Disposition of liposomal daunorubicin during cotreatment with cytarabine in patients with leukaemia.
OBJECTIVE
To investigate the pharmacokinetics and pharmacodynamics of liposomal daunorubicin (DaunoXome) 80 or 100 mg/m(2) on days 1, 2 and 3 coadministered with standard or high-dose cytarabine to patients with poor-risk acute leukaemia.


METHODS
Unblinded pharmacokinetic-pharmacodynamic study.


METHODS
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/m(2), 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/m(2) 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.
Pea
Federico
F
Department of Experimental and Clinical Pathology and Medicine, Institute of Clinical Pharmacology and Toxicology, University of Udine, Udine, Italy. federico.pea@med.uniud.it
Russo
Domenico
D
Michieli
Mariagrazia
M
Damiani
Daniela
D
Fanin
Renato
R
Michelutti
Angela
A
Michelutti
Teresa
T
Piccolrovazzi
Stefano
S
Baccarani
Michele
M
Furlanut
Mario
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage / Q000627:therapeutic use*; D003630:Daunorubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*
D008081:Liposomes; D003561:Cytarabine; D003630:Daunorubicin