A Limited Sampling Strategy for Estimating Busulfan Exposure in Pediatric Hematopoietic Stem Cell Transplantation

Overview

Journal Front Pharmacol

Date 2025 Mar 4

PMID 40034822

Authors

Chenhong Jia

Yabin Qin

Yu Han

Weijing Ding

Yuntao Pei

Yile Zhao

Affiliations

Soon will be listed here.

Abstract

Background: Busulfan (Bu) is the foundation of conditioning regimens for pediatric hematopoietic stem cell transplantation (HSCT). Evidence indicates that the efficacy and side effects of Bu are intimately tied to the area under its concentration-time curve (AUC). Given its cytotoxic nature and a small therapeutic index, coupled with marked inter-individual pharmacokinetic variability, Bu requires therapeutic drug monitoring to facilitate individualized therapy. However, research investigating the relationship between Bu exposure and clinical outcomes among the Chinese population remains scarce. This study aimed to develop a limited sampling strategy (LSS) for estimating Bu exposure in pediatric HSCT recipients using multiple linear regression (MLR) analysis to predict the AUC.

Methods: We enrolled 26 pediatric patients who underwent Bu-based conditioning for HSCT. Blood samples were collected at 11 time points after Bu infusion. Pharmacokinetic parameters were calculated using non-compartmental methods. MLR models were developed using 1-4 sampling points to predict the AUC. Model accuracy was assessed using the Jackknife and Bootstrap methods, with consistency evaluated via intraclass correlation coefficient (ICC) and Bland-Altman (BA) analyses.

Results: The mean ± standard deviation (SD) for AUC, mean residence time , clearance, and volume of distribution were 845.54 ± 111.03 μmol min/L, 181.37 ± 10.55 min, 0.23 ± 0.04 L/h/kg, and 0.73 ± 0.15 L/kg, respectively. Models with 2-4 sampling points showed improved prediction accuracy compared to single-point models. The four-point model (60, 135, 240 and 360 min) demonstrated the highest accuracy with an adjusted of 0.965. Internal validation confirmed the models' stability and accuracy, with the four-point model exhibiting the best performance. External validation using three additional cases supported the predictive accuracy of the model.

Conclusion: The LSS model developed in this study accurately predicts the Bu AUC with 2-4 sampling points, offering a practical and clinically valuable tool for therapeutic drug monitoring in pediatric HSCT recipients. The four-point model was found to be the most accurate and is recommended for clinical applications.

References

Bognar T, Bartelink I, van der Elst K, Kingma J, Smeijsters E, Lindemans C . 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. 2024; 30(10):1007.e1-1007.e10. DOI: 10.1016/j.jtct.2024.07.015. View

Dupuis L, Sibbald C, Schechter T, Ansari M, Gassas A, Theoret Y . IV busulfan dose individualization in children undergoing hematopoietic stem cell transplant: limited sampling strategies. Biol Blood Marrow Transplant. 2008; 14(5):576-82. DOI: 10.1016/j.bbmt.2008.03.002. View

Xiang H, Zhou H, Zhang J, Sun Y, Wang Y, Han Y . Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients. Front Pharmacol. 2021; 12:652333. PMC: 8072337. DOI: 10.3389/fphar.2021.652333. View

Cremers S, Schoemaker R, Bredius R, den Hartigh J, Ball L, Twiss I . Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation. Br J Clin Pharmacol. 2002; 53(4):386-9. PMC: 1874261. DOI: 10.1046/j.1365-2125.2002.01555.x. View

Nakamura H, Sato T, Okada K, Miura G, Ariyoshi N, Nakazawa K . Population pharmacokinetics of oral busulfan in young Japanese children before hematopoietic stem cell transplantation. Ther Drug Monit. 2008; 30(1):75-83. DOI: 10.1097/FTD.0b013e3181621cde. View

Li X, Zhang B, Cheng Y, Chen M, Lin H, Huang B . Evaluation and Validation of the Limited Sampling Strategy of Polymyxin B in Patients with Multidrug-Resistant Gram-Negative Infection. Pharmaceutics. 2022; 14(11). PMC: 9698835. DOI: 10.3390/pharmaceutics14112323. View

Rasor B, Dickerson T, Zhao Q, Elder P, Brammer J, Larkin K . Comparison of fixed dose reduced-intensity conditioning with fludarabine and busulfan to PK-guided busulfan AUC (FluBu4K) in hematopoietic stem cell transplant for AML/MDS. Leuk Lymphoma. 2020; 62(4):944-951. PMC: 8012251. DOI: 10.1080/10428194.2020.1849677. View

Utano T, Kato M, Sakamoto K, Osumi T, Matsumoto K, Tomizawa D . Two-point blood sampling is sufficient and necessary to estimate the area under the concentration-time curve for intravenous busulfan in infants and young children. Pediatr Blood Cancer. 2021; 68(8):e29069. DOI: 10.1002/pbc.29069. View

Marsit H, Philippe M, Neely M, Rushing T, Bertrand Y, Ducher M . Intra-individual Pharmacokinetic Variability of Intravenous Busulfan in Hematopoietic Stem Cell-Transplanted Children. Clin Pharmacokinet. 2020; 59(8):1049-1061. DOI: 10.1007/s40262-020-00877-z. View

10.

Neroutsos E, Athanasiadou I, Paisiou A, Zisaki K, Goussetis E, Archontaki H . Dose individualization of intravenous busulfan in pediatric patients undergoing bone marrow transplantation: impact and in vitro evaluation of infusion lag-time. J Pharm Pharmacol. 2021; 73(10):1340-1350. DOI: 10.1093/jpp/rgab087. View

11.

Bartelink I, Lalmohamed A, van Reij E, Dvorak C, Savic R, Zwaveling J . Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016; 3(11):e526-e536. PMC: 5159247. DOI: 10.1016/S2352-3026(16)30114-4. View

12.

Teitelbaum Z, Nassar L, Scherb I, Fink D, Ring G, Lurie Y . Limited Sampling Strategies Supporting Individualized Dose Adjustment of Intravenous Busulfan in Children and Young Adults. Ther Drug Monit. 2019; 42(3):427-434. DOI: 10.1097/FTD.0000000000000700. View

13.

Faraci M, Tinelli C, Lanino E, Giardino S, Leoni M, Ferretti M . Monitoring of Busulphan Concentrations in Children Undergone Hematopoietic Stem Cell Transplantation: Unicentric Experience over 10 years. Eur J Drug Metab Pharmacokinet. 2017; 43(2):173-181. DOI: 10.1007/s13318-017-0431-0. View

14.

Watanabe E, Nishikawa T, Ikawa K, Yamaguchi H, Abematsu T, Nakagawa S . Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration-time curve in pediatric hematopoietic stem cell transplant recipients. Int J Hematol. 2015; 102(5):611-6. DOI: 10.1007/s12185-015-1853-6. View

15.

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; 33(10):979-87. DOI: 10.1038/sj.bmt.1704446. View