1Pharmacy Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, 2Department of Clinical Epidemiology and
Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 3Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
*Corresponding author: Cholada Ratanatharathorn E-mail: cholada.rat@mahidol.ac.th
Received 1 April 2025 Revised 1 July 2025 Accepted 1 July 2025 ORCID ID:http://orcid.org/0009-0005-4962-8418 https://doi.org/10.33192/smj.v77i8.274573
All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.
ABSTRACT
Results: The study comprised 26 children. Dose adjustments for busulfan were performed in 17 patients (65.4%). Individual average AUCs ranged from 2,566.2 to 6,943.05 µMolar·min. Patients under 10 years had a higher likelihood of an out-of-range target AUC following dose adjustment compared to those aged ≥ 10 years (43.8% and 0%, respectively; P=0.023). A lower-than-target average AUC was significantly related to an earlier disease relapse compared to non-lower range AUCs (P<0.005). Conversely, higher AUCs did not correlate with busulfan-related side effects or treatment-related mortality.
AUC Area under the time curve
AUC1 First day of area under the time curve
EMA European Medicines Agency
GST Glutathione S-transferase
HSCT Hematopoietic stem cell transplantation
TDM Therapeutic drug monitoring
INTRODUCTION
Busulfan, an alkylating agent with a narrow therapeutic index, is widely used in conditioning regimens for pediatric hematopoietic stem cell transplantation (HSCT) conditioning regimens in both malignant and nonmalignant diseases.1 Intravenous administration of busulfan is preferred over oral forms due to reduced intrapatient pharmacokinetic variability from gastrointestinal absorption.2 A lower area under the time curve (AUC), specifically under 950 µMolar·min for every-6-hour intravenous busulfan, increases the risk of disease relapse post-transplantation. Conversely, an AUC exceeding 1,500 µMolar·min is associated with heightened mucositis and veno-occlusive disease/sinusoidal obstructive syndrome, which may escalate to life-threatening conditions.3
The American Society for Blood and Marrow Transplantation guidelines recommend therapeutic drug monitoring (TDM) and personalized dose adjustments
of busulfan within myeloablative conditioning regimens. Achieving target AUC enhances treatment efficacy, reduces side effects, and lowers treatment-related mortality.1 Studies in Europe, Japan, and Thailand administered busulfan intravenously every 6 hours using five fixed weight-based dosages initially, as recommended by the European Medicines Agency (EMA)4, without subsequent dose modification. The percentage of patients achieving target AUC was 75%, 76%, and 42.86%, respectively, across these geographical regions.5-7
The escalating number of transplantation centers in Thailand presents a growing challenge regarding the implementation of TDM for busulfan. Despite global recommendations advocating its use, many transplant centers lack the capacity to perform TDM, highlighting a critical need to optimize busulfan dosing strategies within the Thai population. Research by Jansing et al in Thailand indicated that Thai pediatric patients exhibit a
lower rate of achieving target AUC compared to other studies, suggesting a need for personalized busulfan dosing in this population.7 The traditional schedule of intravenous busulfan administration every 6 hours has been modified to a once-daily regimen. This change enhances convenience without altering pharmacological characteristics, therapeutic efficacy, or side effects.8,9 The optimal target AUC0-24 for once-daily intravenous busulfan is 3,600-6,000 µMolar·min. This range aims to avoid under or over-exposure to prevent disease relapse, improve overall survival, minimize toxicity, and reduce treatment-related mortality risks.1,10
The primary objective of this study was to determine the proportion of patients requiring dose adjustments and the frequency of those adjustments needed to achieve the target AUC, with the secondary objective of observed time to relapse, toxicity, mortality and the relationship between AUC and clinical outcomes.
MATERIALS AND METHODS
Study design and population
This retrospective study included patients under 18 years old who underwent HSCT with a once-daily intravenous busulfan conditioning regimen at the Pediatric Department, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand, from October 2020 to April 2024. Ethical approval was granted by the Mahidol University Multi-Faculty Cooperative IRB Review (MU-MOU 305/2567 [IRB2]). Informed consent was waived for this retrospective analysis.
