Population pharmacokinetics of busulfan in pediatric patients: Optimization of a four-times-daily dosing regimen based on EBMT recommendations

Population pharmacokinetics of busulfan in pediatric patients: Optimization of a four-times-daily dosing regimen based on EBMT recommendations | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Blood & Cancer This is a preprint and has not been peer reviewed. Data may be preliminary. 13 June 2025 V1 Latest version Share on Population pharmacokinetics of busulfan in pediatric patients: Optimization of a four-times-daily dosing regimen based on EBMT recommendations Authors : Zeyuan He 0009-0000-1709-9631 , Ying Wang , Hua Zhu , Yuqing Chen , Chen Ye , Jiebin Ou , Junyan wu 0000-0003-0870-382X , and Xiaoxia Yu [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174982167.76776085/v1 Published Pediatric Blood & Cancer Version of record Peer review timeline 396 views 190 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background The European Society for Blood and Marrow Transplantation (EBMT) recommends a busulfan target cumulative area under the curve (cAUC) of 78-101 mg·h/L for hematopoietic stem cell transplantation (HSCT). Currently, no population pharmacokinetic (PopPK)-optimized four-times-daily (Q6H) regimen reliably achieves this range. We developed a PopPK-guided dosing protocol to address this gap. Methods Clinical and demographic data from pediatric HSCT recipients receiving busulfan were retrospectively analyzed to develop a PopPK model. Bayesian estimation identified the optimal busulfan dose (0.50-1.25 mg/kg/dose) for target attainment in pediatric patients (age 0.5-18 years; weight 5-80 kg). Finally, the proposed dosing strategy was validated using an independent retrospective cohort. Results The PopPK model was developed using data from 65 pediatric patients. Age and body weight identified as significant covariates. Optimized dosing recommendations for the Q6H × 4 days busulfan regimen were established through Bayesian estimation. For validation, two cohorts were retrospectively analyzed: (1) weight-based dosing (n=19) and (2) model-informed dosing (n=15). The groups demonstrated comparable distributions in both age ( p =0.78) and weight ( p =0.63). Notably, the model-informed group achieved significantly higher cAUC values (mean difference, 18.0 mg·h/L; 95% confidence interval, 9.83-26.1 mg·h/L; p < .001), with 67% of these patients reaching the target exposure range. Conclusion We developed a Q6H × 4 days busulfan dosing regimen through PopPK modeling. For a representative 6-year-old patient with a body weight of 20 kg, the recommended dose is 1.25 mg/kg/dose. Therapeutic drug monitoring following the initial dose remains clinically essential. 1 INTRODUCTION Busulfan is essential in pediatric hematopoietic stem cell transplantation (HSCT) conditioning regimens [1] . Historically, busulfan dosing was guided by the area under the curve (AUC) after a single dose, with target ranges of 900–1350 µM·min [2] or 900–1500 µM·min [3] for efficacy and toxicity assessment. However, The European Society for Blood and Marrow Transplantation (EBMT) now defines the therapeutic window in pediatric patients as a cumulative AUC (cAUC) of 78–101 mg·h/L [4] , which defines the therapeutic window in pediatric patients and is strongly associated with improved clinical outcomes in pediatric HSCT recipients. These outcomes include higher overall survival, reduced incidence of graft-versus-host disease, lower risks of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), decreased transplant failure, and lower relapse rates. Busulfan’s narrow therapeutic window and significant pharmacokinetic variability necessitate precise dosing strategies to minimize treatment failure risks and reduce frequent dose adjustments in clinical practice. Population pharmacokinetic (PopPK) modeling offers a robust approach to optimize busulfan dosing regimens by improving the probability of achieving target AUC exposure, thereby reducing the need for repeated dose modifications. Early studies by Booth et al. [5] proposed weight-tiered busulfan dosing (1.1 mg/kg for ≤12 kg; 0.8 mg/kg for >12 kg) targeting an AUC 0–6 of 900–1350 µM·min. Subsequent work by Nguyen et al. [2] and Poinsignon et al. [6] refined these weight categories but retained the same AUC targets, now recognized as inferior to the EBMT’s cAUC-based standard for pediatric HSCT [7] . Substantial differences exist between dosing regimens required to achieve