Brunhild Schiltmeyer1,2, Georg Hempel1,2, Matthias Schwab3, Thomas Klingebiel4 and Joachim Boos2
1 Klinik und Poliklinik für Kinderheilkunde - Pädiatrische Hämatologie/Onkologie-; 2 Institut für Pharmazeutische Chemie; Westfälische Wilhelms-Universität Münster, Germany; 3 Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany; 4 Klinik für Kinderheilkunde III - Pädiatrische Hämatologie und Onkologie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt, Germany
High-dose busulfan is an important part of many conditioning regimens before autologous or allogeneic bone marrow transplantation in adults and children. Age, variability in drug absorption, hepatic function, disease status, circadian rhythmicity and drug interactions (anticonvulsive drugs) were identified as factors contributing to the wide inter- and intrapatient variability of high-dose busulfan disposition. To investigate the pharmacokinetics of busulfan in children, plasma samples were collected from 20 children receiving busulfan orally every 6 hours over 4 days. 19 children received the standard dose of 4 mg/kg/d, one child received a dose of 5 mg/kg/d. The patient demographics were as follows (mean ± rel.SD): age 8.72 ± 4.33 years, height 1.33 ± 0.28 m, weight 33.89 ± 17.03 kg and body surface area (BSA) 1.1 ± 0.38 m2. A total of 349 plasma samples from 147 administrations with 1 to 8 samples per administration were available (mean: 17 samples per patient over 4 days of administration). The samples were analysed for busulfan using a LC-MS-method. Pharmacokinetic modelling was performed by using NONMEM. Busulfan kinetics was best described by a one compartment model (subroutine ADVAN2 TRANS2). The best fit was obtained with calculations based on the BSA included as a covariate for Clearance (Cl) and Volume of distribution (V). The final parameter estimates were: Cl 3.3 l/h m2 ± 17%, V 27.3 l/m2 ± 54 % and Ka (absorption rate constant) 2.56 1/h ± 110% (population mean ± interindividual variability). Inclusion of a parameter for IOV (interoccasion variability) on Cl (22%) improved the fit.
Reference: PAGE 10 () Abstr 210 [www.page-meeting.org/?abstract=210]
Poster: poster