Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation

Abstract

A population pharmacokinetic analysis was performed in 30 patients who received an intravenous busulfan and cyclophosphamide regimen before hematopoietic stem cell transplantation. Each patient received 0.8 mg/kg as a 2 h infusion every 6 h for 16 doses. A total of 690 concentration measurements were analyzed using the nonlinear mixed effect model (NONMEM) program. A onecompartment model with an additive error model as an intraindividual variability including an interoccasion variability (IOV) in clearance (CL) was sufficient to describe the concentration-time profile of busulfan. Actual body weight (ABW) was found to be the determinant for CL and the volume of distribution (V) according to NONMEM analysis. In this limited study, the age (range 7-53 years old; median, 30 years old) had no significant effect on busulfan pharmacokinetics. For a patient weighting 60 kg, the typical CL and V were estimated to be 8.87 l/h and 33.8 l, respectively. The interindividual variability of CL and V were 13.6 and 6.3%, respectively. The IOV (6.6%) in CL was estimated to be less than the intraindividual variability. These results indicate high interpatient and intrapatient consistency of busulfan pharmacokinetics after intravenous administration, which may eliminate the requirement for pharmacokinetic monitoring.

Safe administration of oral BU twice daily during conditioning for stem cell transplantation in a paediatric population: a comparative study between the standard 4-dose and a 2-dose regimen

“…BU has partly solved problems associated with oral administration like the variability in gastric absorption and variations in time to maximum drug concentrations. 27,28 Still, some variability in AUC between patients is observed even with the i.v. formula, and the i.v.…”

Busulfex (i.v. BU) and CY regimen before SCT: Japanese-targeted phase II pharmacokinetics combined study

“…BU pharmacokinetics. 22 However, the value of therapeutic drug monitoring remains crucial. Our study demonstrated no essential difference in PK analysis from earlier published Western data, 19 and this supports the notion that racial factors may not seriously influence the bioactivity of i.v.…”

“…BU pharmacokinetics show high inter-and intrapatient consistency. 22 This study with the same population further focused on complete pharmacokinetic profiles with additional clinical and safety data.…”

Influence of GST gene polymorphisms on busulfan pharmacokinetics in children

“…7,[26][27][28] Dose targeting based on therapeutic drug monitoring (TDM) also seems to improve event-free survival and survival rates and in some studies VOD-free survival compared with conventional BU treatment. 18,29,30 Despite these improvements, inter-patient variability still exists and the percentage of patients reaching the target AUC after the first dose remains low.…”