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ABSTRACT
Introduction: Busulfan (Bu) is an alkylating agent with a limited therapeutic margin and exhibits inter-patient variability in pharmacokinetics (PK). Despite decades of use, mechanisms of Bu PK-based drug-drug interactions (DDIs), as well as the negative downstream effects of these DDIs, have not been fully characterized.
Areas covered: This article provides an overview of Bu PK, with a primary focus on how known and potentially unknown drug metabolism pathways influence Bu-associated DDIs. In addition, pharmacogenomics of Bu chemotherapy and Bu-related DDIs observed in the stem cell transplant clinic (SCT) are summarized. Finally the increasing importance of Bu therapeutic drug monitoring is highlighted.
Expert opinion: Mechanistic studies of Bu metabolism have shown that in addition to GST isoenzymes, other oxidative enzymes (CYP, FMO) and ABC/MDR drug transporters likely contribute to the overall clearance of Bu. Despite many insights, results from clinical studies, especially in polypharmacy settings and between pediatric and adult patients, remain conflicting. Further basic science and clinical investigative efforts are required to fully understand the key factors determining Bu PK characteristics and its effects on complications after SCT. Improved TDM strategies are promising components to further investigate, for instance DDI mechanisms and patient outcomes, in the highly complex SCT treatment setting.
Article highlights
Busulfan (Bu) is a preferred alkylating agent in myeloablative conditioning regimens prior to hematopoietic stem cell transplantation (HSCT), but carries a substantial risk for toxicities (high exposure) and poor efficacy (low exposure) when plasma concentrations are not properly monitored.
A bulk of knowledge shows that Bu has a fascinating, but highly complex, drug elimination profile that consists of both enzymatic and non-enzymatic processes; still, more basic scientific research is required to firmly establish the roles of non-GST enzyme(s) in Bu clearance. Such in vitro findings have potential benefits to support refinements of population PK models used in conjunction with therapeutic drug monitoring (TDM).
Despite decades of study, clinical PK drug-drug interaction (DDI) and pharmacogenomic findings show incongruous results, likely caused in part to polypharmacy (and polychemotherapy) tendencies of HSCT patients and their predisposition to organ toxicities resulting from inferior tumor control and/or multiple procedures prior to HSCT.
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Declaration of interest
Y Nieto has received research support fortm Otsuka Pharmaceuticals Inc. BS Andersson is a former consultant to Otsuke Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.