title: Prospective validation of a novel dosing scheme for intravenous busulfan in adult patients undergoing hematopoietic stem cell transplantation.
abstract: The objective of this study was to externally validate a new dosing scheme for busulfan. Thirty-seven adult patients who received busulfan as conditioning therapy for hematopoietic stem cell transplantation (HCT) participated in this prospective study. Patients were randomized to receive intravenous busulfan, either as the conventional dosage (3.2 mg/kg daily) or according to the new dosing scheme based on their actual body weight (ABW) (23×ABW(0.5) mg daily) targeting an area under the concentration-time curve (AUC) of 5924 µM·min. Pharmacokinetic profiles were collected using a limited sampling strategy by randomly selecting 2 time points at 3.5, 5, 6, 7 or 22 hours after starting busulfan administration. Using an established population pharmacokinetic model with NONMEM software, busulfan concentrations at the available blood sampling times were predicted from dosage history and demographic data. The predicted and measured concentrations were compared by a visual predictive check (VPC). Maximum a posteriori Bayesian estimators were estimated to calculate the predicted AUC (AUCPRED). The accuracy and precision of the AUCPRED values were assessed by calculating the mean prediction error (MPE) and root mean squared prediction error (RMSE), and compared with the target AUC of 5924 µM·min. VPC showed that most data fell within the 95% prediction interval. MPE and RMSE of AUCPRED were -5.8% and 20.6%, respectively, in the conventional dosing group and -2.1% and 14.0%, respectively, in the new dosing scheme group. These fi ndings demonstrated the validity of a new dosing scheme for daily intravenous busulfan used as conditioning therapy for HCT.
authors.affiliation: Department of Clinical Pharmacology, Inha University Hospital, Inha University School of Medicine, Incheon 22332, Korea.
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Cho
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Kyoo-Hyung
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Dae-Young
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Pusan National University Hospital, Busan 49241, Korea.
authors.forename: Sangmin
authors.initials: S
authors.lastname: Choe
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Kyun-Seop
authors.initials: KS
authors.lastname: Bae
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Je-Hwan
authors.initials: JH
authors.lastname: Lee
keywords: Adult; Busulfan; Drug dosage calculations; Hematopoietic stem cell transplantation; Pharmacokinetics