the conventional AUC targets versus the EBMT-recommended cAUC ranges. Bartelink et al. [8] developed a once-daily dosing regimen through pharmacokinetic modeling targeting 90 mg·h/L. However, in clinical practice, four-times-daily (Q6H) dosing remains widely used [9, 10] , and the once-daily regimen cannot be directly extrapolated to Q6H schedules due to fundamental pharmacokinetic differences between these administration frequencies [11, 12] . To date, no pharmacokinetic study has established a Q6H, 4-day busulfan dosing protocol that consistently achieves the therapeutic window of 78–101 mg·h/L. Moreover, most conventional dosing schemes consider only body weight as a covariate [13-15] , neglecting other critical factors such as age—a well-documented determinant of busulfan metabolism and a key contributor to its interindividual variability [16] . This retrospective pediatric PopPK analysis aims to develop a clinically actionable, Q6H busulfan dosing regimen achieving the cAUC target through Bayesian model-informed precision dosing. We anticipate that this optimized regimen will result in improved cAUC target attainment with the first dose. 2 METHODS 2.1 Patient Selection This study retrospectively enrolled pediatric HSCT recipients treated at Sun Yat-sen Memorial Hospital. Patients aged >18 years or lacking AUC sampling data were excluded. All patients received intravenous busulfan every 6 hours for 4 days (total 16 doses) as conditioning. This study was granted exemption from informed consent by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (SYSKY-2022-439-01), in accordance with the Declaration of Helsinki, as it does not involve personal privacy or commercial interests. 2.2 Data Collection The blood concentration data included in this study were all derived from the therapeutic drug monitoring (TDM) data in the laboratory. Blood samples collected at 1, 2, 2.5, 3, 4, and 6 hours post-infusion were analyzed via HPLC-MS. Phoenix NLME™ (v7.0, Certara, USA) was used for AUC estimation using non-compartmental analysis. Furthermore, retrospective collection was performed on laboratory testing results, demographic profiles, and concurrent medication records for patients. Including gender, age, weight, disease diagnosis, transplant type, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), creatinine clearance (CLcr), albumin (ALB). Concomitant medications included phenytoin and acetaminophen, both reported to potentially alter busulfan pharmacokinetics through metabolic interactions [17] . 2.3 Model Development The concentration-time data for busulfan were analyzed by the non-linear mixing method of Phoenix NLME™ software and modeled by first-order conditional estimation with interaction ( FOCE-I ). With -2 log likelihood (-2LL) and goodness-of-fit (GOF) as references, a suitable one or two compartment model was selected. Between-subject variability is evaluated using exponential equation. -2LL and GOF are also used as references to investigate additive, proportional, or mixed (additive and proportional) respectively, and select a suitable model to describe residual error. 2.4 Covariate Analysis The preliminary covariates were screened using stepwise regression, including forward inclusion followed by backward elimination. Each potential covariate was first individually incorporated into the base model through forward inclusion, with a retention criterion defined as a decrease in the objective function value (OFV) greater than 6.64 ( p <0.01). A full model was then built by including all retained covariates, followed by backward elimination based on sequential removal of variables, where an OFV increase of less than 10.83 ( p <0.001) was used as the elimination threshold. 2.5 Model Qualification The model’s GOF was comprehensively evaluated through graphical and numerical assessments. Graphical evaluations included conditional weighted residuals versus time plots, observed versus individual/population predicted concentration plots, and visual inspection of data distribution patterns and fitting trends. For numerical validation, we performed a 1000-replicate nonparametric bootstrap analysis with 95% confidence intervals to verify parameter stability and model robustness. Additionally, prediction-corrected visual predictive checks (pcVPC) were conducted by simulating 1000 datasets from the final model, incorporating population typical values, inter-individual variability, and residual variability. The 5th, 50th, and 95th percentiles of both observed and simulated data were calculated and compared to assess predictive performance. 