicol 18:17

    Article  PubMed  CAS  Google Scholar 

  4. Amantea MA, Forrest A, Northfelt DW et al (1997) Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi’s sarcoma. Clin Pharmacol Ther 61:301

    Article  PubMed  CAS  Google Scholar 

  5. Berry G, Billingham M, Alderman E et al (1998) The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi’s sarcoma patients treated with pegylated liposomal doxorubicin. Ann Oncol 9:711

    Article  PubMed  CAS  Google Scholar 

  6. Briasoulis E, Karavasilis V, Tzamakou E et al (2004) Interaction pharmacokinetics of pegylated liposomal doxorubicin (Caelyx) on coadministration with paclitaxel or docetaxel. Cancer Chemother Pharmacol 53:452

    Article  PubMed  CAS  Google Scholar 

  7. Charrois GJ, Allen TM (2003) Multiple injections of pegylated liposomal doxorubicin: pharmacokinetics and therapeutic activity. J Pharmacol Exp Ther 306:1058

    Article  PubMed  CAS  Google Scholar 

  8. Chin DL, Lum BL, Sikic BI (2002) Rapid determination of PEGylated liposomal doxorubicin and its major metabolite in human plasma by ultraviolet–visible high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 779:259

    Article  PubMed  CAS  Google Scholar 

  9. Colbern GT, Hiller AJ, Musterer RS et al (1999) Significant increase in antitumor potency of doxorubicin HCI by its encapsulation in pegylated liposomes. J Liposome Res 9:523

    Article  CAS  Google Scholar 

  10. Coleman RE, Biganzoli L, Canney P et al (2006) A randomised phase II study of two different schedules of pegylated liposomal doxorubicin in metastatic breast cancer (EORTC-10993). Eur J Cancer 42:882

    Article  PubMed  CAS  Google Scholar 

  11. Da Ros L, Squassante L, Milleri S (2003) Dose linearity of lacidipine pharmacokinetics after single and repeated oral doses in healthy volunteers. Clin Pharmacokinet 42:99

    Article  PubMed  CAS  Google Scholar 

  12. Gabizon A, Catane R, Uziely B et al (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54:987

    PubMed  CAS  Google Scholar 

  13. Gabizon A, Goren D, Horowitz AT et al (1997) Long-circulating liposomes for drug delivery in cancer therapy: a review of biodistribution studies in tumor-bearing animals. Adv Drug Deliv Rev 24:337

    Article  CAS  Google Scholar 

  14. Gabizon A, Shmeeda H, Barenholz Y (2003) Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin Pharmacokinet 42:419

    Article  PubMed  CAS  Google Scholar 

  15. Gabizon A, Tzemach D, Mak L et al (2002) Dose dependency of pharmacokinetics and therapeutic efficacy of pegylated liposomal doxorubicin (DOXIL) in murine models. J Drug Target 10:539

    Article  PubMed  CAS  Google Scholar 

  16. Gabizon AA (1995) Liposome circulation time and tumor targeting: implications for cancer chemotherapy. Adv Drug Deliv Rev 16:285

    Article  CAS  Google Scholar 

  17. Gabizon AA, Lyass O, Berry GJ et al (2004) Cardiac safety of pegylated liposomal doxorubicin (Doxil/Caelyx) demonstrated by endomyocardial biopsy in patients with advanced malignancies. Cancer Invest 22:663

    Article  PubMed  CAS  Google Scholar 

  18. Gordon AN, Fleagle JT, Guthrie D et al (2001) Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19:3312

    PubMed  CAS  Google Scholar 

  19. Hamilton A, Biganzoli L, Coleman R et al (2002) EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx, Doxil) at a 6-week interval in patients with metastatic breast cancer. Ann Oncol 13:910

    Article  PubMed  CAS  Google Scholar 

  20. Huang SK, Lee KD, Hong K et al (1992) Microscopic localization of sterically stabilized liposomes in colon carcinoma-bearing mice. Cancer Res 52:5135

    PubMed  CAS  Google Scholar 

  21. Kim RJ, Peterson G, Kulp B et al (2005) Skin toxicity associated with pegylated liposomal doxorubicin (40 mg/m2) in the treatment of gynecologic cancers. Gynecol Oncol 97:374

    Article  PubMed  CAS  Google Scholar 

  22. Lotem M, Hubert A, Lyass O et al (2000) Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin. Arch Dermatol 136:1475

    Article  PubMed  CAS  Google Scholar 

  23. Lyass O, Hubert A, Gabizon AA (2001) Phase I study of doxil–cisplatin combination chemotherapy in patients with advanced malignancies. Clin Cancer Res 7:3040

    PubMed  CAS  Google Scholar 

  24. Lyass O, Uziely B, Ben-Yosef R et al (2000) Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 89:1037

    Article  PubMed  CAS  Google Scholar 

  25. Marina NM, Cochrane D, Harney E et al (2002) Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: a pediatric oncology group study. Clin Cancer Res 8:413

    PubMed  CAS  Google Scholar 

  26. O’Brien ME, Wigler N, Inbar M et al (2004) Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 15:440

    Article  PubMed  CAS  Google Scholar 

  27. Safra T, Muggia F, Jeffers S, et al (2000) Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 11:1029

    Article  PubMed  CAS  Google Scholar 

  28. Storm G, ten Kate MT, Working PK et al (1998) Doxorubicin entrapped in sterically stabilized liposomes: effects on bacterial blood clearance capacity of the mononuclear phagocyte system. Clin Cancer Res 4:111

    PubMed  CAS  Google Scholar 

  29. Uziely B, Jeffers S, Isacson R et al (1995) Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 13:1777

    PubMed  CAS  Google Scholar 

  30. Vail DM, Amantea MA, Colbern GT et al (2004) Pegylated liposomal doxorubicin: proof of principle using preclinical animal models and pharmacokinetic studies. Semin Oncol 31:16

    Article  PubMed  CAS  Google Scholar 

  31. Woodle MC, Lasic DD (1992) Sterically stabilized liposomes. Biochim Biophys Acta 1113:171

    PubMed  CAS  Google Scholar 

Download references

Acknowledgement

Supported in part by Institute for Advanced Therapies (New York, NY) and Janssen-Cilag (Shefayim, Israel).

Author information

Authors and Affiliations

  1. Department of Oncology, Shaare Zedek Medical Center, POB 3235, Jerusalem, 91031, Israel

    Alberto Gabizon, Rut Isacson, Ora Rosengarten, Dina Tzemach, Hilary Shmeeda & Rama Sapir

  2. Hebrew University-School of Medicine, Jerusalem, Israel

    Alberto Gabizon

Authors
  1. Alberto Gabizon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rut Isacson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ora Rosengarten
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dina Tzemach
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hilary Shmeeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rama Sapir
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alberto Gabizon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gabizon, A., Isacson, R., Rosengarten, O. et al. An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin. Cancer Chemother Pharmacol 61, 695–702 (2008). https://doi.org/10.1007/s00280-007-0525-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0525-5

Keywords

Search

Navigation