Pharmacokinetic monitoring of busulfan in pediatric patients undergoing hematopoietic cell transplantation: Comparison of non-compartmental and compartmental analysis

Abstract

Introduction

Pharmacokinetic monitoring of busulfan allows individualized dosing in patients, which is essential due to its high interindividual variability and narrow therapeutic range. Non-compartmental and compartmental methods are used in clinical practice to analyze busulfan exposure by area under the curve (AUC), which differ in their estimates. We aimed to compare both methods in pediatric patients and to evaluate their implications on dose recommendations.

Methods

A retrospective, observational study including 16 pediatric patients treated with busulfan as preconditioning for hematopoietic stem cell transplantation (HSCT). Trapezoidal method was used to estimate the non-compartmental AUC and the Shukla population model to estimate the compartmental AUC with NONMEM^®. Statistical analysis was performed with R^® software using the Wilcoxon test of paired data.

Results

No significant differences were observed in the estimation of AUC between the non-compartmental and compartmental methods, although the non-compartmental method showed greater variability and lower drug exposure, with a median of 14.985 mg/L*h vs 16.873 mg/L*h, respectively. In addition, the proportion of patients who reached the therapeutic target was similar, only 12.5% in both methods, while the majority were below it. Therefore, the dose adjustment recommendations would be similar, although quantitatively higher in non-compartmental method due to lower exposure.

Conclusions

There is good agreement between the two estimation methods. Most patients were below therapeutic target, indicating that the initial dose used is often lower than necessary and a dose increase is generally required. Bayesian models are more complex, but may provide more precise exposure estimates than the trapezoidal method.