Body Weight-Dependent Pharmacokinetics of Busulfan in Paediatric Haematopoietic Stem Cell Transplantation Patients

Abstract

The wide variability in pharmacokinetics of busulfan in children is one factor influencing outcomes such as toxicity and event-free survival. A meta-analysis was conducted to describe the pharmacokinetics of busulfan in patients from 0.1 to 26 years of age, elucidate patient characteristics that explain the variability in exposure between patients and optimize dosing accordingly. Data were collected from 245 consecutive patients (from 3 to 100 kg) who underwent haematopoietic stem cell transplantation (HSCT) in four participating centres. The inter-patient, inter-occasion and residual variability in the pharmacokinetics of busulfan were estimated with a population analysis using the nonlinear mixed-effects modelling software NONMEM VI. Covariates were selected on the basis of their known or theoretical relationships with busulfan pharmacokinetics and were plotted independently against the individual pharmacokinetic parameters and the weighted residuals of the model without covariates to visualize relations. Potential covariates were formally tested in the model. In a two-compartment model, body weight was the most predictive covariate for clearance, volume of distribution and inter-compartmental clearance and explained 65%, 75% and 40% of the observed variability, respectively. The relationship between body weight and clearance was characterized best using an allometric equation with a scaling exponent that changed with body weight from 1.2 in neonates to 0.55 in young adults. This implies that an increase in body weight in neonates results in a larger increase in busulfan clearance than an increase in body weight in older children or adults. Clearance on the first day was 12% higher than that of subsequent days (p < 0.001). Inter-occasion variability on clearance was 15% between the 4 days. Based on the final pharmacokinetic-model, an individualized dosing nomogram was developed. 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.