Variation in Prescribing Patterns and Therapeutic Drug Monitoring of Intravenous Busulfan in Pediatric Hematopoietic Cell Transplant Recipients

Abstract

Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors’ group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children.

Prediction of intravenous busulfan clearance by endogenous plasma biomarkers using global pharmacometabolomics

“…Unfortunately, the current dosing method of using body weight for dose 1 IV busulfan dose rarely achieves the target AUC. Specifically, using body weight to determine dose 1 of IV busulfan results in only 24% of children (McCune et al 2013) and 23% of adults (Yeh et al 2012) achieving their personalized target IV busulfan AUC.…”

Comparison of Outcomes of Allogeneic Transplantation for Chronic Myeloid Leukemia with Cyclophosphamide in Combination with Intravenous Busulfan, Oral Busulfan, or Total Body Irradiation

“…9 Studies of Bu kinetics revealed that oral Bu is erratically absorbed and that oral administration of a fixed-dose results in wide variations in plasma Bu levels. 10,11,12,13 Low plasma levels are associated with increased risks of graft-failure and relapse and high levels with increased toxicity.…”

Single Daily Busulfan Dosing for Infants with Nonmalignant Diseases Undergoing Reduced-Intensity Conditioning for Allogeneic Hematopoietic Progenitor Cell Transplantation

“…Other than 2 patients for whom test dose PK data were not available, all other patients in our study received either an upward or downward adjustment after the test dose to achieve the total AUC desired, indicating the practicality of the use of the test dose PK results to optimize total Bu exposure. The test doseebased Bu adjustment strategy described thus represents a rational and effective way to address the problem of high variability associated with Bu administration [23]. Data currently available from PK studies of i.v.…”