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Population pharmacokinetics of liposomal daunorubicin in children.

Author(s): Hempel G, Reinhardt D, Creutzig U, Boos J

Affiliation(s): Institut fur Pharmazeutische und Medizinische Chemie, Westfalische Wilhelms-Universitat, Hittorfstrasse 58-62, 48149 Munster, Germany. hempege@uni-muenster.de

Publication date & source: 2003-10, Br J Clin Pharmacol., 56(4):370-7.

Publication type: Clinical Trial; Multicenter Study; Randomized Controlled Trial

AIMS: 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.

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