Conditioning regimen and supportive care
Busulfan-containing myeloablative conditioning regimens varied based on HSCT type and disease, as detailed in Supplementary data (Table S1). Initial busulfan dosing followed the EMA nomogram’s five fixed-dose model4 : 4 mg/kg/day for patients under 9 kg, 4.8 mg/ kg/day for those 9-16 kg, 4.4 mg/kg/day for 16-23 kg,
3.8 mg/kg/day for 23-34 kg, and 3.2 mg/kg/day for those over 34 kg. Busulfan was administered for 3-4 days, depending on the specific regimen. Busulfan was further
diluted with normal saline to a final concentration of
count exceeded 1,000/cumm. Veno-occlusive disease/ sinusoidal obstructive syndrome prophylaxis used ursodeoxycholic acid at 20 mg/kg/day, divided into two doses, starting with the conditioning regimen and continuing for 14-30 days.
Antifungal prophylaxis used itraconazole at 5 mg/ kg/day twice daily from day+1 to day+100. Patients with a prior fungal infection before HSCT received management based on the specific infection. Acyclovir, dosed at 250 mg/m2/dose intravenously every 8-12 hours, was used in herpes simplex virus seropositive patients from day+1 until engraftment. For Pneumocystis jirovecii pneumonia prophylaxis, sulfamethoxazole/trimethoprim was administered at 5 mg/kg/day of trimethoprim three times per week after engraftment.
Busulfan TDM
Blood samples were collected for at least 2 days, using sodium heparin tubes, during once-daily intravenous busulfan administration to analyze pharmacokinetics and calculate the AUC. The plasma concentration of busulfan was mainly determined using gas chromatography- mass spectrometry11, but liquid chromatography-mass spectrometry was also utilized. Both methods underwent internal validation by the Siriraj Poison Control Center, focusing on selectivity, accuracy, precision, stability, and linearity across a calibration range of 50-12,000 ng/ml (r2 > 0.995).
On the first day, blood samples were collected at six time points1: immediately after finishing the busulfan administration, and then at 15 minutes, 1 hour, 2 hours, 3 hours, and 5 hours post-administration. The AUC of busulfan was calculated using the trapezoidal method. If the AUC0-24 did not fall within the recommended range (3,600-6,000 µMolar·min), or as determined by the physician, dose adjustments were made using equation
(a) shown below. On the subsequent day, samples were collected before starting the infusion, immediately after completing the administration, and at 15 minutes, 1 hour, 3 hours, and 5 hours afterward. Daily blood sample collection continued until the target AUC was achieved.
approximately 0.5 mg/ml and infused intravenously over a 3-hour period once daily.
Levetiracetam was provided for seizure prophylaxis at 10 mg/kg/dose every 12 hours, starting 12 hours
Personalized dose = (Administered dose x target AUC)
AUC0-24
(a)
before busulfan infusion and continuing until 48 hours post-infusion. Graft-versus-host disease prophylaxis varied by HSCT type and conditioning regimen (Table S1). Filgrastim, at 5-10 mg/kg/day, was administered intravenously from day+1 until the absolute neutrophil
Busulfan-related side effects and treatment-related mortality were monitored for 100 days post-transplantation. Hepatic veno-occlusive disease/sinusoidal obstructive syndrome was diagnosed according to the Baltimore criteria, which include hyperbilirubinemia ≥2 mg/dL
combined with at least two of the following findings: hepatomegaly, ascites, or ≥5% weight gain. All toxicities were graded using the Common Terminology Criteria for Adverse Events version 5.0. Disease relapse was defined as the re-emergence of the primary disease for which the transplantation was indicated. The specific criteria for relapse were determined by the characteristics of the individual disease.
Statistical analyses were performed using Python version 3.11 with the lifelines library for survival analysis and Stata version 17 SE for other statistical computations. Descriptive statistics summarize patient demographics, clinical characteristics, busulfan pharmacokinetics, and treatment outcomes. The normality of continuous variables was assessed using the Shapiro-Wilk test, with results expressed as means with standard deviations or medians with ranges. Categorical variables are presented as frequencies and percentages.
Patients were grouped based on their average busulfan AUC into three categories: below target range (< 3,600 µMolar·min), within target range (3,600-6,000 µMolar·min), and above target range (> 6,000 µMolar·min). Survival analysis was conducted to evaluate the time to disease relapse among these AUC groups. Kaplan-Meier survival curves were created, and differences between survival distributions were assessed using the log-rank test.
