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Disposition of Liposomal Daunorubicin During Cotreatment with Cytarabine in Patients with Leukaemia

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Abstract

Objective: To investigate the pharmacokinetics and pharmacodynamics of liposomal daunorubicin (DaunoXome™) 80 or 100 mg/m2 on days 1, 2 and 3 coadministered with standard or high-dose cytarabine to patients with poor-risk acute leukaemia.

Design: Unblinded pharmacokinetic-pharmacodynamic study.

Participants: Twenty-three adult patients with acute leukaemia.

Methods: Blood, bone marrow and urine samples were collected at appropriate intervals on days 1–6. Total daunorubicin and daunorubicinol concentrations in plasma, bone marrow, peripheral blood cells and urine were measured by high performance liquid chromatography.

Results: Liposomal daunorubicin exhibited a markedly different pharmacokinetic behaviour from the free drug due to a slow distribution of the liposomal moiety into the body. The ratio of area under the concentration-time curve (AUC) for metabolite to parent drug was lower for liposomal daunorubicin than for free daunorubicin, mainly due to higher concentrations of the parent drug in plasma, whereas daunorubicinol exposure was more or less comparable, if not higher. After liposomal daunorubicin at both 80 and 100 mg/m2, total daunorubicin concentrations in leukaemic cells were at least similar to those observed for free daunorubicin, and significant accumulation was also observed in bone marrow blast cells. Nineteen of 23 patients obtained a complete remission, although 13 had P-glycoprotein-overexpressing blast cells. Grade 3–4 mucositis was found only in three patients with very high AUCs for total daunorubicin and daunorubicinol.

Conclusions: Liposomal daunorubicin at both 80 and 100 mg/m2 in combination with cytarabine may represent a valid treatment for high-risk acute leukaemia. Liposomal daunorubicin may be helpful in overcoming multidrug resistance, since it shows significant accumulation into tumour target cells, irrespective of P-glycoprotein expression. The tolerability profile suggests that toxicity may be related to exposure to both the parent drug and the metabolite.

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Acknowledgements

The authors would like to thank Mr Andrea Tandelle for his technical assistance. There was no conflict of interest directly relevant to the content of this study.

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Authors and Affiliations

  1. Department of Experimental and Clinical Pathology and Medicine, Institute of Clinical Pharmacology and Toxicology, University of Udine, P. le S.M. Misericordia 3, 33100, Udine, Italy

    Federico Pea & Mario Furlanut

  2. Department of Medical and Morphologic Research, and Division of Hematology, Chair of Hematology, Udine University Hospital, Udine, Italy

    Domenico Russo, Daniela Damiani, Renato Fanin, Angela Michelutti & Teresa Michelutti

  3. Division of Medical Oncology, Istituto Nazionale Tumori, Aviano, Italy

    Mariagrazia Michieli

  4. Gilead Sciences, Milano, Italy

    Stefano Piccolrovazzi

  5. Institute of Hematology and Medical Oncology ‘L. and A. Seragnoli’, University of Bologna, Bologna, Italy

    Michele Baccarani

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  1. Federico Pea
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  2. Domenico Russo
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Correspondence to Federico Pea.

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Pea, F., Russo, D., Michieli, M. et al. Disposition of Liposomal Daunorubicin During Cotreatment with Cytarabine in Patients with Leukaemia. Clin Pharmacokinet 42, 851–862 (2003). https://doi.org/10.2165/00003088-200342090-00004

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