Individualizing busulfan dose in specific populations and evaluating the risk of pharmacokinetic drug-drug interactions

ABSTRACT

Introduction

Busulfan is an alkylating agent widely used in the conditioning of hematopoietic stem cell transplantation possessing a complex metabolism and a large interindividual and intra-individual variability, especially in children. Combined with the strong rationale of busulfan PK/PD relationships, factors altering its clearance (e.g. weight, age, and GST-A genetic polymorphism mainly) can also affect clinical outcomes.

Areas covered

This review aims to provide an overview of the current knowledge on busulfan pharmacokinetics, its pharmacokinetics variabilities in pediatric populations, drug-drug interactions (DDI), and their consequences regarding dose individualization. This review was based on medical literature up until October 2021.

Expert opinion

To ensure effective busulfan exposure in pediatrics, different weight-based nomograms have been established to determine busulfan dosage and provided improved results (65–80% of patients correctly exposed). In addition to nomograms, therapeutic drug monitoring (TDM) of busulfan measuring plasmatic concentrations to estimate busulfan pharmacokinetic parameters can be used. TDM is now widely carried out in routine practices and aims to ensure the targeting of the reported therapeutic windows by individualizing busulfan dosing based on the clearance estimations from a previous dose.

KEYWORDS:

• Busulfan
• drug-drug interactions
• pharmacokinetics
• PK/PD relationships
• therapeutic drug monitoring

Article highlights

• Busulfan is a widely used chemotherapic agent in hematopoietic stem cell transplantation (HSCT), exhibiting considerable interindividual and intra-individual variability in pediatrics.

• Different covariates such as pharmacogenetics, anthropometric data, age, or DDI may influence busulfan clearance and clinical outcomes, particularly in pediatrics.

• Although PK/PD relationship studies lead to conflicting results because of the heterogeneity of the data, most studies conclude that busulfan cumulative area under the curve (AUC) is significantly associated with both efficacy and toxicity.

• Busulfan therapeutic drug monitoring (TDM) is now widely used in pediatrics to ensure good exposure of patients and demonstrated a significant clinical improvement in efficacy and toxicities. Results led the American Society for Transplantation and Cellular Therapy (ASTCT) to recommend busulfan TDM in pediatrics.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed an NIH grant on busulfan, which ended in 2020. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.