Busulfan pharmacokinetics in adults – a real-world evaluation of intra-individual variabil-ity and the impact of obesity and deferasirox

Busulfan pharmacokinetics in adults – a real-world evaluation of intra-individual variabil-ity and the impact of obesity and deferasirox | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Busulfan pharmacokinetics in adults – a real-world evaluation of intra-individual variabil-ity and the impact of obesity and deferasirox Claudia Langebrake, Eva-Maria Wansing, Dietlinde Janson, Christine Wolschke, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7660052/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Apr, 2026 Read the published version in Bone Marrow Transplantation → Version 1 posted 9 You are reading this latest preprint version Abstract To avoid under- or overexposure caused by a high variability of busulfan’s pharmacokinetic parameters, therapeutic drug monitoring (TDM) is highly recommended. Nevertheless, it is not widely used in European transplant centers. We retrospectively analyzed real-world busulfan TDM data in adults in our center between 9/2016 and 11/2024 with special focus on overweight/obesity and comedication with deferasirox. Overall 287 patients (161 male/126 female), median age 59.6 years (19.4–77.7) were included. Median calculated AUC after the first TDM was 17.1 mg*h/L with high interindividual variability (range: 9.6–37.9). Target attainment without TDM would only have been achieved in 59 patients (20.6%) using the standard dose, even if adjusted for overweight/obesity and comedication with deferasirox. Busulfan clearance (CL) was significantly reduced in patients receiving deferasirox (0.13 L/kg dosing weight [0.07–0.22] vs 0.20 [0.12–0.33], p < 0.001), while no influence of body weight was detectable. Overall, there were no Intra -individual changes in both CL (-0.65% [-41.72–57.79]) and V d (-1.40% [-36.85–69.04) between doses. However, in one third of patients relevant deviations were observed, regardless of either body weight or comedication with deferasirox. In contrast to some published data, no general decrease in CL over time was observed. Health sciences/Medical research/Translational research Health sciences/Medical research/Preclinical research Busulfan Therapeutic drug monitoring Hematopoietic stem cell transplantation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction The alkylating agent busulfan (Bu) is often used as part of a conditioning therapy prior to an allogeneic hematopoietic stem cell transplant (allo-HSCT). It is known that Bu exhibits high variability between dose and exposure (area under the curve, AUC), even when administered intravenously. 1 Because of its narrow therapeutic index, over- or underexposure results in either toxic adverse effects and increased transplantation-related mortality or higher rates of graft rejection or relapse rates. 2 – 7 For this reason, about a decade ago, it was recommended to personalize busulfan dosing using a patient-individual therapeutic drug monitoring (TDM), especially in children and patients receiving myeloablative conditioning regimens. 8 However, busulfan TDM is not widely established among European transplantation centers, despite wide use of busulfan. 9 To increase the level of knowledge about the practical implementation of busulfan TDM and to overcome potential barriers to its introduction, European recommendations have recently been published. 10 Busulfan is a small and highly lipophilic drug that crosses the blood brain barrier resulting in similar concentrations in plasma and cerebrospinal fluid. The volume of distribution (V d ) ranges between 0.62 and 0.85 L/kg body weight in adult patients. It is extensively metabolized in the liver. The main step is spontaneous or glutathione-S-transferase (GST) derived conjugation with endogenous glutathione (GSH). Subsequent steps involve metabolism via the mercapturic acid pathway or dissociation and further oxidation steps or further binding with GSH. 11 Presumably none of the metabolites contributes significantly to efficacy or toxicity. Typical clearance (CL) for intravenous busulfan in adults is 0.2 L/h/kg, with a high inter -individual (between two different patients) variability in a range of up to 3-fold reported in large studies. 1 , 12 , 13 In patients with obesity, CL best correlates with adjusted ideal body weight (AIBW). 14 Therefore, the use of AIBW is recommended for dose calculation in patients with a body mass index of 25 kg/m² and above. Known clinically relevant drug-drug interactions with busulfan exist among others with acetaminophen, metronidazole, azoles, phenytoin or deferasirox resulting in subtherapeutic or supratherapeutic exposures. 15 , 16 Especially in children, significant but hardly predictable intra -individual variability of busulfan’s pharmacokinetic parameters has been reported, with an overall decrease of busulfan CL between doses resulting in a risk of busulfan overexposure. 17 – 19 Respective data for adults are sparsely available at present. The aim of this study is to analyze real-world busulfan TDM data in adults with special focus on overweight/obesity, comedication with deferasirox and intra -individual changes of busulfan’s pharmacokinetic parameters. Methods Pharmacokinetic data of adult patients treated with TDM-guided busulfan-based conditioning as part of standard care treatment prior to allo-HSCT in the Department of Stem Cell Transplantation at the University Medical Center Hamburg between September 2016 and November 2024 were retrospectively analyzed. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee. Busulfan was administered intravenously over 3 hours with an initial dose of 3.2 mg/kg once daily. The basis for dose calculation was total body weight (TBW) for patients with a body mass index (BMI) ≤ 25 kg/m 2 , while AIBW25 - calculated as ideal body weight (IBW) plus 25% of the difference between total and IBW - was used for patients with BMI > 25 kg/m 2 . In the following, the respective reference weight is referred to as “dosing weight”. With this approach, we aimed for an average busulfan-AUC of 20 mg*h/L (± 10%) with initial dosing. Depending on the respective conditioning protocol and the intensity of conditioning - myeloablative (MAC) or reduced intensity (RIC) conditioning - two to four consecutive dosages were planned to achieve the desired cumulative target AUC between 40 and 80 mg*h/L. TDM was performed as part of standard of care on the first or second day of application and the busulfan dose was adjusted accordingly based on these results. Busulfan plasma levels were drawn according to a local sampling schedule 5 minutes, 1, 2 and 3 hours after the end of busulfan infusion, whereas the exact infusion and sampling times were documented. Quantification was performed at the Department of Legal Medicine at the University Medical Center Hamburg-Eppendorf using