Georg Hempel 1,2, Nina Griese1,2, Petra Schulze Westhoff1, Dirk Reinhardt1, Ursula Creutzig1 and Joachim Boos1
1) Klinik und Poliklinik für Kinderheilkunde - Pädiatrische Hämatologie /Onkologie, 2) Institut für Pharmazeutische Chemie, -, Westfälische Wilhelms-Universität Münster, Germany
Daunorubicin is an important part of many treatment protocols in pediatric oncology. In an attempt to reduce the serious cardiotoxic side effects of daunorubicin, Daunoxome® , a liposomal formulation of daunorubicin has been developed showing reduced acute cardiotoxicity in adults.
To investigate the pharmacokinetics Daunoxome® in children, plasma samples were collected from 18 children with relapsed acute myeloic leukaemia and 5 children with other malignancies. Daunoxome® was administered as a 1 to 2.5 h infusion with doses ranging from 30 to 60 mg/m2. The patients demographics were as follows (mean ± rel. SD): age 14.2± 5.1 years, height 1.41± 0.42 m, weight 46.6± 19.5 kg and body surface area (BSA) 1.41± 0.42 m2. A total of 149 plasma samples from 72 cycles with 1 to 5 samples per cycle were available (2.1 samples per cycle). Samples were analysed for total daunorubicin using capillary electrophoresis. Pharmacokinetic modelling was done using NONMEM.
The data could be well described using a one compartment model (subroutine ADVAN1 TRAN2). The inclusion of weight or height as a covariate strongly decreased interindividual variability. However, the best fit was obtained with calculations based on the absolute dose and BSA included as a covariate for clearance (Cl) and volume of distribution (V). The final parameter estimates were: Cl 0.22 l/h m2 ± 37% and V 1.82 l/m2 ± 24% (population mean ± interindividual variability). In comparison to literature data of free daunorubicin, DaunoxomeÒ shows a low volume of distribution and a lower interindividual variability. Work is in progress to quantify free daunorubicin and the main metabolite in the plasma samples.
Reference: PAGE 9 (2000) Abstr 104 [www.page-meeting.org/?abstract=104]
Poster: poster