2003
   Verona, Italy

Population Pharmacokinetics of Intravenous Busulfan in Children

Brunhild Schiltmeyer1, Joachim Boos1, Matthias Schwab2, Thomas Mürdter2, Thomas Klingebiel3, G. Fleischhack5, Josef Vormoor1, Bernd Gruhn4 and Georg Hempel1

1 Universitätsklinikum Münster, Klinik und Poliklinik für Kinderheilkunde, Pädiatrische Hämatologie/Onkologie, Münster; 2 Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart; 3 Klinik für Kinderheilkunde III - Pädiatrische Hämatologie und Onkologie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt; 4 Klinik für Kinderheilkunde III - Pädiatrische Hämatologie und Onkologie, Universitätsklinik Jena; 5 Universität Bonn, Zentrum für Kinderheilkunde, Pädiatrische Hämatologie/Onkologie, Bonn, Germany

Background: High-dose busulfan (bu) is an important part of many conditioning regimens before autologous or allogeneic bone marrow transplantation in children. Problems arise with oral bu due to high intra- and interpatient variability in the apparent clearance resulting in a varying systemic exposure, measured as the area under the curve (AUC). A new intravenous (i.v.). formulation (Busulfex™) was developed in 1999 in order to reduce both intra- and interindividual variability of bu pharmacokinetics (PK).

Objective: To evaluate the PK of the new i.v. formulation of bu in children with the purpose to produce a dose intensity similar to that achieved by oral bu with a lower interindividual variability of the AUC (target AUC 1600 ± 600 µM x Min).

Methods: Overall, 19 children from 4 clinical sites were included into the trial (Median: 4 years, range: 0.9-16.1). They received 80% of the required oral bu dose according to the respective protocol in 15 doses with the first infusion over 4 h and the following administrations given 12 h thereafter over 2 h every 6 h. PK sampling was performed with 7 samples from the first dose, 2 trough levels from intermediate doses and 5 optional samples from the last dose. The samples were analysed for bu using a new LC-MS-method requiring only 200 µl of plasma. Pharmacokinetic modelling was performed by using NONMEM.

Results: Bu kinetics were best described by a one-compartment model. The best fit was obtained with calculations based on the actual body weight as a covariate for Clearance (Cl) and Volume of distribution (V). The final parameter estimates were: Cl 0.18 l/h kg ± 20% and V 0.38 l/kg ± 49% (population mean ± interindividual variability). Inclusion of a parameter for IOV (interoccasion variability) on Cl (11%) improved the fit. The AUC after the 1st dose (AUC 1st dose / 2) ranged from 850-1670 µMol x Min (geometric mean = 1200 µMol x Min, CV = 16%, n=18). In 2 out of 18 patients, the AUC after the 1st dose was out of the target range. The AUC after the last dose ranged from 1090-1790 µMol x Min (Geom. mean = 1310 µMol x Min, CV = 16%, n=10). After the last dose, the AUC of all patients was in the target range.

Conclusion: Our results suggest that i.v. bu can reduce the interpatient variability in systemic exposure compared to oral bu (CV of 16% after i.v. bu vs. CV of 37% after oral bu). The applied dosing of i.v. bu with 80% of the oral standard dose appears to be too low. Comparison with oral data is ongoing.