a validated gas chromatography with mass spectrometric (GC-MS) detection method. Subsequently, model-based calculation of the AUC was carried out in the hospital pharmacy by means of Bayesian prediction using pharmacokinetics software (MW-Pharm, Version 3.60). If the calculated AUC was not within a target range of ± 10% of the target cumulative AUC, busulfan dose was adjusted accordingly. In cases of dose deviations > 25%, new busulfan concentration measurements and AUC calculations were carried out after the subsequent dose, and, if necessary, a repeated dose adjustment was made. Standard supportive treatment included levetiracetam for seizure prophylaxis in all patients and deferasirox during conditioning in patients with a serum ferritin of > 1000 µg/L, while other drugs known to interact with busulfan (e.g. acetaminophen, metronidazole, azoles) were avoided. The statistical analysis was carried out using IBM SPSS Statistics software version 29. Discrete variables were expressed as counts (percentages), whereas continuous variables were expressed as median and range. For group comparisons of categorial variables, chi-square, or Fisher’s exact tests were used as appropriate. Continuous variables that were not normally distributed were analyzed using Mann-Whitney-U-Test. A p-value < 0.05 was defined as statistically significant. Results Overall, 287 patients (161 male, 56.1%) with a median age of 59.6 years (19.4–77.7) were included. Basic characteristics of the patient cohort are shown in table 1. Initial dosing of busulfan was 3.2 mg/kg dosing weight once daily, calculated on TBW in 157 patients (54.7%) with BMI ≤ 25 kg/m² and on AIBW25 in 130 patients (45.3%) with BMI > 25 kg/m². During conditioning, 99 patients (34.5%) received deferasirox, 60 of them with an initial dose reduction of busulfan to 75–80%. TDM was performed at least twice in 138 patients (48%). Median calculated AUC after the first TDM was 17.1 mg*h/L with high inter -individual variability in busulfan-exposure (range: 9.6–37.9) as shown in Fig. 1 . Overall, 59 patients (20.6%) reached the target-AUC (20 h*mg/L ± 10%) at the first TDM, while 165 patients (57.5%) needed a dose increase and 63 patients (22.0%) a dose reduction. There were no statistically significant differences in initial AUC or target attainment with regard to overweight/obesity (AUC: 17.5 [9.6–37.9] vs. 16.8 [9.7–32.4] h*mg/L). Concomitant deferasirox treatment resulted in significantly higher AUC at the first TDM (23.42 [14.26–37.86] vs. 15.54 [9.57–26.04, p < 0.001] mg*h/L), whereupon an initial dose reduction was implemented into the local conditioning protocols in 3/2023, resulting in more adequate median AUC-levels (20.25 mg*h (L [12.76–35.63]). Overall, busulfan CL was highly variable in the overall population with a median of 0.183 L/h/kg dosing−weight and a range of 0.068 to 0.334, translating into a 4.89-fold inter -individual variability in CL. In patients receiving deferasirox, busulfan CL was 38% lower compared to patients without deferasirox comedication (0.127 L/kg dosing weight [0.068–0.223 vs. 0.204 [0.119–0.334], p < 0.001); absolute difference − 0.079 (95% CI: -0.088 to -0.069), translating into a 3.26 and 2.79-fold inter -individual variability, respectively (see Fig. 2 ). No influence of overweight/obesity on busulfan CL was detectable. In the overall population, median V d was 54.41 L (range: 21.19-101.19 L) and 0.77 L/kg dosing−weight (range: 0.31–1.36), with an inter -individual variability of 4.8- and 4.4-fold in V d , respectively, as shown in Fig. 3 . Median V d was significantly higher in overweight/obese patients (60.09 [24.4–99.9] vs 48.64L [21.19–11.19]). When normalized to dosing weight, the difference still remained statistically significant, but the relative median difference accounted only for 7% (0.81L/kg dosing weight [0.31–1.10] vs 0.75 [0.39–1.36], p = 0.001). Intra -individual changes of pharmacokinetic parameters between day 1 and day 2 of busulfan amounted to less than 1.5% in median: CL (-0.65% [-41.72–57.79]) or V d (-1.40% [-36.85-69.04]). However, clinically relevant changes in CL of more than ± 10% between doses occurred in 32% of patients, with 21/108 patients (19%) showing a decrease in CL of at least 10% and 14/108 patients (13%) an increase in CL of at least 10% (see Fig. 4 ). These intra -individual between-dose changes in CL were similar in patients with and without overweight/obesity. In patients with or without comedication with deferasirox, median intra -individual changes in CL were below 4% in both groups (1.5% and 3.5%, respectively). However, we observed an increase in CL of more than 10% between day 1 and day 2 in more patients receiving deferasirox (26% vs 5%), and less frequently a decrease in CL of more than 10% (14% vs 23%) compared to patients not receiving deferasirox (see Fig. 5 ). Intra -individual changes of V d between doses 1 and 2 were similar in patients with and without overweight/obesity and with or without comedication with deferasirox. Discussion We present real-world data on busulfan TDM in a large cohort of adult allo-HSCT patients. Target attainment without TDM would have been achieved in about 20% of patients using the standard dose, even when adjusted for overweight/obesity and comedication with deferasirox. The confirmed decrease in busulfan CL due to deferasirox can be compensated by an initial dose reduction of busulfan to 80%. High intra - and inter -individual variability of both CL and V d was not different within subgroups of patients with either overweight/obesity or comedication with deferasirox. In contrast to some published data, no general decrease in CL after the first dose was observed, although relevant intra -individual (between-dose) changes of PK parameters frequently occur. To avoid under- or overexposure caused by a high inter -individual variability of busulfan’s pharmacokinetic (PK) parameters, TDM - especially in children, for myeloablative conditioning or for regimes that were developed with PK-guided busulfan - is highly recommended. 4 , 8 However, according to a European Survey, only 10–20% of transplant centers regularly perform busulfan TDM. 9 To overcome potential obstacles, a practical guidance on busulfan TDM including a step-by-step guide, was recently published and centers are encouraged to implement TDM for busulfan. 10 Using standard approved doses of busulfan, the majority of patients does not reach target exposure: about three out of five patients in our real-world analysis would have resulted in underexposure, while one out of five patients would have experienced overexposure, if no dose adjustment had been performed. This up to four-fold inter -individual variability between dose and exposure as well as the assymetrical distribution of busulfan exposure after the first dose are well known and is mainly explained by up to five-fold differences in drug CL. 1,12,14,20–22 As expected, absolute V d is higher in overweight/obese patients, but if normalized to dosing weight (AIBW in patients with BMI > 25 kg/m², otherwise TBW), these differences are less pronounced. This emphasizes the necessity of using adjusted weight measures for initial dosing, unless model-informed precision dosing (MIPD) is applied a priori . 