title: Pediatric patients undergoing hematopoietic stem cell transplantation can greatly benefit from a novel once-daily intravenous busulfan dosing nomogram.
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.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Su-Jin
authors.identifier: http://orcid.org/0000-0002-4010-0837
authors.initials: SJ
authors.lastname: Rhee
authors.affiliation: Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyung Taek
authors.initials: KT
authors.lastname: Hong
authors.affiliation: Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung Yoon
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Che Ry
authors.initials: CR
authors.lastname: Hong
authors.affiliation: Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyung Duk
authors.initials: KD
authors.lastname: Park
authors.affiliation: Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Shin
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Song
authors.affiliation: Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyoung Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.|Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
authors.forename: Howard
authors.initials: H
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000628:therapy; D008297:Male; D019653:Myeloablative Agonists / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012189:Retrospective Studies; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019653:Myeloablative Agonists; D002066:Busulfan