Christian Diestelhorst (1), Joachim Boos (2), Jeannine S. McCune (3), Georg Hempel (1,2)
(1) Department of Pharmaceutical and Medical Chemistry - Clinical Pharmacy, University of Münster, Germany; (2) Department of Paediatric Haematology and Oncology, University Children’s Hospital Münster, Germany; (3) Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA
Objectives: Busulfan (Bu), a DNA-alkylating agent, is widely used for conditioning prior to bone marrow transplantation in both children and adults. Low Bu plasma exposure, expressed as area under the curve (AUC), is associated with a higher risk of graft rejection while an elevated Bu AUC is associated with a higher risk of toxicity. Therefore, optimal dosing of intravenous (i.v.) Bu is critical. Despite years of investigation there are still open questions regarding the best schedule of administration as well as the optimal dosing in children. According to the European Medicines Agency (EMA) labelling of i.v. Bu in children, dosing is based on five different body weight strata. In addition, current pharmacokinetic (PK) studies showed conflicting results regarding an optimal dosing of Bu in children, especially for underweight or obese patients. In this context, the external evaluation of two models from our working group [1] indicated a bias caused by inclusion of data after oral administration. Therefore, a new merged dataset with data only after i.v. administration was used to develop a revised population pharmacokinetic (PopPK) model for Bu in children. Subsequently, dosing based on the final PopPK model was compared with dosing strategies suggested by other groups.
Methods: Model building was done with NONMEM® 7.2. The model building dataset is based on 82 children receiving Bu four-times daily for four days. Model evaluations were performed by a bootstrap analysis and a Standardized Visual Predictive Check (SVPC) procedure (internal evaluation, each with 1,000 runs) and by comparison to an external dataset (external evaluation).
Results: Data were best described by a one-compartment model, inter-individual variability (IIV) and inter-occasion variability (IOV) on both clearance (CL) and volume of distribution (V) and a proportional residual error model. Covariates included were body surface area (BSA) as an exponential function on V and actual body weight (ABW) as an allometric function on CL. The final model-derived dosing strategy was:
Dose [mg] = Target AUC [mg*h/L] x 3.04 L/h x (ABW/16.1)0.797
Nomograms were used to compare the different suggested dosing recommendations demonstrating differences for the very small and heavyweight patients.
Conclusion: Dosing strategies for i.v. busulfan differ for the very young and heavyweight patients and need to be evaluated in a prospective study.
References:
[1] Trame MN, Bergstrand M, Karlsson MO, Boos J, Hempel G. Population pharmacokinetics of busulfan in children: increased evidence for body surface area and allometric body weight dosing of busulfan in children. Clin Cancer Res. 2011 Nov 1; 17(21):6867-77
Reference: PAGE 22 () Abstr 2698 [www.page-meeting.org/?abstract=2698]
Poster: Paediatrics