14 , 20 , 23 , 24 Consequently, median busulfan exposure after the first dose was similar in normal weight compared with overweight/obese patients. Furthermore, we could show, that the inter -individual variability of AUC, CL and V d was not different between the two weight groups. In a previous study, we demonstrated, that concomitant deferasirox significantly reduces busulfan CL by one third. 16 We validated these findings in our current, even larger cohort of patients and could further show that an initial reduction to 75–80% of the body weight-adapted busulfan dose leads to an excellent median target AUC attainment. Notably, similar inter -patient variability between dose and exposure is observed in this patient group, necessitating dose reductions or increases in around 40% of the patients, respectively. Data on intra -individual changes in busulfan CL over time exist mainly for children using four-times daily dosing of busulfan: Marsit et al. described, that 80% of children experienced a decrease in busulfan CL, with a median change of -7.9% between day 1 and day 2, with high variability ranging from − 48.5 to + 44%. Over day 1 to day 3 mean CL significantly decreased by 15%. 17 In patients from 0.1 to 26 years, Bartelink et al. detected a 12% higher busulfan CL on the first day compared to subsequent days. 18 In a cohort of 58 pediatric and young adult patients, a decrease of busulfan CL of approximately 15% between first dose and steady-state dose PK sampling was detected by Long-Boyle et al.. 19 McCune et al. observed a slight decrease in busulfan CL over time and that children under four years of age have lower busulfan CL than adults. 25 Using a semi-mechanistic model, Langenhorst et al. observed an overall decrease of 7% in busulfan CL with a range of -82 to + 44% in children and adults. Interestingly, there was an association between older age (> 40 years) and a stronger time-dependent effect that increased by 4% per year of age. It has been suggested, that this effect may be related to glutathione depletion. 26 On the other hand, McCune et al. described only minimal alterations of busulfan CL between doses of i.v. busulfan, with 71.4% of patients having < 10% change between doses 1 and 2. 1 Similar observations were described by Protzenko et al. with no general difference in busulfan CL between the first and the last dose, but marked changes of at least 20% in one third of the patients. 22 A recent publication by Bognar et al. analyzed changes in busulfan CL between day 1 and day 4 in 161 adult patients. They observed a considerable variance in clearance with 78.5% showing a decrease in busulfan CL (median decrease: 3.6%) and 21.5% showing an increase (median increase: 1.6%). 21 In contrast, our results show no overall decrease in busulfan CL in adult patients receiving once daily intravenous busulfan. The median difference on an individual patient basis between day 1 and day 2 was − 0.65% and the proportions of patients exhibiting changes of less than ± 10% accounts for 68%. However, one third of patients experience relevant differences in busulfan CL between doses of more than 10% that range from − 42 to + 58%, reflecting the high variability also reported in other studies. 17 , 21 , 26 One limitation of our study is that it is a single-center study. On the other hand, the standardized procedure for the application, blood level measurements and performance of the TDM offers advantages. Our center regularly participates successfully in the Busulfan-TDM interlaboratory proficiency testings. 27 In our center, busulfan TDM is performed as part of routine care on the first day of busulfan administration and on subsequent days only if dose deviations of more than 25% are required. This could theoretically result in a bias when analyzing the change in PK parameters. However, due to the high number of patients analyzed here, this appears to be negligible. Since only very few patients required TDM on day 3 (n = 13) or day 4 (n = 1), we cannot make reliable statements as to whether clearance in patients may change over time. However, other studies also described changes in clearance between only day 1 and day 2. 1,17,18 Furthermore, we have no data on GST polymorphisms for which a possible influence on busulfan CL is discussed. 28 In conclusion, with our real-world data we confirm the high variability of the pharmacokinetic parameters of busulfan administered intravenously once daily. This occurs both between different patients ( inter -individual) and between doses within a patient ( intra -individual). The decreased busulfan CL caused by deferasirox, can be compensated by an initial busulfan dose reduction to 75–80%, whereby similar inter - or intra -individual variability of pharmacokinetic parameters need to be considered. TDM of busulfan is therefore highly recommended to ensure target attainment and optimal clinical outcome. Declarations Competing Interests: The authors declare no competing financial interests Author Contributions CL performed the busulfan TDM,wrote the manuscript, designed the study and interpreted the data. AD performed the busulfan TDM, interpreted the data and edited the manuscript. EMW interpreted the data and edited the manuscript. DJ, CW, CL, FA and NMK reviewed the manuscript and provided clinical data. All authors approved the final version of the manuscript. Data Availability Statement Data are available upon data-specific request. References McCune, J. S. & Holmberg, L. A. Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol 5, 957–969 (2009). https://doi.org:10.1517/17425250903107764 Klyuchnikov, E. et al. Individualized busulfan dosing improves outcomes compared to fixed dose administration in pre-transplant MRD positive AML patients with intermediate risk undergoing allogeneic stem cell transplantation in CR. Eur J Haematol (2022). https://doi.org:10.1111/ejh.13893 Andersson, B. S. et al. Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients. Bone Marrow Transplant 52, 580–587 (2017). https://doi.org:10.1038/bmt.2016.322 Bartelink, I. H. et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol 3, e526-e536 (2016). https://doi.org:10.1016/S2352-3026(16)30114-4 Seydoux, C. et al. Impact of busulfan pharmacokinetics on outcome in adult patients receiving an allogeneic hematopoietic cell transplantation. Bone Marrow Transplant (2022). https://doi.org:10.1038/s41409-022-01641-6 Perkins, J. B. et al. Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 18, 1099–1107 (2012). https://doi.org:10.1016/j.bbmt.2011.12.584 Tamari, R. et al. Association between busulfan exposure and survival in patients undergoing a CD34 + selected stem cell transplantation. Blood Adv 7, 5225–5233 (2023). https://doi.org:10.1182/bloodadvances.2023009708 Palmer, J. et al. Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transplant (2016). https://doi.org:10.1016/j.bbmt.2016.07.013 Ruutu, T. et al. Use of busulfan in conditioning for allogeneic hematopoietic stem cell transplantation in adults: a survey by the Transplant Complications Working Party of the EBMT. 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Therapeutic drug monitoring-guided dosing of busulfan differs from weight-based dosing in hematopoietic stem cell transplant patients. Hematology/Oncology and Stem Cell Therapy 10, 70–78 (2017). https://doi.org: https://doi.org/10.1016/j.hemonc.2017.03.003 Nguyen, L., Leger, F., Lennon, S. & Puozzo, C. Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study. Cancer Chemother Pharmacol 57, 191–198 (2006). https://doi.org:10.1007/s00280-005-0029-0 Bauters, T. & Dadkhah, A. in The EBMT Handbook: Hematopoietic Cell Transplantation and Cellular Therapies (eds A. Sureda, S. Corbacioglu, R. Greco, N. Kröger, & E. Carreras) 273–280 (Springer, 2024). Essmann, S. et al. Iron Chelation With Deferasirox Increases Busulfan AUC During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation. Transplant Cell Ther 28, 115.e111-115.e115 (2022). https://doi.org:10.1016/j.jtct.2021.11.003 Marsit, H. et al. Intra-individual Pharmacokinetic Variability of Intravenous Busulfan in Hematopoietic Stem Cell-Transplanted Children. Clin Pharmacokinet 59, 1049–1061 (2020). https://doi.org:10.1007/s40262-020-00877-z Bartelink, I. H. et al. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet 51, 331–345 (2012). https://doi.org:10.2165/11598180-000000000-00000 Long-Boyle, J. R. et al. Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use. Ther Drug Monit 37, 236–245 (2015). https://doi.org:10.1097/ftd.0000000000000131 Shukla, P. et al. Assessment of a Model-Informed Precision Dosing Platform Use in Routine Clinical Care for Personalized Busulfan Therapy in the Pediatric Hematopoietic Cell Transplantation (HCT) Population. Front Pharmacol 11, 888 (2020). https://doi.org:10.3389/fphar.2020.00888 Bognar, T. et al. Busulfan Exposure Target Attainment in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation: A Single Day Versus a Multiple Day Therapeutic Drug Monitoring Regimen. Transplant Cell Ther 30, 1007 e1001-1007 e1010 (2024). https://doi.org:10.1016/j.jtct.2024.07.015 Protzenko, D. et al. Adaptive dosing of high-dose busulfan in real-world adult patients undergoing haematopoietic cell transplant conditioning. Br J Clin Pharmacol 91, 1171–1181 (2025). https://doi.org:10.1111/bcp.16343 Ben Hassine, K. et al. Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study. CPT Pharmacometrics Syst Pharmacol 10, 1043–1056 (2021). https://doi.org:10.1002/psp4.12683 Bubalo, J. et al. Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation practice guideline committee. Biol Blood Marrow Transplant 20, 600–616 (2014). https://doi.org:10.1016/j.bbmt.2014.01.019 McCune, J. S., Bemer, M. J., Barrett, J. S., Scott Baker, K., Gamis, A. S. & Holford, N. H. Busulfan in infant to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and Bayesian dose personalization. Clin Cancer Res 20, 754–763 (2014). https://doi.org:10.1158/1078-0432.Ccr-13-1960 Langenhorst, J. B. et al. A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance. Br J Clin Pharmacol 86, 1499–1509 (2020). https://doi.org:10.1111/bcp.14256 McCune, J. S. et al. Quality Control of Busulfan Plasma Quantitation, Modeling, and Dosing: An Interlaboratory Proficiency Testing Program. Ther Drug Monit 43, 657–663 (2021). https://doi.org:10.1097/FTD.0000000000000862 Ansari, M. et al. GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study. Oncotarget 8, 90852–90867 (2017). https://doi.org:10.18632/oncotarget.20310 Table 1 Table 1 is available in the Supplementary Files section. Additional Declarations The authors have declared there is NO conflict of interest to disclose. Supplementary Files Table1Patientcharacteristics.xlsx Table 1 Cite Share Download PDF Status: Published Journal Publication published 14 Apr, 2026 Read the published version in Bone Marrow Transplantation → Version 1 posted Editorial decision: revise 14 Nov, 2025 Review # 2 received at journal 13 Nov, 2025 Reviewer # 2 agreed at journal 28 Oct, 2025 Review # 1 received at journal 05 Oct, 2025 Reviewer # 1 agreed at journal 23 Sep, 2025 Reviewers invited by journal 23 Sep, 2025 Submission checks completed at journal 22 Sep, 2025 Editor assigned by journal 19 Sep, 2025 First submitted to journal 19 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7660052","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":519129559,"identity":"1f5748fc-e1dc-4700-832f-12c90bbeb67a","order_by":0,"name":"Claudia 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11:49:56","extension":"html","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":90803,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7660052/v1/ddc0fc06dcecd169716053e2.html"},{"id":92858038,"identity":"f63c54df-58eb-480a-a540-6285f38a0ae0","added_by":"auto","created_at":"2025-10-06 11:49:56","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":190410,"visible":true,"origin":"","legend":"\u003cp\u003eBusulfan exposition after the first dose in patients without and with deferasirox comedication, the latter divided into patients without and with initial busulfan dose reduction.\u003c/p\u003e","description":"","filename":"Figure1zugeschnitten.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7660052/v1/64ed2e36807b0c1808499cf6.jpg"},{"id":92858040,"identity":"4a0726bf-1d40-447c-884e-e6bbd6a7f64e","added_by":"auto","created_at":"2025-10-06 11:49:56","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":304121,"visible":true,"origin":"","legend":"\u003cp\u003eBusulfan clearance (CL) in patients with and without comedication with deferasirox.\u003c/p\u003e","description":"","filename":"Figure2zugeschnitten.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7660052/v1/091b8c17313951567fb4f41d.jpg"},{"id":92857172,"identity":"0c25a67a-3400-460e-b18d-a0e18ced6fd9","added_by":"auto","created_at":"2025-10-06 11:41:56","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":287327,"visible":true,"origin":"","legend":"\u003cp\u003eVolume of distribution (Vd) normal weight vs overweight patients (absolute Vd vs Vd/dosing weight)\u003c/p\u003e","description":"","filename":"Figure3zugeschnitten.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7660052/v1/3b633f6ca86312c64769ddc9.jpg"},{"id":92857170,"identity":"6a4506b7-b3b1-4918-9b73-509ce60c5040","added_by":"auto","created_at":"2025-10-06 11:41:56","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":215167,"visible":true,"origin":"","legend":"\u003cp\u003eRelative change in busulfan CL at day 2 in relation to day 1.