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Pediatric patients undergoing hematopoietic stem cell transplantation can greatly benefit from a novel once‐daily intravenous busulfan dosing nomogram
Author(s) -
Rhee Sujin,
Lee Ji Won,
Yu KyungSang,
Hong Kyung Taek,
Choi Jung Yoon,
Hong Che Ry,
Park Kyung Duk,
Shin Hee Young,
Song Sang Hoon,
Kang Hyoung Jin,
Lee Howard
Publication year - 2017
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.24734
Subject(s) - busulfan , dosing , nomogram , medicine , hematopoietic stem cell transplantation , body surface area , pharmacokinetics , therapeutic drug monitoring , population , regimen , transplantation , area under the curve , surgery , environmental health
Abstract Busulfan, a bifunctional alkylating agent, has been used as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to derive a novel once‐daily intravenous (IV) busulfan dosing nomogram for pediatric patients undergoing HSCT using a population pharmacokinetic (PK) model. A population PK analysis was performed using 2183 busulfan concentrations in 137 pediatric patients (age: 0.6‐22.2 years), who received IV busulfan once‐daily for 4 days before undergoing HSCT. Based on the final population PK model, an optimal once‐daily IV busulfan dosing nomogram was derived. The percentage of simulated patients achieving the daily target area under the concentration‐time curve (AUC) by the new nomogram was compared with that by other busulfan dosing regimens including the FDA regimen, the EMA regimen, and the empirical once‐daily regimen without therapeutic drug monitoring (TDM). A one‐compartment open linear PK model incorporating patient's body surface area, age, dosing day, and aspartate aminotransferase as a significant covariate adequately described the concentration–time profiles of busulfan. An optimal dosing nomogram based on the PK model performed significantly better than the other dosing regimens, resulting in >60% of patients achieving the target AUC while the percentage of patients exceeding the toxic AUC level was kept <25% during the entire treatment period. A novel once‐daily busulfan dosing nomogram for pediatric patients undergoing HSCT is useful for clinicians, particularly in a setting where TDM service is not readily available or to optimize the dose on day 1.