Effect of Weight and Maturation on Busulfan Clearance in Infants and Small Children Undergoing Hematopoietic Cell Transplantation

Abstract

Little information is currently available regarding the pharmacokinetics of busulfan in infants and small children to help guide decisions for safe and efficacious drug therapy. The objective of this study was to develop an algorithm for individualized dosing of intravenous busulfan in infants and children weighing less than or equal to 12kg, that would achieve targeted exposure with the first dose of busulfan. Population pharmacokinetic modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of busulfan in 149 patients from 8 centers. Busulfan pharmacokinetics were well described by a 1-compartment base model with linear elimination. The important clinical covariates impacting busulfan pharmacokinetics were actual body weight and age. Based on our model, the predicted clearance of busulfan increases approximately 1.7-fold between 6 weeks to 2 years of life. For infants less than 5 months of age, the model-predicted doses (mg/kg) required to achieve the therapeutic Css range of 600–900 ng/mL (AUC range = 900–1350 uM·min) were much lower compared to standard busulfan doses of 1.1mg/kg. These results could help guide clinicians and inform better dosing decisions for busulfan in young infants and small children undergoing hematopoietic cell transplantation.

Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning

“…therap*").tw. 12 8 or 9 or 10 13 7 and 12 a TBW < 10 kg, Savic et al [12] excluded patients with a TBW > 12 kg, and the supplementary dose calculator tool for the Long-Boyle dosing guideline excluded patients < 12 kg and those > 17 years of age (Dr. J.R. Long-Boyle, personal communication, March 16, 2015).…”

“…Eleven publications describing 12 busulfan dosing guidelines were identified (Table 3) [6,7,[12][13][14][15][16][17][18][19][20]. One dosing guideline [19] was supplemented by an online dosage calculation tool (see http://holford.fmhs.auckland.ac.nz/ docs/busulfan-integrated-pk.pdf) [21].…”

“…Six guidelines [6,[13][14][15]17,18] used body weight to determine the initial dose of busulfan; 2 guidelines [16,20] used age, 2 [7,12] used a combination of body weight and age, 1 guideline [17] used body surface area (BSA), whereas another used an equation based on busulfan clearance scaled to normal fat mass based on sex, age, and height [19]. Six dosing guidelines included the target AUC or Css as a variable [7,12,14,17,19]. Three dosing guidelines had weight restrictions: Buffery et al [13] excluded patients with Limit 5 to "all child (0 to 18 years)" 7 Limit 6 to English language 8…”

Immune reconstitution and survival of 100 SCID patients post–hematopoietic cell transplant: a PIDTC natural history study

“…Careful targeting of busulfan exposure, while identifying the lowest possible effective exposure, is essential to decrease morbidity in very young infants. 17,18 Consideration of genotype in the decision process regarding chemotherapy is practical now that a molecular diagnosis can be made in the majority of patients. This may lead to improved outcomes given that prior data support improved sustained immune reconstitution with the use of conditioning in certain SCID genotypes, including RAG1/RAG2/DCLRE1C and other forms of B-cell SCID.…”

Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children

“…compared with older children. 19,20,22,38,48 Savic et al 50 proposed a model-dosing strategy based on age for infants and children weighing ⩽ 12 kg, to achieve a target of 900-1250 μmol min/L. 49 According to their model, a 1.7-fold increase in busulfan clearance would occur between the ages of 6 weeks and 2 years.…”