\u003c/p\u003e","description":"","filename":"Figure4zugeschnitten.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7660052/v1/87d9a26a827f7d7e36a9e47d.jpg"},{"id":92858874,"identity":"92f56ec4-aa7d-4fb1-9909-cc681ee88365","added_by":"auto","created_at":"2025-10-06 11:57:56","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":240313,"visible":true,"origin":"","legend":"\u003cp\u003eRelative between-dose change of busulfan CL at day 2 in relation to day 1 in patients with and without comedication with deferasirox.\u003c/p\u003e","description":"","filename":"Figure5zugeschnitten.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7660052/v1/f98128519d809ac3960b14e6.jpg"},{"id":106948614,"identity":"d7ee3702-f270-4ae3-a834-53fbc29bffb9","added_by":"auto","created_at":"2026-04-15 07:06:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1696654,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7660052/v1/2deaffe5-5484-46e0-863e-7f6a420fd4f8.pdf"},{"id":92857165,"identity":"2e07d27e-88a3-423f-abf2-ce4c49da70a9","added_by":"auto","created_at":"2025-10-06 11:41:56","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11836,"visible":true,"origin":"","legend":"Table 1","description":"","filename":"Table1Patientcharacteristics.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7660052/v1/3e85b439a487d7553193d0ff.xlsx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Busulfan pharmacokinetics in adults – a real-world evaluation of intra-individual variabil-ity and the impact of obesity and deferasirox","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe alkylating agent busulfan (Bu) is often used as part of a conditioning therapy prior to an allogeneic hematopoietic stem cell transplant (allo-HSCT). It is known that Bu exhibits high variability between dose and exposure (area under the curve, AUC), even when administered intravenously.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eBecause of its narrow therapeutic index, over- or underexposure results in either toxic adverse effects and increased transplantation-related mortality or higher rates of graft rejection or relapse rates.\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e For this reason, about a decade ago, it was recommended to personalize busulfan dosing using a patient-individual therapeutic drug monitoring (TDM), especially in children and patients receiving myeloablative conditioning regimens.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e However, busulfan TDM is not widely established among European transplantation centers, despite wide use of busulfan.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e To increase the level of knowledge about the practical implementation of busulfan TDM and to overcome potential barriers to its introduction, European recommendations have recently been published.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eBusulfan is a small and highly lipophilic drug that crosses the blood brain barrier resulting in similar concentrations in plasma and cerebrospinal fluid. The volume of distribution (V\u003csub\u003ed\u003c/sub\u003e) ranges between 0.62 and 0.85 L/kg body weight in adult patients. It is extensively metabolized in the liver. The main step is spontaneous or glutathione-S-transferase (GST) derived conjugation with endogenous glutathione (GSH). Subsequent steps involve metabolism via the mercapturic acid pathway or dissociation and further oxidation steps or further binding with GSH.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Presumably none of the metabolites contributes significantly to efficacy or toxicity. Typical clearance (CL) for intravenous busulfan in adults is 0.2 L/h/kg, with a high \u003cem\u003einter\u003c/em\u003e-individual (between two different patients) variability in a range of up to 3-fold reported in large studies.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e In patients with obesity, CL best correlates with adjusted ideal body weight (AIBW).\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Therefore, the use of AIBW is recommended for dose calculation in patients with a body mass index of 25 kg/m² and above.\u003c/p\u003e\u003cp\u003eKnown clinically relevant drug-drug interactions with busulfan exist among others with acetaminophen, metronidazole, azoles, phenytoin or deferasirox resulting in subtherapeutic or supratherapeutic exposures.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eEspecially in children, significant but hardly predictable \u003cem\u003eintra\u003c/em\u003e-individual variability of busulfan’s pharmacokinetic parameters has been reported, with an overall decrease of busulfan CL between doses resulting in a risk of busulfan overexposure.\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Respective data for adults are sparsely available at present.\u003c/p\u003e\u003cp\u003eThe aim of this study is to analyze real-world busulfan TDM data in adults with special focus on overweight/obesity, comedication with deferasirox and \u003cem\u003eintra\u003c/em\u003e-individual changes of busulfan’s pharmacokinetic parameters.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003ePharmacokinetic data of adult patients treated with TDM-guided busulfan-based conditioning as part of standard care treatment prior to allo-HSCT in the Department of Stem Cell Transplantation at the University Medical Center Hamburg between September 2016 and November 2024 were retrospectively analyzed. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee.\u003c/p\u003e\u003cp\u003eBusulfan was administered intravenously over 3 hours with an initial dose of 3.2 mg/kg once daily. The basis for dose calculation was total body weight (TBW) for patients with a body mass index (BMI) ≤ 25 kg/m\u003csup\u003e2\u003c/sup\u003e, while AIBW25 - calculated as ideal body weight (IBW) plus 25% of the difference between total and IBW - was used for patients with BMI \u0026gt; 25 kg/m\u003csup\u003e2\u003c/sup\u003e. In the following, the respective reference weight is referred to as “dosing weight”. With this approach, we aimed for an average busulfan-AUC of 20 mg*h/L (± 10%) with initial dosing. Depending on the respective conditioning protocol and the intensity of conditioning - myeloablative (MAC) or reduced intensity (RIC) conditioning - two to four consecutive dosages were planned to achieve the desired cumulative target AUC between 40 and 80 mg*h/L. TDM was performed as part of standard of care on the first or second day of application and the busulfan dose was adjusted accordingly based on these results.