2.6 Simulation The dose recommendations were established by bayesian estimation of the model. GraphPad Prism (version 8.2.1, Windows edition, San Diego) was employed for conducting graphical analyses. Based on collected patient information and physiological characteristics specific to pediatric patients [18, 19], the age range was set from 0.5 to 18 years old, while the weight range spanned from 5 to 80 kg. The simulated doses ranged from 0.50 to 1.25 mg/kg/dose with an increment of 0.05 mg/kg/dose [8]. For each dosing regimen, we performed 1000 simulations to estimate the cAUC following 16 administrations. The targeted cAUC range is 78–101 mg·h/L. The simulation results were compiled into simplified heatmaps. We subsequently conducted a retrospective comparison of cAUC values achieved by two dosing strategies: (1) conventional weight-based dosing ( Supplementary Table 1 ) [2] and (2) model-informed regimens, with both treatment courses completed prior to pharmacokinetic modeling. Bayesian estimation was employed to assess drug exposure for both approaches. 3 RESULTS 3.1 Participants’ Characteristics This PopPK model retrospectively included 65 pediatric HSCT patients at Sun Yat-sen Memorial Hospital from November 2020 to June 2025. β -thalassemia was diagnosed in 49.2% of the patients and 72.3% patients received an unrelated donor transplant. A total of 390 specimens were collected for modeling purposes. The patient characteristics are shown in Table 1 . To evaluate the clinical applicability of our optimized dosing regimen, we retrospectively analyzed 15 historical patients whose actual doses matched our model-recommended ranges and 19 contemporaneous patients receiving conventional weight-based dosing. 3.2 Pharmacokinetic Modeling The pharmacokinetic data were interpreted by a one-compartment model. First-order conditional estimation method with extended least squares method and additive were selected to account for PopPK typical values and inter-individual variability. The GOF diagram of the model is shown in Supplementary Figure 1 , showing that both the experimentally observed and model-predicted concentrations exhibit acceptable agreement remaining within ±2 standard deviations of the conditional weighted residuals.In the first covariates screening process, incorporating weight into volume of distribution (Vd) resulted in an OFV decrease of 112.8 ( p <0.05). In the second screening, adding age to clearance led to an OFV reduction of 38.9 ( p <0.05). Weight and age are eventually included as covariates as their removal leads to an increase in the OFV by more than 10.83 ( p The final model parameters are shown in Table 2 . The clearance, Vd, and lag time (Tlag) describing the PopPK model are shown by formulas 1 , 2 and 3 . \(\text{Vd\ }\text{(L)}\text{=}\text{14.97}\text{×}{\text{(}\frac{\text{WT}}{\text{20}}\text{)}}^{\text{0.87}}\text{×}\text{exp}\text{\ (0.02)}\) (2) Tlag (h)=0.38×exp (0.54) (3) Where CL is clearance, Vd is volume of distribution, WT is weight, and Tlag is lag time. 3.3 Model Qualification A non-parametric bootstrap (n = 1000) was applied to validate the robustness of the final model, with successful convergence percentage was 100%. The median and 95% CI of the bootstrap parameters are shown in Table 2 . The pcVPC of the final model are shown in Supplementary Figure 2 . Based on the pcVPC, most of measured concentrations fall within 90% confidence intervals of the model. 3.4 Formulation of Dosage Recommendation Bayesian estimators were employed to simulate busulfan dosing regimens for varying age-weight groups, the resulting simulated cAUC data were processed and analyzed. For patients of the same age (excluding 0.5-year-olds), the recommended dose decreases with increasing weight, while for patients of the same weight, the recommended dose increases with age. The simulated cAUC values for the typical patients are presented in Figure 1 . For 20 kg children, the optimal dose increases with age: 1.15 mg/kg at 3 years versus 1.25 mg/kg at 6 years to achieve target cAUC. Select the dosing regimen that optimizes the cAUC to remain within the 78–101 mg·h/L range. The recommended intravenous dosage of busulfan for HSCT pediatric patients is shown in Figure 2 . 