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Population Pharmacokinetic Model of Intravenous Busulfan in Hematopoietic Cell Transplantation: Systematic Review and Comparative Simulations

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Abstract

Background

Busulfan is commonly used in the chemotherapy prior to hematopoietic cell transplantation (HCT). Busulfan has a narrow therapeutic window and a well-established exposure–response relationship with important clinical outcomes. Model-informed precision dosing (MIPD) based on population pharmacokinetic (popPK) models has been implemented in the clinical settings. We aimed to systematically review existing literature on popPK models of intravenous busulfan.

Methods

We systematically searched Ovid MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science databases from inception to December 2022 to identify original popPK models (nonlinear mixed-effect modeling) of intravenous busulfan in HCT population. Model-predicted busulfan clearance (CL) was compared using US population data.

Results

Of the 44 eligible popPK studies published since 2002, 68% were developed predominantly in children, 20% in adults, and 11% in both children and adults. The majority of the models were described using first-order elimination or time-varying CL (69% and 26%, respectively). All but three included a body-size descriptor (e.g., body weight, body surface area). Other commonly included covariates were age (30%) and GSTA1 variant (15%). Median between-subject and between-occasion variabilities of CL were 20% and 11%, respectively. Between-model variabilities in predicted median CL were < 20% in all of the weight tiers (10–110 kg) in the simulation based on US population data.

Conclusion

Busulfan PK is commonly described using a first-order elimination or time-varying CL. A simple model with limited covariates were generally sufficient to attain relatively small unexplained variabilities. However, therapeutic drug monitoring may still be necessary to attain a narrow target exposure.

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Change history

  • 15 March 2024

    The original online version of this article was revised to remove the reference text from the Discussion section.

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Authors and Affiliations

  1. Division of Stem Cell Transplantation, Department of Pediatrics, Boston Children’s Hospital/Dana-Farber Cancer Institute, Boston, MA, USA

    Takuto Takahashi

  2. Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, USA

    Takuto Takahashi, Mutaz M. Jaber & Mahmoud Al-Kofahi

  3. Gilead Sciences, Inc., Foster City, CA, USA

    Mutaz M. Jaber & Mahmoud Al-Kofahi

  4. Health Sciences Library, University of Minnesota, Minneapolis, MN, USA

    Sarah J. Brown

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  1. Takuto Takahashi
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Correspondence to Takuto Takahashi.

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The datasets generated and/or analyzed during the current study are available in the supplementary files.

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TT conceived and designed the study. SJB performed systematic literature search. TT and MMJ performed review the literature and data extraction. TT wrote the manuscript with input from all authors.

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Takahashi, T., Jaber, M.M., Brown, S.J. et al. Population Pharmacokinetic Model of Intravenous Busulfan in Hematopoietic Cell Transplantation: Systematic Review and Comparative Simulations. Clin Pharmacokinet 62, 955–968 (2023). https://doi.org/10.1007/s40262-023-01275-x

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