\u003c/p\u003e\u003cp\u003eBusulfan plasma levels were drawn according to a local sampling schedule 5 minutes, 1, 2 and 3 hours after the end of busulfan infusion, whereas the exact infusion and sampling times were documented. Quantification was performed at the Department of Legal Medicine at the University Medical Center Hamburg-Eppendorf using a validated gas chromatography with mass spectrometric (GC-MS) detection method. Subsequently, model-based calculation of the AUC was carried out in the hospital pharmacy by means of Bayesian prediction using pharmacokinetics software (MW-Pharm, Version 3.60). If the calculated AUC was not within a target range of ± 10% of the target cumulative AUC, busulfan dose was adjusted accordingly. In cases of dose deviations \u0026gt; 25%, new busulfan concentration measurements and AUC calculations were carried out after the subsequent dose, and, if necessary, a repeated dose adjustment was made.\u003c/p\u003e\u003cp\u003eStandard supportive treatment included levetiracetam for seizure prophylaxis in all patients and deferasirox during conditioning in patients with a serum ferritin of \u0026gt; 1000 µg/L, while other drugs known to interact with busulfan (e.g. acetaminophen, metronidazole, azoles) were avoided.\u003c/p\u003e\u003cp\u003eThe statistical analysis was carried out using IBM SPSS Statistics software version 29. Discrete variables were expressed as counts (percentages), whereas continuous variables were expressed as median and range. For group comparisons of categorial variables, chi-square, or Fisher’s exact tests were used as appropriate. Continuous variables that were not normally distributed were analyzed using Mann-Whitney-U-Test. A p-value \u0026lt; 0.05 was defined as statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOverall, 287 patients (161 male, 56.1%) with a median age of 59.6 years (19.4\u0026ndash;77.7) were included. Basic characteristics of the patient cohort are shown in table 1.\u003c/p\u003e\u003cp\u003eInitial dosing of busulfan was 3.2 mg/kg\u003csub\u003edosing weight\u003c/sub\u003e once daily, calculated on TBW in 157 patients (54.7%) with BMI\u0026thinsp;\u0026le;\u0026thinsp;25 kg/m\u0026sup2; and on AIBW25 in 130 patients (45.3%) with BMI\u0026thinsp;\u0026gt;\u0026thinsp;25 kg/m\u0026sup2;. During conditioning, 99 patients (34.5%) received deferasirox, 60 of them with an initial dose reduction of busulfan to 75\u0026ndash;80%. TDM was performed at least twice in 138 patients (48%).\u003c/p\u003e\u003cp\u003eMedian calculated AUC after the first TDM was 17.1 mg*h/L with high \u003cem\u003einter\u003c/em\u003e-individual variability in busulfan-exposure (range: 9.6\u0026ndash;37.9) as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Overall, 59 patients (20.6%) reached the target-AUC (20 h*mg/L\u0026thinsp;\u0026plusmn;\u0026thinsp;10%) at the first TDM, while 165 patients (57.5%) needed a dose increase and 63 patients (22.0%) a dose reduction. There were no statistically significant differences in initial AUC or target attainment with regard to overweight/obesity (AUC: 17.5 [9.6\u0026ndash;37.9] vs. 16.8 [9.7\u0026ndash;32.4] h*mg/L). Concomitant deferasirox treatment resulted in significantly higher AUC at the first TDM (23.42 [14.26\u0026ndash;37.86] vs. 15.54 [9.57\u0026ndash;26.04, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001] mg*h/L), whereupon an initial dose reduction was implemented into the local conditioning protocols in 3/2023, resulting in more adequate median AUC-levels (20.25 mg*h (L [12.76\u0026ndash;35.63]).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOverall, busulfan CL was highly variable in the overall population with a median of 0.183 L/h/kg\u003csub\u003edosing\u0026minus;weight\u003c/sub\u003e and a range of 0.068 to 0.334, translating into a 4.89-fold \u003cem\u003einter\u003c/em\u003e-individual variability in CL. In patients receiving deferasirox, busulfan CL was 38% lower compared to patients without deferasirox comedication (0.127 L/kg\u003csub\u003edosing weight\u003c/sub\u003e [0.068\u0026ndash;0.223 vs. 0.204 [0.119\u0026ndash;0.334], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); absolute difference \u0026minus;\u0026thinsp;0.079 (95% CI: -0.088 to -0.069), translating into a 3.26 and 2.79-fold \u003cem\u003einter\u003c/em\u003e-individual variability, respectively (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No influence of overweight/obesity on busulfan CL was detectable.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn the overall population, median V\u003csub\u003ed\u003c/sub\u003e was 54.41 L (range: 21.19-101.19 L) and 0.77 L/kg\u003csub\u003edosing\u0026minus;weight\u003c/sub\u003e (range: 0.31\u0026ndash;1.36), with an \u003cem\u003einter\u003c/em\u003e-individual variability of 4.8- and 4.4-fold in V\u003csub\u003ed\u003c/sub\u003e, respectively, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Median V\u003csub\u003ed\u003c/sub\u003e was significantly higher in overweight/obese patients (60.09 [24.4\u0026ndash;99.9] vs 48.64L [21.19\u0026ndash;11.19]). When normalized to dosing weight, the difference still remained statistically significant, but the relative median difference accounted only for 7% (0.81L/kg\u003csub\u003edosing weight\u003c/sub\u003e [0.31\u0026ndash;1.10] vs 0.75 [0.39\u0026ndash;1.36], p\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eIntra\u003c/em\u003e-individual changes of pharmacokinetic parameters between day 1 and day 2 of busulfan amounted to less than 1.5% in median: CL (-0.65% [-41.72\u0026ndash;57.79]) or V\u003csub\u003ed\u003c/sub\u003e (-1.40% [-36.85-69.04]). However, clinically relevant changes in CL of more than \u0026plusmn;\u0026thinsp;10% between doses occurred in 32% of patients, with 21/108 patients (19%) showing a decrease in CL of at least 10% and 14/108 patients (13%) an increase in CL of at least 10% (see Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThese \u003cem\u003eintra\u003c/em\u003e-individual between-dose changes in CL were similar in patients with and without overweight/obesity. In patients with or without comedication with deferasirox, median \u003cem\u003eintra\u003c/em\u003e-individual changes in CL were below 4% in both groups (1.5% and 3.5%, respectively). However, we observed an increase in CL of more than 10% between day 1 and day 2 in more patients receiving deferasirox (26% vs 5%), and less frequently a decrease in CL of more than 10% (14% vs 23%) compared to patients not receiving deferasirox (see Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eIntra\u003c/em\u003e-individual changes of V\u003csub\u003ed\u003c/sub\u003e between doses 1 and 2 were similar in patients with and without overweight/obesity and with or without comedication with deferasirox.