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 (PK) 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 i.v. busulfan in infants and children weighing ≤12 kg, that would achieve targeted exposure with the first dose of busulfan. Population PK modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of busulfan in 149 patients from 8 centers. Busulfan PK was well described by a 1-compartment base model with linear elimination. The important clinical covariates affecting busulfan PK 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 age <5 months, the model-predicted doses (mg/kg) required to achieve a therapeutic concentration at steady state of 600-900 ng/mL (area under the curve range, 900-1350 μM·min) were much lower compared with standard busulfan doses of 1.1 mg/kg. These results could help guide clinicians and inform better dosing decisions for busulfan in young infants and small children undergoing hematopoietic cell transplantation.

Keywords: Busulfan; Hematopoietic cell transplantation; Pediatrics; Pharmacokinetics.

Figure I

Fraction of busulfan clearance for infants compared to an average 2-year-old child by (a) change in busulfan clearance verses weight and (b) change in busulfan clearance verses age.

Figure II

Visual Predictive Check for (a) every 6-hour dosing and (b) once-daily administration. Tick solid line is data median. Upper and lower dashed lines are 97.5^th and 2.5^th data percentile. Upper, middle and lower shaded areas are simulated 97.5^th percentile, median and 2.5 the percentile with uncertainty, respectively. Appropriate model fit is indicated if lines are contained within shaded areas.

Figure III

Model-based estimated dose (mg/kg) required to achieve a therapeutic Css of 600–900ng/mL (solid line). For comparison, the dashed line represents conventional dosing of 1.1mg/kg in children less than 12kg.

Figure IV

Plot demonstrating estimated Css with conventional dosing vs the model-based algorithm for achieving a therapeutic target of 600–900ng/mL by age. Currently recommended dose (1.1mg/kg) is shown for reference (horizontal dashed line)