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. 2025 Apr;91(4):1171-1181.
doi: 10.1111/bcp.16343. Epub 2024 Nov 20.

Adaptive dosing of high-dose busulfan in real-world adult patients undergoing haematopoietic cell transplant conditioning

Dorian Protzenko  1 , Benjamin Bouchacourt  2 , Laure Carriat  3 , Paul Maroselli  3 , Clara Boéri  3 , Raynier Devillier  2   4 , Joseph Ciccolini  1   3
Affiliations

Adaptive dosing of high-dose busulfan in real-world adult patients undergoing haematopoietic cell transplant conditioning

Dorian Protzenko et al. Br J Clin Pharmacol. 2025 Apr.

Abstract

Aim: To evaluate the effectiveness of a Bayesian adaptive dosing strategy in achieving target busulfan exposure in adult patients undergoing haematopoietic cell transplantation (HCT).

Methods: This study included 71 adult patients scheduled to receive high-dose busulfan. Busulfan was administered to achieve a cumulative area under the curve (AUC) of 66.0 mg.h/L (16 000 μM.min), 82.60 mg.h/L (20 000 μM.min) or 87.6 mg.h/L (21 200 μM.min) depending on the regimen. Individual pharmacokinetic (PK) parameters of busulfan were estimated from three blood samples using a one-compartment model and Bayesian estimation after the first standard dose. Individual PK parameters were used to adjust subsequent doses to achieve the target exposure.

Results: All patients had their dose adjusted after the first dose administration. The final deviation from the target AUC was significantly improved compared to the initial deviation after standard mg/kg dosing (mean absolute deviation 19.5% vs 11.7%, P < .01). In addition, the proportion of patients with marked deviation from target exposure (ie, >25%) decreased significantly from 31% after standard dosing to 10% after PK-guided dosing (P < .01). Canonical busulfan-related toxicity, specifically veno-occlusive disease, was observed in 5% of patients who achieved successful PK-guided dosing. In contrast, one-third of patients with off-target exposure with poor dosing experienced toxicity.

Conclusion: The Bayesian adaptive dosing strategy significantly improves the accuracy of achieving the target busulfan AUC in patients undergoing HCT. This approach not only reduces marked deviations from target exposure, but also reduces the incidence of busulfan-related toxicity, thereby maintaining a favourable toxicity/efficacy ratio.

Keywords: Bayesian; adaptive dosing; busulfan; haematopoietic cell transplant; pharmacokinetics.

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Conflict of interest statement

The authors declare no conflict of interest related to this work.

Figures

FIGURE 1
FIGURE 1
Comparison of the percentage deviation from the intermediate target area under the curve (AUC) (ie, after standard dosing) and the cumulative target AUC (ie, after Bayesian adaptative dosing) (P < .001, n = 71).
FIGURE 2
FIGURE 2
Comparison of the percentage deviation rate from the intermediate target area under the curve (AUC) (first administration using standard dosing) and the cumulative target AUC reached after Bayesian adaptive dosing.
FIGURE 3
FIGURE 3
Comparison of the cumulative cumulated area under the curve (AUC) distribution (normalized).
FIGURE 4
FIGURE 4
Comparison of the estimated clearance of busulfan after the first and last administration (P = .09, n = 71).
FIGURE 5
FIGURE 5
Comparison of the intra‐patient variability on busulfan clearance between the first and last administrations.
FIGURE 6
FIGURE 6
Impact of the clearance status on the exposure target (P < .05, n = 71).
FIGURE 7
FIGURE 7
Impact of the deviation from the target area under the curve on overall survival (A) and non‐relapse mortality (B).
See this image and copyright information in PMC

References

    1. Vriesendorp HM. Aims of conditioning. Exp Hematol. 2003;31(10):844‐854. doi:10.1016/S0301-472X(03)00229-7 - DOI - PubMed
    1. Spyridonidis A, Labopin M, Savani BN, et al. Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients. Bone Marrow Transplant. 2020;55(6):1114‐1125. doi:10.1038/s41409-020-0803-y - DOI - PubMed
    1. Giralt S, Ballen K, Rizzo D, et al. Reduced‐intensity conditioning regimen workshop: defining the dose Spectrum. Report of a workshop convened by the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2009;15(3):367‐369. doi:10.1016/j.bbmt.2008.12.497 - DOI - PMC - PubMed
    1. Hassan M. The role of busulfan in bone marrow transplantation. Med Oncol. 1999;16(3):166‐176. doi:10.1007/BF02906128 - DOI - PubMed
    1. Nagler A, Rocha V, Labopin M, et al. Allogeneic hematopoietic stem‐cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (cy) versus total‐body irradiation plus cy as conditioning regimen—a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2013;31(28):3549‐3556. doi:10.1200/JCO.2013.48.8114 - DOI - PubMed

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