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Busulfan target exposure attainment in children undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiday therapeutic drug monitoring regimen

Bone Marrow Transplantation volume 58, pages 762–768 (2023)Cite this article

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Abstract

Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all children receiving busulfan-based allogeneic hematopoietic cell transplantation. Primary outcome was the percentage of patients achieving busulfan target attainment in both TDM regimens. Secondary outcomes were the variance in busulfan exposure and day-4 clearance (Clday4) estimates between both TDM regimens and dosing day 1 and 2. In regimen d1, 84.3% (n = 91/108) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 90.9% was found (n = 30/33, not-significant). Variance of Clday4 estimate based on busulfan day 2 concentrations was significantly smaller than the variance of Clday4 estimates based on day 1 concentrations (p < 0.001). Therefore, day 1-guided TDM (pharmacometric model-based) of busulfan may be sufficient for attaining optimal target exposure, provided that subsequent TDM is carried out if required. However, performing TDM on subsequent days may be beneficial, as measurements on day 2 seemed to reduce the variance in the estimated clearance as compared to day 1 sampling.

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Fig. 1: Two busulfan therapeutic drug monitoring (TDM) sampling strategies were applied: either blood sampling was performed on day 1 (regimen d1), with a dose adjustment based on the day 1 AUC, or blood sampling was performed on days 1 + 2 (regimen d1 + 2), with a dose adjustment based on the days 1 + 2 AUC.
Fig. 2: Overview of the reasons for patient exclusion and the number of patients that were included in the study in the regimen d1 group (day 1-guided therapeutic drug monitoring (TDM)) and the TDM regimen d1 + 2 group (days 1 + 2-guided TDM).
Fig. 3: The variance of the busulfan cumulative exposure (target cumulative area under the curve = 80–100 mg*h/L) for both therapeutic drug monitoring (TDM) regimens, stratified for age (0–2, 2–5, 5–12, and 12–18 years).
Fig. 4: The agreement between the estimated and derived day 4 busulfan clearance (CLday4) for both TDM regimens and concentrations that were measured on day 1 and day 2.

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Data availability

The data that support the findings of this study are available from the corresponding author, TB, upon reasonable request.

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Author information

Author notes

  1. These authors contributed equally: I. H. (Imke) Bartelink, A. (Arief) Lalmohamed.

Authors and Affiliations

  1. Department of Clinical Pharmacy, University Medical Center Utrecht/Wilhelmina Children’s Hospital, Utrecht, the Netherlands

    T. (Tim) Bognàr, J. S. (Jurjen) Kingma, E. H. (Erin) Smeijsters, K. C. M. (Kim) van der Elst, A. C. G. (Toine) Egberts & A. (Arief) Lalmohamed

  2. Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands

    J. S. (Jurjen) Kingma

  3. Department of Pharmacy, Curaçao Medical Center, Willemstad, Curaçao

    C. T. M. (Klaartje) de Kanter

  4. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands

    C. A. (Caroline) Lindemans

  5. Department of Pediatrics, University Medical Center Utrecht/Wilhelmina Children’s Hospital, Utrecht, the Netherlands

    C. A. (Caroline) Lindemans

  6. Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands

    A. C. G. (Toine) Egberts & A. (Arief) Lalmohamed

  7. Pharmacy & Clinical Pharmacology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

    I. H. (Imke) Bartelink

  8. Cancer Center Amsterdam, Amsterdam, the Netherlands

    I. H. (Imke) Bartelink

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  1. T. (Tim) Bognàr
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Contributions

TB, JSK, EHS, KCME, CTMK, CAL, ACGE, IHB and AL designed the research and participated in the manuscript. TB, JSK and CL collected the data. IHB performed the pharmacometric analysis of the data. TB, ACGE and AL performed the statistical analysis. TB, ACGE, IHB and AL wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to T. (Tim) Bognàr.

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Bognàr, T.(., Kingma, J.S.(., Smeijsters, E.H.(. et al. Busulfan target exposure attainment in children undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiday therapeutic drug monitoring regimen. Bone Marrow Transplant 58, 762–768 (2023). https://doi.org/10.1038/s41409-023-01971-z

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