Disposition of liposomal daunorubicin during cotreatment with cytarabine in patients with leukaemia

Federico Pea, Domenico Russo, Mariagrazia Michieli, Daniela Damiani, Renato Fanin, Angela Michelutti, Teresa Michelutti, Stefano Piccolrovazzi, Michele Baccarani, Mario Furlanut

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Abstract

Objective: To investigate the pharmacokinetics and pharmacodynamics of liposomal daunombicin (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 daunombicin and daunombicinol 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 daunombicin than for free daunombicin, mainly due to higher concentrations of the parent drug in plasma, whereas daunombicinol 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.

Original languageEnglish
Pages (from-to)851-862
Number of pages12
JournalClinical Pharmacokinetics
Volume42
Issue number9
DOIs
Publication statusPublished - 2003

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Daunorubicin
Cytarabine
Leukemia
Pharmacokinetics
Parents
P-Glycoprotein
Pharmaceutical Preparations
Bone Marrow
Urine
Mucositis
Multiple Drug Resistance
Bone Marrow Cells
Area Under Curve
Blood Cells
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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Disposition of liposomal daunorubicin during cotreatment with cytarabine in patients with leukaemia. / Pea, Federico; Russo, Domenico; Michieli, Mariagrazia; Damiani, Daniela; Fanin, Renato; Michelutti, Angela; Michelutti, Teresa; Piccolrovazzi, Stefano; Baccarani, Michele; Furlanut, Mario.

In: Clinical Pharmacokinetics, Vol. 42, No. 9, 2003, p. 851-862.

Research output: Contribution to journalArticle

Pea, F, Russo, D, Michieli, M, Damiani, D, Fanin, R, Michelutti, A, Michelutti, T, Piccolrovazzi, S, Baccarani, M & Furlanut, M 2003, 'Disposition of liposomal daunorubicin during cotreatment with cytarabine in patients with leukaemia', Clinical Pharmacokinetics, vol. 42, no. 9, pp. 851-862. https://doi.org/10.2165/00003088-200342090-00004
Pea, Federico ; Russo, Domenico ; Michieli, Mariagrazia ; Damiani, Daniela ; Fanin, Renato ; Michelutti, Angela ; Michelutti, Teresa ; Piccolrovazzi, Stefano ; Baccarani, Michele ; Furlanut, Mario. / Disposition of liposomal daunorubicin during cotreatment with cytarabine in patients with leukaemia. In: Clinical Pharmacokinetics. 2003 ; Vol. 42, No. 9. pp. 851-862.
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abstract = "Objective: To investigate the pharmacokinetics and pharmacodynamics of liposomal daunombicin (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 daunombicin and daunombicinol 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 daunombicin than for free daunombicin, mainly due to higher concentrations of the parent drug in plasma, whereas daunombicinol 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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AU - Pea, Federico

AU - Russo, Domenico

AU - Michieli, Mariagrazia

AU - Damiani, Daniela

AU - Fanin, Renato

AU - Michelutti, Angela

AU - Michelutti, Teresa

AU - Piccolrovazzi, Stefano

AU - Baccarani, Michele

AU - Furlanut, Mario

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