Thirteen Years' Experience of Pharmacokinetic Monitoring and Dosing of Busulfan: Can the Strategy be Improved?

  title={Thirteen Years' Experience of Pharmacokinetic Monitoring and Dosing of Busulfan: Can the Strategy be Improved?},
  author={Pamela J Buffery and Kirstie M Allen and Paul K L Chin and Grant A. Moore and Murray L Barclay and Evan James Begg},
  journal={Therapeutic Drug Monitoring},
Background: A busulfan concentration monitoring and dosing service has been provided by Christchurch Hospital since 1998. This study aimed to see (1) the percentage of patients with an area under the concentration time curve (AUC) outside the target range and had dose adjustment, (2) how busulfan clearance (CL) relates to body weight, and (3) if fewer samples could be used to predict doses. Methods: Blood samples were taken from patients after oral administration, usually at 0.5, 1, 1.5, and 6… 
Limited Sampling Strategies Supporting Individualized Dose Adjustment of Intravenous Busulfan in Children and Young Adults.
MLR-based estimates of AUCLSS provide dose adjustment recommendations (DARs) that deviate minimally from the reference and may encourage wider use of busulfan TDM, supporting safe and efficacious personalized dosing.
Dose individualization of intravenous busulfan in pediatric patients undergoing bone marrow transplantation: impact and in vitro evaluation of infusion lag-time.
TDM, applied successfully to 76 children, confirmed the need for Busulfan dose-individualization in paediatric patients and infusion lag-time was proved clinically significant for younger, low body-weight patients and those close to the lower therapeutic-range limit.
Accurate Prediction of Initial Busulfan Exposure Using a Test Dose With 2‐ and 6‐Hour Blood Sampling in Adult Patients Receiving a Twice‐Daily Intravenous Busulfan‐Based Conditioning Regimen
A test dose with a 2‐sampling scheme was sufficient to personalize the initial busulfan dosing in hematopoietic cell transplant recipients, and the Bland‐Altman plot showed that the 2‐Sampling scheme provided an acceptably accurate prediction of the AUC1.
Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation.
Can First-Dose Therapeutic Drug Monitoring Predict the Steady State Area Under the Blood Concentration-Time Curve of Busulfan in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation?
It is indicated that first dose concentrations cannot accurately predict steady state busulfan concentrations; therefore, follow-up TDM may be required for optimal dosing.
Therapeutic drug monitoring for either oral or intravenous busulfan when combined with pre- and post-transplantation cyclophosphamide
The BuCy/PTCy platform has a low incidence of treatment-related toxicity, including hepatotoxicity, in hematologic malignancies when using pharmacokinetics for a target AUC of 800–1400 μmol*min/L, irrespective of Bu administration route.
Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning.
  • J. Zao, T. Schechter, L. Dupuis
  • Medicine
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
  • 2015
Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children
Therapeutic drug monitoring (TDM)-guided dosing to reach the conventional area under the concentration–time curve (AUC) target range of 900–1500 μmol min/L is associated with better outcomes and busulfan TDM combined with model-based dose adjustment was associated with an increased probability of AUC target attainment.
Limited sampling strategy for predicting busulfan exposure in hematopoietic stem cell transplantation recipients
The 2-sample model is an effective and reliable approach to predict the AUC0-12 of twice-daily intravenous busulfan in Chinese adult patients.
A Nonparametric Method to Optimize Initial Drug Dosing and Attainment of a Target Exposure Interval: Concepts and Application to Busulfan in Pediatrics
The approach can be applied for OPT dosing of many drugs, when the target objective is an interval, and outperformed the traditional model-based dosing approach, with earlier and better achievement of busulfan target AUC.


Plasma concentration monitoring of busulfan: does it improve clinical outcome?
Therapeutic drug monitoring of busulfan should be performed to maximise the likelihood of engraftment and minimise the risk of toxicity and relapse in HSCT patients receiving the BU/CY preparative regimen.
Population Pharmacokinetic–Based Dosing of Intravenous Busulfan in Pediatric Patients
The objective of this study was to characterize the pharmacokinetics of intravenous busulfan in pediatric patients and provide dosing recommendations and Therapeutic drug monitoring and dose adjustment to improve therapeutic targeting.
A limited sampling strategy for pharmacokinetic directed therapy with intravenous busulfan.
It is validated that LSS for IV busulfan will make possible meaningful and accurate comparisons ofBusulfan versus TBI-based preparative regimens and comparison of dose intensity of bus sulfuran-containing preparativeregimens in trials of submyeloablative transplantation.
Development of a Population Pharmacokinetics‐Based Sampling Schedule to Target Daily Intravenous Busulfan for Outpatient Clinic Administration
The optimal 6‐hour outpatient sampling schedule was constructed using a simulation approach that sought to minimize scaled mean squared error for the clearance and volume parameters for each simulated individual and the maximum a posteriori (MAP) Bayesian estimation was superior to maximum likelihood estimation with more samples.
Once-daily intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics and early clinical outcomes
It is concluded that intravenous busulfan in children administered once daily is safe, convenient and feasible, and can be dosed surface-based, independent of age.
Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity
It is concluded that, in accordance with previous data, within the observed AUCs no clear relationship was observed between Bu AUC and outcome with respect to toxicity, engraftment and relapse.
Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study
A limited sampling strategy based on a Bayesian methodology was developed and validated on an independent dataset: AUCs obtained from one to two samplings were demonstrated to be reliably estimated and no dose adjustment is required in obese patients when using a AIBW- or BSA-based dose calculation.
I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients
A retrospective population pharmacokinetic analysis was performed in 24 pediatric patients (PEDS) receiving i.v. Bu prior to allogeneic hematopoietic stem cell transplantation, and age-based dosing was demonstrated not to be clinically relevant with i.V. Bu.
Busulphan in blood and marrow transplantation: dose, route, frequency and role of therapeutic drug monitoring.
Administration of single daily doses of Bu has been shown to be safe and effective with oral Bu and has been used with i.v. preparations, and provides the possibility of defining a target exposure level associated with a good outcome.
Body Weight-Dependent Pharmacokinetics of Busulfan in Paediatric Haematopoietic Stem Cell Transplantation Patients
The model-based individual dosing nomogram is expected to result in predictive busulfan exposures in patients ranging between 3 and 65 kg and thereby to a safer and more effective conditioning regimen for HSCT in children.