Population pharmacokinetics of liposomal daunorubicin in children

Abstract

AimsTo 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.

Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004

“…23 Low accumulation of L-DNR in the heart has been proven in animals, and minimal cardiotoxicity despite significant antileukemic activity was found in a mouse model. 8,9 In 277 AIDS patients with Kaposi sarcoma, no cardiotoxicity of L-DNR was seen, after cumulative doses of up to 1700 mg/m 2 .…”

Population Pharmacokinetics of Liposomal Amphotericin B and Caspofungin in Allogeneic Hematopoietic Stem Cell Recipients

“…The high PK variability of LAMB may be founded in differences in the uptake of the liposomal carrier with bound drug into nonblood compartments or in the dissolution of the drug from the liposomal carriers with consequences for its disposition in the blood; further potential factors include differences in disease status and inflammatory molecules, the composition of plasma proteins, and solutions used for concomitant parenteral nutrition (3). Interestingly, liposomal encapsulation of daunorubicin with liposomes of similar structure (Daunoxome) resulted in a substantial reduction of IIV in the PK parameters (17).…”

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

“…This is the first paediatric study with liposomal Daunorubicin that has shown a significant degree of cardiac toxicity, albeit with repeated dosing. Three other paediatric studies have been performed, but none of these raised concerns over the degree of cardiac toxicity (Baruchel, personal communication;Lippens, 1999;Hempel et al, 2003). The treatment regimes used in these studies differ significantly from the present study: in both, patients were given four doses over a 4-week time period.…”