I.H. Bartelink1,9, C. van Kesteren9, J.J. Boelens2, A.C.G. Egberts1,8, M.B. Bierings2, G.D.E. Cuvelier3, R.F.Wynn4, M.A.Slatter5, R. Chiesa6,7, M. Danhof9, C.A.J. Knibbe9,10
Departments of (1) Clinical Pharmacy and (2) Pediatric blood and marrow transplantation program of the University Medical Center Utrecht, the Netherlands, (3) Pediatric Blood and Marrow Transplant, Pediatric Hematology-Oncology CancerCare, University of Manitoba, Manitoba, Canada (4) Blood and Marrow Transplant Unit Royal Manchester Children's Hospital, Manchester, United Kingdom(5) Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom (6) Bone Marrow Transplantation Department, Great Ormond Street Hospital, London, United Kingdom (7) San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy (8) Department of Pharmaco-epidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands Pharmacology, (9) Department of Pharmacology of the Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands, (10) Clinical Pharmacy of the St. Antonius Hospital, Nieuwegein, the Netherlands
Objectives: Recently a paediatric pharmacokinetic (PK) model was developed for busulfan in order to explain the wide variability in PK of busulfan in children, as this variability is known to influence the outcome of hematopoietic stem cell transplantation (HSCT) in terms of toxicity and event free survival. The current study assesses the predictive performance of this busulfan PK-model in a new, more diverse pediatric population, including data from patients with different underlying diseases, ethnicities, body weights, ages and body mass indices, from five international paediatric transplant centers.
Methods: The previously published (original) busulfan PK-model was developed from data of 245 patients (0.1-26 years of age). To externally validate this model, data were collected from another 158 patients (0.1-35 years) who underwent HSCT in five international transplant centers. Observed versus predicted plots, normalized prediction distribution error analysis, refit of the model on the external (n=158) and combined datasets (n=403), and subpopulation analyses were evaluated.
Results: The original busulfan PK-model was found to be stable and parameter estimates precise. Concentrations predicted by this model were in good agreement with the observed concentrations from the five external datasets. Plasma concentrations in patients with different underlying diseases, ethnicities, body weights, ages and body mass indices were adequately predicted.
Conclusions: Our pediatric busulfan PK-model has been externally validated. This model predicts busulfan concentrations in pediatric and young adult patients ranging between 3 and 86 kg without bias and with good precision, regardless of transplant center, underlying disease, ethnicity, body weight, age or body mass index. This busulfan PK-model forms the basis for individualized busulfan dosing.
Reference: PAGE 21 () Abstr 2475 [www.page-meeting.org/?abstract=2475]
Poster: Paediatrics