Razan Sakran 1,2, Xiaomei Chen 1, Daniel Kurnik 2, Elisabet Nielsen 1
1 Department of Pharmacy; Clinical Pharmacy and Pharmacotherapy, Uppsala University (Uppsala, Sweden), 2 Clinical Pharmacology Unit, Rambam Health Care Campus (Haifa, Israel)
Introduction: Busulfan is a cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation (HCT). It has a narrow therapeutic window, high interindividual variability, and an established pharmacokinetic–pharmacodynamic relationship, with cumulative area under the concentration–time curve (AUC) closely associated with both efficacy and toxicity.1
In clinical practice, the initial busulfan dose is usually selected from weight-based dosing tables derived from population PK (PopPK) models.2,3 However, these dosing guidelines were developed from relatively small and selected cohorts, mainly children, often excluding infants and adults. Moreover, since these guidelines rely solely on body weight, they are intended for the “average” patient, assuming a typical age for a given weight—a premise that may not hold for the medically complex HCT population.
Objectives: This study aimed to i) develop an optimized IV busulfan initial dosing regimen, applicable from infancy to adulthood, targeting a cumulative AUC of 79 mg·h/L over 4 days of treatment1, and ii) to assess this newly proposed dosing regimen versus standard dosing recommendations.
Methods: A one-compartment PopPK model was developed, based on 3,025 samples from 309 HCT recipients, aged 0.08-79 years, and subsequently used to derive an optimized initial IV busulfan dosing regimen. Simulations were conducted for 1,000 virtual patients whose age and body weight were collected from the National Health and Nutrition Examination Survey (NHANES).4 Cumulative AUCs over 4 days of treatment (AUC0-4days), with once-daily IV dosing, were predicted. Assuming linear PK, doses were proportionally adjusted to achieve the target exposure (AUC0-4days 79 mg·h/L) and summarized for combined weight and age ranges. Monte Carlo simulations were then performed with 10,000 iterations to compare the developed alternative regimen with the standard dosing regimens recommended by European Medicines Agency (EMA)3 and the dosing table proposed by Bartelink2 et al, adjusted to the same target exposure (AUC0-4days 79 mg·h/L). Comparisons were performed in terms of the simulated AUC0-4days, summarized according to mean percentage error (MPE), and root mean square error (RMSE), and the proportion of patients achieving an optimized AUC0-4days (range 75-83 mg·h/L), low exposures (<60 mg·h/L), or high exposures (>90 mg·h/L).
Results: A combined weight- and age-based dosing nomogram was developed, and across the simulated population, the proposed dosing regimen achieved the target exposure with acceptable bias and precision (median AUC0-4days 79 mg·h/L, MPE +3%, RMSE 19 mg·h/L). In comparison, using the adjusted dosing recommendations from EMA and Bartelink et al., the median exposures were below the target AUC (74.5 and 67.5 mg·h/L, respectively), with corresponding MPE values of -3% and -10% and RMSE values of 20.7 and 20.6 mg·h/L, respectively.
Consistent with the observed high inter- and intraindividual PK variability of busulfan, the attainment of the optimized AUC0-4days target of 75-83 mg·h/L was low (17%), slightly higher than that achieved with the EMA and Bartelink et al. dosing tables (15% and 13%, respectively). Importantly, a lower proportion of patients (12%) were markedly underdosed (AUC0-4days<60 mg·h/L) compared to the EMA (20.8%) and Bartelink (31.8%) dosing guidelines, underscoring the need for concentration- and model-informed precision dosing. The performances of the three dosing regimens were also evaluated in age and weight subgroups. The EMA and Bartelink weight-based dosing regimens tended to result in overexposure in younger (age <1 year) and lower-weight (weight <9 kg) patients. Specifically, 50% of patients dosed according to EMA and 60% according to Bartelink achieved substantial overexposure (>90 mg·h/L), compared to 30% when dosed according to the proposed dosing regimen. In patients weighing >34 kg and aged>5 years, the previous dosing recommendations achieved significant underexposure in 26% (EMA) and 40% (Bartelink), while this proportion was 12% using the newly proposed dosing.
Conclusion: A novel initial dosing regimen, based on body weight and age, was developed to optimize initial busulfan dosing, showing promise in predicting higher target attainment across a broad weight range (5–120 kg), and thereby contributing to safer and more effective conditioning regimens. Furthermore, incorporating age in addition to weight could improve target attainment in infants, underscoring the impact of developmental maturation on drug dosing in this population. Nevertheless, busulfan concentration measurements and subsequent model-informed precision dosing remain essential to ensure achievement of the target exposure.
References:
1. Domingos, V., Nezvalova-Henriksen, K., Dadkhah, A. et al. A practical guide to therapeutic drug monitoring in busulfan: recommendations from the Pharmacist Committee of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 59, 1641–1653 (2024).
2. Bartelink IH, Boelens JJ, Bredius RG, Egberts AC, Wang C, Bierings MB, Shaw PJ, Nath CE, Hempel G, Zwaveling J, Danhof M, Knibbe CA. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet. 2012 May 1;51(5):331-45.
3. Nguyen L, Fuller D, Lennon S, Leger F, Puozzo C. I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant. 2004 May;33(10):979-87
4. Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. 2017-2020.
Reference: PAGE 34 (2026) Abstr 11986 [www.page-meeting.org/?abstract=11986]
Poster: Clinical Applications