title: Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration-time curve in pediatric hematopoietic stem cell transplant recipients.
abstract: Optimizing systemic busulfan exposure, the area under the concentration-time curve (AUC), improves the outcomes for hematopoietic stem cell transplantation (HSCT). The AUC is conventionally calculated using six plasma concentrations (AUC(0-∞)) drawn after the first of 16 intravenous busulfan doses given as a 2-h infusion every 6 h. The aim of the present study was to develop limited sampling strategies using three or fewer busulfan concentrations to reliably calculate AUC(0-∞) in patients undergoing HSCT. We investigated the pharmacokinetics of busulfan 46 times in 29 pediatric patients receiving intravenous busulfan. Limited sampling strategies using one, two, or three plasma busulfan concentrations were developed by multiple linear regression that showed excellent agreement with AUC(0-∞). In single-point sampling strategies, the AUC(0-∞) predicted based on C(6) (trough level: busulfan plasma concentration 6 h after the start of the infusion) was significantly correlated with, and not statistically different from, actual values as follows: AUC(0-∞) = 2556.5 C6 + 320.9 (r(2) = 0.929, P < 0.0001, mean bias 0.282 %, precision 7.91 %). In contrast, the predicted AUCs derived from the other sampling single points did not meet the criteria. The trough level well correlated with actual AUC(0-∞), suggesting that this time-point is acceptable for busulfan monitoring.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Watanabe
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan. adu44150@ams.odn.ne.jp.
authors.forename: Takuro
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Department of Clinical Pharmacotherapy, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazuro
authors.initials: K
authors.lastname: Ikawa
authors.affiliation: Department of Hematology, Nippon Medical School, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
authors.forename: Takanari
authors.initials: T
authors.lastname: Abematsu
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kurauchi
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tanabe
authors.affiliation: Department of Pediatrics, Kagoshima City Hospital, Kagoshima, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shinkoda
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kawano
mesh_terms: D000293:Adolescent; D064591:Allografts; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D008991:Monitoring, Physiologic; D009369:Neoplasms / Q000097:blood / Q000401:mortality / Q000628:therapy; D015996:Survival Rate
chemical_list: D002066:Busulfan
keywords: Busulfan; Children; Hematopoietic stem cell transplantation; Limited sampling strategy; Pharmacokinetics