Korean J Physiol Pharmacol.  2016 May;20(3):245-251. 10.4196/kjpp.2016.20.3.245.

Prospective validation of a novel dosing scheme for intravenous busulfan in adult patients undergoing hematopoietic stem cell transplantation

• Cho SH
• Lee JH
• Lim HS
• Lee KH
• Kim DY
• Choe S
• Bae KS
• Lee JH

• KMID: 2285596
• DOI: http://doi.org/10.4196/kjpp.2016.20.3.245

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 (AUC(PRED)). The accuracy and precision of the AUC(PRED) 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.

Keyword

Adult; Busulfan; Drug dosage calculations; Hematopoietic stem cell transplantation; Pharmacokinetics

MeSH Terms

Adult*
Area Under Curve
Behavior Therapy
Body Weight
Busulfan*
Drug Dosage Calculations
Hematopoietic Stem Cell Transplantation*
Hematopoietic Stem Cells*
Humans
Pharmacokinetics
Prospective Studies*
Busulfan

Figure

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  Fig. 1 Visual predictive check of the busulfan population pharmacokinetic model in the reference arm and the test armThe simulated 95% prediction interval is shaded and observations (plasma busulfan concentrations in µM) are depicted as circles and the solid line depicts the model predicted median.

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  Fig. 2 Predicted versus measured plasma busulfan concentrations in the external validation datasetOpen and closed circles represent values for the patients in the test arm and the reference arm, respectively. The dashed line represents the line of identity.

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  Fig. 3 Box plot showing the distribution of the predicted area under the concentration time curve (AUC) in the reference arm and the test armThe dashed line represents the target AUC of 5924 µM·min.

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