The study analyzed the relationships between HSCT type, EMA dosing groups, and age (< 10 vs ≥ 10 years) with busulfan in-range versus out-of-range of a first day AUC (AUC1) and mean AUC after adjusted levels using Fisher’s exact test. The association between type of disease (cancer/ non-cancer) and AUC1 range was analyzed using the Chi-square test, while the association between type of disease and mean AUC was analyzed using Fisher’s exact test. All statistical tests were two- sided, with a P value of less than 0.05 indicating statistical significance.
RESULTS
Twenty-six children, aged between 2 and 15 years (median age 8.5 years), were included in the study. Detailed patient characteristics are presented in Table 1.
AUC of busulfan and dosage adjustments
The average AUC of busulfan per patient varied from 2,566.2 to 6,943.05 µMolar·min, compared to a AUC1 range of 2,709.24 to 11,618.6 µMolar·min (Fig 1). The pharmacokinetics of busulfan were observed in
TABLE 1. Patient demographics and clinical characteristics.
Characteristics N (%)
Sex
Female 7 (26.9)
Indication Malignant ALL
APL MDS AML CML JMMoL
Nonmalignant
Thalassemia
15 (57.7)
7
1
1
4
1
1
11 (42.3)
9
Male 19 (73.1)
Age < 10 years | 6 |
Age ≥ 10 years | 3 |
Severe congenital neutropenia | 1 |
Wiskott–Aldrich syndrome | 1 |
Stem cell source
Bone marrow 8 (30.8)
Donor source Autologous Allogeneic
MRD MUD
Haploidentical
1 (3.8)
11 (42.3)
6 (23.1)
8 (30.8)
PBSC 18 (69.2)
Duration of busulfan
3 days 9 (34.6)
4 days 17 (65.4)
Fig 1. Distribution of area under the time curve ranges for first AUC (AUC1) and total mean AUC per patient (n = 26). The recommended target AUC (3,600–6,000 µMolar·min) is highlighted in green.
dose 1 (N=26), dose 2 (N=24) and dose 3 (N=9). The median of clearance was 0.2 (0.08-0.43), 0.19 (0.07-0.31) and 0.2 (0.1-0.4) L/hr/kg. The median half-life of busulfan was 2.28 (1.42-4.51), 2.19 (0.42-5.97) and 2.69 (1.9-3.59)
hours respectively. AUC1 was within the recommended range for 14 patients (53.84%). However, in the case of two patients who had AUC1 values in the lower normal range, the physician decided to adjust the busulfan dose the next day. Busulfan TDM was initially conducted over a 2-day period, with blood samples collected on day 1 and day 3 for two patients, and on day 1 and day 2 for the remainder. Dosage adjustments were made in 17 patients (65.38%). Among these, eight patients required a single dose adjustment; five required two adjustments; and another four needed three adjustments. For three patients, the target AUC was not achieved even after three dose adjustments. Of the 14 patients receiving dose adjustments after AUC1, half required an increase in
dosage (12%-44% change), while the other half required a decrease (17.81%-55.56%). Three patients with AUC1 within the target range had their doses decreased one time after the second AUC to reach the target AUC (11.11%-16.67% change).
Clinical outcomes and toxicity
Three patients experienced confirmed disease relapse. Two of these had mean AUC values below the target range (2,566.2 and 3,226 µMolar·min), while one had an in-range mean AUC (3,746.99 µMolar·min). One patient with a below-target mean AUC (2,897.38 µMolar·min) maintained complete remission 3.4 years post-HSCT. A lower average AUC than the target range was significantly correlated with earlier time to disease relapse compared to those non-lower target range of average AUCs, although the statistical analysis was underpowered (P < 0.005; Fig 2).
Fig 2. Kaplan–Meier curve of time to relapse in patients with lower-range and non-lower range mean area under the time curve.
In contrast, a higher average AUC did not correlate with an increase in busulfan-related side effects (P = 0.598) or treatment-related mortality (P = 1) when compared to non-high average AUC. No patient in higher average AUC group died, while four patients with an in-range average AUC died from infection post-transplantation. Busulfan toxicity was mainly associated with veno-occlusive disease/sinusoidal obstructive syndrome and mucositis. Three patients (11.5%) developed veno-occlusive disease/ sinusoidal obstructive syndrome of grades 1 to 3, with onset typically observed between Day +13 and Day +21 post-transplant. Their mean AUCs were consistently in the lower or in-target range, and no patient with a mean AUC in the higher or above-target range experienced this adverse effect. Mucositis occurred in 13 patients (50%), with onset typically observed between Day +3 and Day +10 post-transplant. Of these, 12 patients had
lower or in-target mean AUCs, while one patient with a higher mean AUC experienced grade 3 mucositis.