3.5 Verification of Recommended Dosage We retrospectively identified 19 pediatric HSCT patients receiving conventional weight-based dosing and 15 historical patients whose actual pre-modeling doses matched our subsequently developed model recommendations ( Table 3 ). The age distributions were similar between weight-based (median 8 years, interquartile range [IQR] 6-11 years) and model-informed (median 9 years, IQR 3.50-11.5 years) groups ( p =0.78; α =0.05, 2-tailed Mann-Whitney test). Body weights were comparable between weight-based (median 22.1 kg, IQR 20.7-27.7 kg) and model-informed (median 29.2 kg, IQR 15.8-42.8) dosing groups ( p =0.63; α =0.05, 2-tailed Mann-Whitney test). There was a significant difference in cAUC between the two groups (mean difference, 18.0 mg·h/L; 95% confidence interval [CI], 9.83-26.1 mg·h/L; p dosing achieved the target cAUC after the initial dose, necessitating dose adjustments in the majority. In contrast, model-informed precision dosing enabled 67% of patients to attain therapeutic exposure levels ( Figure 3 ). 4 Discussion Using PopPK modeling, we developed an age- and weight-guided dosing regimen for intravenous busulfan administered Q6H over 4 days (16 doses). Compared to conventional protocols targeting single-dose AUC of 900-1350 μM·min, our dosing regimen targets the EBMT-recommended cAUC range of 78–101 mg·h/L, which corresponds to a per-dose AUC range of 1225-1575 μM·min for the 16-dose regimen [7] . This necessitates systematically higher doses compared to conventional protocols. Our model-derived dosing recommendations demonstrate a biphasic relationship with body weight: doses initially increase until peaking at 9 kg, then gradually decrease with further weight gain. This pattern aligns with established findings from Nguyen et al. [2] and Bartelink et al [20] . Dose recommendations increased progressively with patient age, reflecting the well-characterized developmental enhancement of busulfan clearance in children [21-23] . This pharmacokinetic maturation necessitated higher doses to achieve target exposure. Our simulations illustrated this phenomenon in 20 kg patients: optimal exposure required 1.15 mg/kg/dose at age 3 years versus 1.25 mg/kg/dose at age 6 years. Conventional weight-based dosing regimens may lead to excessive AUC exposure in obese children and subtherapeutic exposure in underweight children [24] . In contrast, our model-informed dosing strategy accounts for interindividual clearance variability among children with identical body weights, thereby optimizing target attainment. In the retrospective validation of model simulations, the two groups showed no statistically significant differences in the key dosing determinants of age and weight distribution. Among the 15 patients receiving model-aligned dosing, 10 (67%) achieved the target cAUC range (78–101 mg·h/L), compared to only 4 of 19 (21%) in the weight-based group. This difference underscores the substantial discordance between conventional AUC targets (900–1350 μM·min) and the EBMT-recommended cAUC exposure. Based on conventional dosing regimens, it is evidently challenging to achieve the novel exposure targets. These findings suggest that the traditional dosage protocols may require adjustment when following EBMT recommendations. Busulfan’s autoinduction and interpatient variability complicate dose adjustment and steady-state AUC prediction [14] . Validated PopPK modeling of initial-dose AUC [5, 25, 26] enables targeted exposure through guided dose optimization. The primary objective of model-based dosing is first-dose target attainment to minimize regimen changes. As dose modifications necessitate additional blood draws for TDM - increasing distress in children and resource utilization - our findings show model-informed busulfan dosing improves first-dose accuracy while maintaining need for individualized adjustments in selected cases. Despite standard ursodeoxycholic acid prophylaxis for VOD prevention prior to busulfan therapy [27] , we observed 6 VOD cases (6%) among 99 pediatric patients. Notably, 4 of 6 VOD cases (including 2 mild and 2 severe cases) exhibited subtherapeutic cAUC levels (<101 mg·h/L), challenging the conventional dose-toxicity paradigm [28] . This aligns with reports of VOD at low exposures [29] . Our data suggest low-cAUC VOD may be underrecognized in clinical practice. While our model considered both age and body weight as covariates, no additional significant variables were identified. A notable limitation was the absence of glutathione S-transferase (GST) genotyping data, which has been established to significantly influence busulfan pharmacokinetics [30, 31] . In clinical practice, routine GST polymorphism testing remains uncommon due to cost and implementation barriers, potentially introducing unaccounted variability into our model. An additional limitation is that our model validation relied on retrospective data, and the number of analyzable cases was inherently limited. Prospective randomized trials are needed to systematically evaluate the target attainment rate of this dosing protocol. 