Su-jin Rhee1, Seung Hwan Lee1, Ji Won Lee2, Kyung-Sang Yu1, Hyoung Jin Kang2, In-Jin Jang1, Howard Lee1,3
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea; 2Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; 3Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University
Objectives: Busulfan is a bifunctional alkylating agent, which is indicated for use in combination with cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). The aims of this study were 1) to characterize the population pharmacokinetics of once-daily intravenous (IV) busulfan in pediatric patients undergoing HSCT, and 2) to identify significant covariates that might affect the pharmacokinetic parameters of busulfan in this population.
Methods: A population pharmacokinetic analysis was performed using 2183 busulfan concentrations in 137 pediatric patients, who received an IV busulfan and cyclophosphamide regimen for 4 days before undergoing HSCT. The First-Order Conditional Estimation with Interaction estimation method implemented in NONMEM (version 7.2) was used, which was followed by model qualification using bootstrapping and visual predictive checks (VPCs).
Results: A one-compartment open linear model with proportional residual error, which also included inter-individual (IIV) and inter-occasion variability (IOV) for clearance (CL), and IIV for volume of distribution (V), and their covariance, adequately described the concentration–time profiles of busulfan. Body surface area (BSA) was a significant covariate for CL and V, while plasma ferritin level and dosing day were significant only for CL. The typical population estimates of CL and V for an adult with BSA of 1.73 m2 were 11.2 L/h and 43.8 L, respectively. The IIV of CL and V was 23.4% and 22.5%, respectively, while the IOV of CL was 10.5%. Model evaluation by bootstrapping and VPCs indicated that the proposed model was adequate, robust, and stable, and the parameters were estimated with a good precision.
Conclusions: The population pharmacokinetic model for IV busulfan can be utilized to develop and improve the dosing regimen in pediatric patients undergoing HSCT.
Reference: PAGE 24 (2015) Abstr 3496 [www.page-meeting.org/?abstract=3496]
Poster: Drug/Disease modeling - Paediatrics