Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review

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.

Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children

“…Itraconazole is also reported to decrease the CL of busulfan and increase the AUC . In the present study, busulfan was given along with itraconazole in three patients.…”

“…Fludarabine has been reported to decrease the CL of busulfan and increase the AUC . In the present study, fludarabine was co‐administered in three patients, wherein fludarabine was given before the first dose of busulfan in two patients (UPN18 and UPN20), and was given between the first and second doses of busulfan in the third patient (UPN3).…”

Test Dose Pharmacokinetics in Pediatric Patients Receiving Once‐Daily IV Busulfan Conditioning for Hematopoietic Stem Cell Transplant: A Reliable Approach?

“…Phenytoin, 1 of multiple options for seizure prophylaxis in this patient population, is another medication that has been implicated in reducing busulfan exposures via induction of drug‐metabolizing enzymes . All patients detailed in this article received levetiracetam, which has not been implicated in altering busulfan exposures . Acetaminophen is another medication that is theorized to interact with busulfan through competition with glutathione, resulting in decreased busulfan clearance, but this is in contrast to the increased clearance observed in patient 3, who received acetaminophen.…”

“…Busulfan test doses were infused over 2 hours, followed by serial PK sampling through 4 to 6 hours postinfusion. PK samples for patients 1, 2, and 4 were collected at time 0 (immediately postinfusion), 15,30,60,120,180,240, and 360 minutes postinfusion. PK samples for patients 3 and 5 were collected at time 0 (immediately postinfusion), 60, 120, and 240 minutes postinfusion.…”

Debate on Bioavailability and Bioequivalence (BA/BE) Studies Using Limited Sampling Strategy: Views and Perspectives

“…Although the use of limited sampling strategy has been successfully employed in therapeutic drug monitoring (TDM) of narrow therapeutic index drugs [8][9][10][11], it is not the same situation in the case of application of the concept to a BA/BE study. While the application of limited sampling strategy in TDM is specifically applied for safety and efficacy assessment at an individual patient level undergoing clinical therapy, the use of the same concept in BA/BE study is generally in healthy subjects for extrapolation of data to a population level.…”