Relationship between AUC and treatment variables
There were no significant differences in AUC1 or mean AUC when stratifying by disease type (malignant vs nonmalignant), HSCT type (autologous, human leukocyte antigen-matched related and unrelated donor, and haploidentical), or EMA dosing group (Table 2). No statistical difference was seen in AUC1 between patients younger than 10 years and those aged 10 years or older (P = 0.701). However, an out-of-range target average AUC after dose adjustment was significantly more common in patients under 10 years of age (43.75%) compared to older patients, all of whom were within the target AUC range (P = 0.023; Fig 3).
TABLE 2. Relationship between AUC and treatment variables.
AUC1 | Mean AUC | |||||
In-range (n) | Out-range (n) | P value | In-range (n) | Out-range (n) | P value | |
Type of disease | 0.126 | 1 | ||||
Malignant | 10 | 5 | 11 | 4 | ||
Nonmalignant | 4 | 7 | 8 | 3 | ||
Type of HSCT | 0.310 | 0.895 | ||||
Autologous | 1 | 0 | 1 | 0 | ||
Allogeneic | ||||||
MRD | 4 | 7 | 8 | 3 | ||
MUD | 3 | 3 | 5 | 1 | ||
Haploidentical | 6 | 2 | 5 | 3 | ||
Busulfan OD dose | 0.185 | 0.365 | ||||
4 mg/kg | 0 | 0 | 0 | 0 | ||
4.8 mg/kg | 2 | 2 | 3 | 1 | ||
4.4 mg/kg | 6 | 1 | 6 | 1 | ||
3.8 mg/kg | 1 | 4 | 2 | 3 | ||
3.2 mg/kg | 5 | 5 | 8 | 2 | ||
Age | 0.701 | 0.023* | ||||
<10 years | 8 | 8 | 9 | 7 | ||
≥10 years | 6 | 4 | 10 | 0 |
*; P value was statistical significant
Fig 3. Comparison of area under the time curve (AUC) ranges across patient age groups.
DISCUSSION
Our protocol for busulfan initial dosing and TDM in this study followed the American Society for Blood and Marrow Transplantation guidelines.1 However, alternative dosing recommendations exist, particularly those from the EMA and the US Food and Drug Administration. The recommended initial dosing of busulfan for every 6-hour administration of EMA guidelines dosing is determined by actual body weight: patients weighing
≤ 9 kg are recommended 1 mg/kg; those between 9 and < 16 kg receive 1.2 mg/kg; individuals from 16 to
< 23 kg are prescribed 1.1 mg/kg; patients from 23 to 34 kg are given 0.95 mg/kg; and those weighing ≥ 34 kg are administered 0.8 mg/kg. The acceptable AUC range for EMA guidelines is 900–1,500 µMolar·min. Conversely, the US Food and Drug Administration guidelines base dosing on the lower value between actual and ideal body weight: patients weighing less than 12 kg are recommended 1.1 mg/kg, while those 12 kg or more receive 0.8 mg/kg with acceptable AUC range between 900–1,350 ± 5% µMolar·min. These guidelines use population pharmacokinetics modeling to target an AUC of 1125 µMolar·min for busulfan administered every 6 hours. The EMA method is particularly favored by the American Society for Blood and Marrow Transplantation and achieved target AUCs of approximately 70% in several studies.1,5 In Thailand, previous research using the EMA dosing model for every-6-hour busulfan administration reported that only 42.86% of patients reached the target AUC.7 In comparison, our study achieved a target AUC of 53.84% in the initial AUC (AUC1) before any dose adjustments. While some localized research exists, there is a recognized absence of nationally validated guidelines or broad, generalizable evidence in Thailand regarding busulfan dosing strategies specifically tailored for pediatric patients. Consequently, current practices are often limited
to institutional protocols rather than comprehensive, evidence-based recommendations applicable across all transplant centers.
The EMA dosing method typically uses actual body weight for dosage calculations. However, in one case within our study, the physician decided to use adjusted body weight12,13 due to the patient’s high body mass index of 30.9 kg/m2 and a total body weight/ideal body weight ratio of 1.45. For this particular patient, the initial AUC1 was within the target AUC range (5,197.14 µMolar·min), eliminating the need for dose adjustments. Existing literature on busulfan dosing for overweight patients, particularly children, is limited. As this study’s only patient with a body mass index categorized as overweight, no direct comparisons could be made with other patients. This single case underscores the importance of further research into dosing strategies for pediatric patients with elevated body mass index to optimize treatment outcomes and ensure safe pharmacokinetic profiles.