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe present real-world data on busulfan TDM in a large cohort of adult allo-HSCT patients. Target attainment without TDM would have been achieved in about 20% of patients using the standard dose, even when adjusted for overweight/obesity and comedication with deferasirox. The confirmed decrease in busulfan CL due to deferasirox can be compensated by an initial dose reduction of busulfan to 80%. High \u003cem\u003eintra\u003c/em\u003e- and \u003cem\u003einter\u003c/em\u003e-individual variability of both CL and V\u003csub\u003ed\u003c/sub\u003e was not different within subgroups of patients with either overweight/obesity or comedication with deferasirox. In contrast to some published data, no general decrease in CL after the first dose was observed, although relevant \u003cem\u003eintra\u003c/em\u003e-individual (between-dose) changes of PK parameters frequently occur.\u003c/p\u003e\u003cp\u003eTo avoid under- or overexposure caused by a high \u003cem\u003einter\u003c/em\u003e-individual variability of busulfan\u0026rsquo;s pharmacokinetic (PK) parameters, TDM - especially in children, for myeloablative conditioning or for regimes that were developed with PK-guided busulfan - is highly recommended.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e However, according to a European Survey, only 10\u0026ndash;20% of transplant centers regularly perform busulfan TDM.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e To overcome potential obstacles, a practical guidance on busulfan TDM including a step-by-step guide, was recently published and centers are encouraged to implement TDM for busulfan.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eUsing standard approved doses of busulfan, the majority of patients does not reach target exposure: about three out of five patients in our real-world analysis would have resulted in underexposure, while one out of five patients would have experienced overexposure, if no dose adjustment had been performed. This up to four-fold \u003cem\u003einter\u003c/em\u003e-individual variability between dose and exposure as well as the assymetrical distribution of busulfan exposure after the first dose are well known and is mainly explained by up to five-fold differences in drug CL.\u003csup\u003e1,12,14,20\u0026ndash;22\u003c/sup\u003e As expected, absolute V\u003csub\u003ed\u003c/sub\u003e is higher in overweight/obese patients, but if normalized to dosing weight (AIBW in patients with BMI\u0026thinsp;\u0026gt;\u0026thinsp;25 kg/m\u0026sup2;, otherwise TBW), these differences are less pronounced. This emphasizes the necessity of using adjusted weight measures for initial dosing, unless model-informed precision dosing (MIPD) is applied \u003cem\u003ea priori\u003c/em\u003e.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Consequently, median busulfan exposure after the first dose was similar in normal weight compared with overweight/obese patients. Furthermore, we could show, that the \u003cem\u003einter\u003c/em\u003e-individual variability of AUC, CL and V\u003csub\u003ed\u003c/sub\u003e was not different between the two weight groups.\u003c/p\u003e\u003cp\u003eIn a previous study, we demonstrated, that concomitant deferasirox significantly reduces busulfan CL by one third.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e We validated these findings in our current, even larger cohort of patients and could further show that an initial reduction to 75\u0026ndash;80% of the body weight-adapted busulfan dose leads to an excellent median target AUC attainment. Notably, similar \u003cem\u003einter\u003c/em\u003e-patient variability between dose and exposure is observed in this patient group, necessitating dose reductions or increases in around 40% of the patients, respectively.\u003c/p\u003e\u003cp\u003eData on \u003cem\u003eintra\u003c/em\u003e-individual changes in busulfan CL over time exist mainly for children using four-times daily dosing of busulfan: Marsit et al. described, that 80% of children experienced a decrease in busulfan CL, with a median change of -7.9% between day 1 and day 2, with high variability ranging from \u0026minus;\u0026thinsp;48.5 to +\u0026thinsp;44%. Over day 1 to day 3 mean CL significantly decreased by 15%.\u003csup\u003e17\u003c/sup\u003e In patients from 0.1 to 26 years, Bartelink et al. detected a 12% higher busulfan CL on the first day compared to subsequent days.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e In a cohort of 58 pediatric and young adult patients, a decrease of busulfan CL of approximately 15% between first dose and steady-state dose PK sampling was detected by Long-Boyle et al..\u003csup\u003e19\u003c/sup\u003e McCune et al. observed a slight decrease in busulfan CL over time and that children under four years of age have lower busulfan CL than adults.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eUsing a semi-mechanistic model, Langenhorst et al. observed an overall decrease of 7% in busulfan CL with a range of -82 to +\u0026thinsp;44% in children and adults. Interestingly, there was an association between older age (\u0026gt;\u0026thinsp;40 years) and a stronger time-dependent effect that increased by 4% per year of age. It has been suggested, that this effect may be related to glutathione depletion.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e On the other hand, McCune et al. described only minimal alterations of busulfan CL between doses of i.v. busulfan, with 71.4% of patients having\u0026thinsp;\u0026lt;\u0026thinsp;10% change between doses 1 and 2.\u003csup\u003e1\u003c/sup\u003e Similar observations were described by Protzenko et al. with no general difference in busulfan CL between the first and the last dose, but marked changes of at least 20% in one third of the patients.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e A recent publication by Bognar et al. analyzed changes in busulfan CL between day 1 and day 4 in 161 adult patients. They observed a considerable variance in clearance with 78.5% showing a decrease in busulfan CL (median decrease: 3.6%) and 21.5% showing an increase (median increase: 1.6%).\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIn contrast, our results show no overall decrease in busulfan CL in adult patients receiving once daily intravenous busulfan. The median difference on an individual patient basis between day 1 and day 2 was \u0026minus;\u0026thinsp;0.65% and the proportions of patients exhibiting changes of less than \u0026plusmn;\u0026thinsp;10% accounts for 68%. However, one third of patients experience relevant differences in busulfan CL between doses of more than 10% that range from \u0026minus;\u0026thinsp;42 to +\u0026thinsp;58%, reflecting the high variability also reported in other studies.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eOne limitation of our study is that it is a single-center study. On the other hand, the standardized procedure for the application, blood level measurements and performance of the TDM offers advantages. Our center regularly participates successfully in the Busulfan-TDM interlaboratory proficiency testings.