Highlights
- Real-world data demonstrate that only ~20% of patients achieve busulfan target AUC without therapeutic drug monitoring (TDM), even when doses are adjusted for body weight and comorbidities.
- The iron chelator deferasirox significantly reduces busulfan clearance (CL) by nearly 35%, posing a high risk for overexposure and toxicity.
- Body weight normalization (AIBW or BSA) effectively manages the influence of obesity on busulfan clearance, but significant inter- and intra-individual variability remains.
- Contrary to previous population PK models, recent longitudinal data suggest no general decrease in busulfan clearance over the course of multi-day conditioning regimens.
Background
Busulfan (Bu) is a bifunctional alkylating agent that serves as a cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation (HSCT). Since its introduction, the primary clinical challenge has been its narrow therapeutic index. Underexposure is linked to an increased risk of graft failure and disease relapse, whereas overexposure is a primary driver of regimen-related toxicities, most notably sinusoidal obstruction syndrome (SOS) and neurotoxicity.
Historically, oral busulfan was plagued by erratic bioavailability and high inter-individual variability. The transition to intravenous (IV) busulfan significantly improved dosing predictability, yet clinical studies continue to report high pharmacokinetic (PK) variability. This variability stems from factors including age, body composition, disease subtype, and drug-drug interactions. Despite international guidelines strongly recommending therapeutic drug monitoring (TDM) to ensure patients reach the target Area Under the Curve (AUC), adoption across European transplant centers remains inconsistent. This synthesis evaluates the current evidence regarding busulfan PK parameters, with a focus on real-world data involving obesity and pharmacological interactions.
Key Content
Evolution of Busulfan Dosing Strategies
The refinement of busulfan dosing has progressed from weight-based oral administration to individualized IV regimens. Early evidence (1999) established that oral busulfan clearance (CL/F) was significantly affected by body size. Research indicated that while actual body weight (BW) was a strong determinant of clearance, it did not account for the differences observed between normal-weight and obese patients. Specifically, obese patients exhibited higher absolute clearance, but when normalized to Body Surface Area (BSA) or Adjusted Ideal Body Weight (AIBW), the differences were eliminated. This foundational work suggested that dosing based on AIBW or BSA could mitigate the PK impact of obesity, though it also noted that disease type—specifically Non-Hodgkin’s Lymphoma (NHL)—correlated with lower clearance compared to Chronic Myelogenous Leukemia (CML).
With the advent of IV busulfan, a population PK study (2006) involving 127 adult patients confirmed that AIBW and BSA remained the most robust covariates for explaining inter-patient variability. This study demonstrated that an IV dose of 0.8 mg/kg of AIBW (every 6 hours) could place approximately 80% of patients within the therapeutic AUC range (900–1,500 µM·min). This era established the standard of using AIBW for obese patients to avoid over-dosing, as clearance based on actual body weight would lead to excessive concentrations.
Real-World Assessment of Intra-Individual Variability (2016–2024)
Recent longitudinal data (Langebrake et al., 2026) provide a more granular look at busulfan PK in contemporary practice. In a retrospective analysis of 287 patients, the median AUC after the first TDM was 17.1 mg*h/L. Crucially, the study revealed that without TDM, only 20.6% of patients would have achieved target attainment using standard dosing, even with current body-weight adjustments.
A key finding in this latest research is the analysis of intra-individual variability. While the average change in CL and volume of distribution (Vd) between doses was minimal (-0.65% and -1.40% respectively), approximately one-third of the cohort experienced relevant deviations between doses. This indicates that a single TDM measurement at the start of conditioning may not be sufficient for all patients. Furthermore, this study challenged the long-held belief that busulfan clearance generally decreases over the four days of conditioning, finding no such systematic trend.
The Impact of Obesity and Deferasirox
The interaction between busulfan and comedications is a critical safety consideration. The 2026 real-world data identified a significant reduction in busulfan clearance in patients receiving deferasirox, an iron chelator often used in transfusion-dependent HSCT candidates. The median clearance was 0.13 L/kg dosing weight in the deferasirox group versus 0.20 L/kg in those not receiving it (p < 0.001). This interaction suggests that deferasirox may inhibit metabolic pathways (likely via cytochrome P450 or glutathione-S-transferase interactions) responsible for busulfan elimination.
Regarding obesity, current data reaffirm that while absolute clearance is higher in patients with high BMI, the use of dosing weights (AIBW) effectively normalizes these differences. However, the 2026 study noted that neither body weight nor deferasirox status could fully explain the intra-individual deviations observed in 33% of the patients, reinforcing the unpredictable nature of busulfan PK even in controlled clinical settings.
Expert Commentary
The synthesis of evidence over the last three decades underscores a persistent paradox: while we have identified the best covariates for initial dosing (AIBW and BSA), these are insufficient to guarantee therapeutic success without real-time monitoring. The finding that only 20.6% of patients hit the target AUC on the first dose is a stark reminder of the limitations of population-based dosing formulas.
The interaction with deferasirox is particularly noteworthy for clinicians. Iron overload is common in the transplant population, and many patients are on chelation therapy up until the start of conditioning. The substantial decrease in busulfan clearance (approx. 35%) means these patients are at a significantly higher risk of toxic overexposure. It is recommended that deferasirox be discontinued well in advance of busulfan administration, or that TDM-guided dose reductions be implemented aggressively in these individuals.
Furthermore, the observation of relevant intra-individual variability in one-third of patients suggests that the “one-and-done” TDM approach is inadequate for a significant portion of the transplant population. Factors such as changes in hydration, hepatic blood flow, or physiological stress during conditioning may contribute to these shifts. Clinicians should consider repeat TDM, especially in patients who show initial results at the edges of the therapeutic window.
Conclusion
Busulfan remains a highly effective but volatile component of HSCT conditioning. While AIBW-based dosing has improved outcomes in obese populations, it does not account for the high inter- and intra-individual variability that characterizes the drug’s metabolism. The significant impact of deferasirox on busulfan clearance highlights the need for meticulous medication reconciliation. Moving forward, the integration of real-time TDM should be considered mandatory rather than optional to ensure patient safety and maximize the curative potential of the transplant. Future research should focus on identifying the biological markers—beyond body weight—that drive the intra-individual shifts in clearance observed in a third of the clinical population.
References
- Langebrake C, Wansing EA, Janson D, Wolschke C, Lueck C, Ayuk F, Kröger NM, Dadkhah A. Busulfan pharmacokinetics in adults – a real-world evaluation of intra-individual variability and the impact of obesity and deferasirox. Bone Marrow Transplant. 2026 Apr 14. PMID: 41981079.
- De Castro N, et al. Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study. Cancer Chemother Pharmacol. 2006 Jan;57(2):191-8. PMID: 16133536.
- Radich JP, et al. The impact of obesity and disease on busulfan oral clearance in adults. Blood. 1999 Jun 15;93(12):4436-40. PMID: 10361142.
