Population pharmacokinetics of liposomal daunorubicin in children.
OBJECTIVE
To investigate the population pharmacokinetics of daunorubicin in children after administration of liposomal daunorubicin (Daunoxome).


METHODS
Plasma samples from 19 children with relapsed acute myeloic leukaemia and five children with other malignancies were collected. Daunoxome was administered as a 1- to 2.5 h infusion with doses ranging from 30 to 60 mg m(-2). Overall, 214 samples were analysed for daunorubicin using capillary electrophoresis, and population pharmacokinetic modelling was performed using NONMEM.


RESULTS
The data were best described by a one compartment model. Inclusion of interoccasion variability in the model (16.7% for clearance) improved strongly the precision of the estimates. The inclusion of body surface area or height as a covariate decreased interindividual variability. However, the best fit was obtained using the absolute dose, and when weight was included as a covariate for clearance (CL) and volume of distribution (V ). The final parameter estimates were: CL 6.41 ml h(-1) kg(-1) +/- 0.5 51% and V 65.4 ml kg(-1) +/- 0.5 27% (population mean +/- 0.5 interindividual variability). The area under the curve at a dose of 60 mg m(-2) was 231 mg l (-1)h.


CONCLUSIONS
In comparison with free daunorubicin, Daunoxome shows a low volume of distribution, a lower clearance and a lower interindividual variability in these parameters. This might be advantageous in reducing the variability in exposure to the drug.
Hempel
Georg
G
Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität, Hittorfstrasse 58-62, 48149 Münster, Germany. hempege@uni-muenster.de
Reinhardt
Dirk
D
Creutzig
Ursula
U
Boos
Joachim
J
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003630:Daunorubicin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004337:Drug Carriers; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007951:Leukemia, Myeloid / Q000188:drug therapy; D008081:Liposomes; D009369:Neoplasms / Q000188:drug therapy; D012008:Recurrence
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D003630:Daunorubicin