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e In our center, busulfan TDM is performed as part of routine care on the first day of busulfan administration and on subsequent days only if dose deviations of more than 25% are required. This could theoretically result in a bias when analyzing the change in PK parameters. However, due to the high number of patients analyzed here, this appears to be negligible. Since only very few patients required TDM on day 3 (n\u0026thinsp;=\u0026thinsp;13) or day 4 (n\u0026thinsp;=\u0026thinsp;1), we cannot make reliable statements as to whether clearance in patients may change over time. However, other studies also described changes in clearance between only day 1 and day 2.\u003csup\u003e1,17,18\u003c/sup\u003e Furthermore, we have no data on GST polymorphisms for which a possible influence on busulfan CL is discussed.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIn conclusion, with our real-world data we confirm the high variability of the pharmacokinetic parameters of busulfan administered intravenously once daily. This occurs both between different patients (\u003cem\u003einter\u003c/em\u003e-individual) and between doses within a patient (\u003cem\u003eintra\u003c/em\u003e-individual). The decreased busulfan CL caused by deferasirox, can be compensated by an initial busulfan dose reduction to 75\u0026ndash;80%, whereby similar \u003cem\u003einter\u003c/em\u003e- or \u003cem\u003eintra\u003c/em\u003e-individual variability of pharmacokinetic parameters need to be considered. TDM of busulfan is therefore highly recommended to ensure target attainment and optimal clinical outcome.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting Interests:\u003c/h2\u003e\u003cp\u003eThe authors declare no competing financial interests\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contributions\u003c/h2\u003e\u003cp\u003eCL performed the busulfan TDM,wrote the manuscript, designed the study and interpreted the data. AD performed the busulfan TDM, interpreted the data and edited the manuscript. EMW interpreted the data and edited the manuscript. DJ, CW, CL, FA and NMK reviewed the manuscript and provided clinical data. All authors approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability Statement\u003c/h2\u003e\u003cp\u003eData are available upon data-specific request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMcCune, J. S. \u0026amp; Holmberg, L. A. 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S. \u003cem\u003eet al.\u003c/em\u003e Quality Control of Busulfan Plasma Quantitation, Modeling, and Dosing: An Interlaboratory Proficiency Testing Program. \u003cem\u003eTher Drug Monit\u003c/em\u003e 43, 657\u0026ndash;663 (2021). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.1097/FTD.0000000000000862\u003c/span\u003e\u003cspan address=\"https://doi.org:10.1097/FTD.0000000000000862\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAnsari, M. \u003cem\u003eet al.\u003c/em\u003e GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study. \u003cem\u003eOncotarget\u003c/em\u003e 8, 90852\u0026ndash;90867 (2017). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.18632/oncotarget.20310\u003c/span\u003e\u003cspan address=\"https://doi.org:10.18632/oncotarget.20310\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Busulfan, Therapeutic drug monitoring, Hematopoietic stem cell transplantation","lastPublishedDoi":"10.21203/rs.3.rs-7660052/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7660052/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTo avoid under- or overexposure caused by a high variability of busulfan\u0026rsquo;s pharmacokinetic parameters, therapeutic drug monitoring (TDM) is highly recommended. Nevertheless, it is not widely used in European transplant centers. We retrospectively analyzed real-world busulfan TDM data in adults in our center between 9/2016 and 11/2024 with special focus on overweight/obesity and comedication with deferasirox.\u003c/p\u003e\u003cp\u003eOverall 287 patients (161 male/126 female), median age 59.6 years (19.4\u0026ndash;77.7) were included. Median calculated AUC after the first TDM was 17.1 mg*h/L with high interindividual variability (range: 9.6\u0026ndash;37.9). Target attainment without TDM would only have been achieved in 59 patients (20.6%) using the standard dose, even if adjusted for overweight/obesity and comedication with deferasirox. Busulfan clearance (CL) was significantly reduced in patients receiving deferasirox (0.13 L/kg\u003csub\u003edosing weight\u003c/sub\u003e [0.07\u0026ndash;0.22] vs 0.20 [0.12\u0026ndash;0.33], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while no influence of body weight was detectable. Overall, there were no \u003cem\u003eIntra\u003c/em\u003e-individual changes in both CL (-0.65% [-41.72\u0026ndash;57.79]) and V\u003csub\u003ed\u003c/sub\u003e (-1.40% [-36.85\u0026ndash;69.04) between doses. However, in one third of patients relevant deviations were observed, regardless of either body weight or comedication with deferasirox. In contrast to some published data, no general decrease in CL over time was observed.\u003c/p\u003e","manuscriptTitle":"Busulfan pharmacokinetics in adults – a real-world evaluation of intra-individual variabil-ity and the impact of obesity and deferasirox","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-06 11:41:51","doi":"10.21203/rs.3.rs-7660052/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-11-14T15:16:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-11-13T22:24:42+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-10-28T11:18:28+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-10-05T08:04:44+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-23T06:28:12+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-09-23T05:10:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-22T11:11:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-19T15:36:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Marrow Transplantation","date":"2025-09-19T15:36:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b87b9523-2459-4ea5-b254-db321767245d","owner":[],"postedDate":"October 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":55162868,"name":"Health sciences/Medical research/Translational research"},{"id":55162869,"name":"Health sciences/Medical research/Preclinical research"}],"tags":[],"updatedAt":"2026-04-15T07:05:56+00:00","versionOfRecord":{"articleIdentity":"rs-7660052","link":"https://doi.org/10.1038/s41409-026-02833-0","journal":{"identity":"bone-marrow-transplantation","isVorOnly":false,"title":"Bone Marrow Transplantation"},"publishedOn":"2026-04-14 04:00:00","publishedOnDateReadable":"April 14th, 2026"},"versionCreatedAt":"2025-10-06 11:41:51","video":"","vorDoi":"10.1038/s41409-026-02833-0","vorDoiUrl":"https://doi.org/10.1038/s41409-026-02833-0","workflowStages":[]},"version":"v1","identity":"rs-7660052","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7660052","identity":"rs-7660052","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}