There are no definitive recommendations for the number or specific time points for collecting busulfan blood samples. While the European Society for Blood and Marrow Transplantation recently suggested a sampling protocol of four time points14, various studies incorporate 5-7 samples per AUC calculation, although at different time points.15-18 Our institution follows the American Society for Blood and Marrow Transplantation guideline1, collecting six plasma concentrations at specified intervals. Initially, we scheduled blood sampling for days 1 and 3 of busulfan infusion due to time constraints in reporting levels. The busulfan levels from day 1 and the AUC1 were calculated after the day-2 infusion, allowing for dose adjustments on day 3 if necessary. For two patients, the day-3 AUC remained below target, and further dose adjustments were not feasible by day 4. One of these patients experienced disease relapse and died 1 year
after transplantation. This prompted us to reschedule busulfan infusions to the afternoon, facilitating timely dose adjustments before the next infusion day. Consequently, blood collection primarily occurred on days 1 and 2, with the option to extend if required.
The study’s limitations include a small sample size and a lack of all daily plasma busulfan concentration monitoring throughout the infusion course. Many studies advocate maintaining the total AUC for the entire 4-day busulfan infusion as the target.1,14 We collected and analyzed busulfan AUC for at least 2 days, assuming pharmacokinetic consistency when the AUC was within the target range.
While busulfan-related toxicities are a critical focus, including severe veno-occlusive disease or sinusoidal obstructive syndrome and mucositis, other complications from methotrexate, used for GVHD prophylaxis, notably include severe methotrexate-induced mucositis —a consistent finding in our patient cohort often leading to drug discontinuation by day +11—and lymphoproliferative disorders19 frequently necessitate intensive care interventions for pediatric patients, a population characterized by chronic conditions and elevated mortality risks.20
Busulfan metabolism involves hepatic glutathione conjugation mediated by glutathione S-transferase (GST) enzymes. The GSTA1 subfamily, a key area of research, explores the impact of polymorphisms on metabolism1,4,21, including a study in Thailand.22 Certain GSTA1 alleles correspond to fast or slow metabolizers, affecting busulfan clearance and requiring careful consideration.21 Nonetheless, genetic polymorphism testing is not currently recommended for routine clinical integration in busulfan dose personalization.1
The European Society for Blood and Marrow Transplantation guidelines advise caution with dose adjustments exceeding 25%, recommending repeated TDM on the adjustment day.14 Our study observed dose changes of 12%-55%, tailored to achieve a narrower target AUC of 4,500-5,000 µMolar·min to avoid over- or underexposure. However, some studies suggest the optimal AUC in a myeloablative setting should range between 1,225-1,575 µMolar·min (equivalent to 4,900- 6,300 µMolar·min for once-daily dosing), correlating with superior outcomes compared to previous recommendations for children.23
CONCLUSION
Our study supports TDM as an effective strategy to enhance the efficacy of once-daily intravenous busulfan in HSCT among Thai pediatric patients. Dose adjustments for out-of-range AUCs may help reduce the frequency
of subtherapeutic exposures, thereby mitigating early relapse risks.
The data supporting the findings of this study are not publicly available due to ethical restrictions related to privacy and confidentiality.
ACKNOWLEDGEMENTS
We express our sincere gratitude to the nursing and support staff of the Pediatric Bone Marrow Transplant Ward at Siriraj Hospital for their exceptional care, dedication, and compassion throughout the blood sampling process during the conditioning regimen. Special thanks are due to Mr. Paiboon Tummarintra and the laboratory unit staff for their invaluable assistance in sample processing and data analysis. Their expertise and unwavering support were critical to the success of this research.
DECLARATIONS
No Grants or Funding are provided.
The authors declare no conflicts of interest related to this article.
None.
Conceptualization and methodology, CD.R., U.M., CT.R. and K.S.; Investigation, CD.R.; Formal analysis, CT.R.; Visualization and writing – original draft, CD.R.; Writing – review and editing, CD.R., U.M., K.S.; Supervision,
K.S. All authors have read and agreed to the final version of the manuscript.
None.
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