5 Conclusion We established a PopPK model-based dosing regimen for pediatric HSCT recipients, featuring weight- and age-based adjustments with Q6H dosing over four days to maintain cAUC within the therapeutic window (78–101 mg·h/L). For a 6-year-old child weighing 20 kg, the proposed dose is 1.25 mg/kg/dose. TDM after the first dose is strongly advised. While this study provides a substantive basis for busulfan dosing optimization, further prospective studies are warranted to validate its clinical utility. Acknowledgements We are thankful to all nurses in department of Pediatric ( Blood and Marrow Transplantation) for their assistance. Conflicts of interest The authors declare that they have no conflicts of interest to disclose. Author contributions All authors participated in designing and commenting on earlier versions of the paper and read and approved the final version. Funding This work is funded by the Guangdong Provincial Hospital Association Pharmaceutical Research Foundation (China, 2022YXKY03). Ethics approval This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (SYSKY-2022-439-01). References 1. Aschan, J., Risk assessment in haematopoietic stem cell transplantation: conditioning. Best Pract Res Clin Haematol, 2007. 20 (2): p. 295-310.2. Nguyen, L., et al., I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant, 2004. 33 (10): p. 979-87.3. 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Yin, J., et al., Once-daily i.v. BU-based conditioning regimen before allogeneic hematopoietic SCT: a study of influence of GST gene polymorphisms on BU pharmacokinetics and clinical outcomes in Chinese patients. Bone Marrow Transplant, 2015. 50 (5): p. 696-705.31. Ansari, M., et al., Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients. Bone Marrow Transplant, 2016. 51 (3): p. 377-83. Figure 1 Box plots of the simulated cAUC for a typical patients (aged 3 and 6 with a body weight of 20 kg) with different doses. The dashed line indicates the 78–101 mg·h/L therapeutic target range.The horizontal bars in the middle are the median values and the whiskers represent the 90% percentiles of AUC. Figure 2 Recommended IV busulfan dosing regimen (16 doses) targeting cAUC 78–101 mg·h/L in pediatric HSCT patients. Figure 3 Impact of dosing regimens on busulfan cumulative AUC in pediatric patients. Horizontal thick bars represent group means, with error bars denoting ±1 SD. The dashed line indicates the 78–101 mg·h/L therapeutic target range. Supplementary Material File (table 1.docx) Download 17.49 KB File (table 2.docx) Download 17.85 KB File (table 3.docx) Download 17.46 KB Information & Authors Information Version history V1 Version 1 13 June 2025 Peer review timeline Published Pediatric Blood & Cancer Version of Record 8 Aug 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Blood & Cancer Keywords pediatric hematology/oncology pharmacokinetics pharmacology stem cell transplantation Authors Affiliations Zeyuan He 0009-0000-1709-9631 Sun Yat-Sen Memorial Hospital View all articles by this author Ying Wang Sun Yat-Sen Memorial Hospital View all articles by this author Hua Zhu Sun Yat-Sen Memorial Hospital View all articles by this author Yuqing Chen Sun Yat-Sen Memorial Hospital View all articles by this author Chen Ye Sun Yat-Sen Memorial Hospital View all articles by this author Jiebin Ou Sun Yat-Sen Memorial Hospital View all articles by this author Junyan wu 0000-0003-0870-382X Sun Yat-Sen Memorial Hospital View all articles by this author Xiaoxia Yu [email protected] Sun Yat-Sen Memorial Hospital View all articles by this author Metrics & Citations Metrics Article Usage 396 views 190 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Zeyuan He, Ying Wang, Hua Zhu, et al. Population pharmacokinetics of busulfan in pediatric patients: Optimization of a four-times-daily dosing regimen based on EBMT recommendations. Authorea . 13 June 2025. DOI: https://doi.org/10.22541/au.174982167.76776085/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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