A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance Journal Article


Authors: Langenhorst, J. B.; Boss, J.; van Kesteren, C.; Lalmohamed, A.; Kuball, J.; Egberts, A. C. G.; Boelens, J. J.; Huitema, A. D. R.; van Maarseveen, E. M.
Article Title: A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance
Abstract: Aim: To develop a semi-mechanistic model, based on glutathione depletion and predict a previously identified intra-individual reduction in busulfan clearance to aid in more precise dosing. Methods: Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semi-mechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi-mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi-mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment. Results: In both models, a similar clearance decrease of 7% (range −82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6–8%, P = 0.009), causing the effect to increase more than a 2-fold over the observed age-range (0–73 years). Compared to the empirical model, the final semi-mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients. Conclusion: These results suggest that the time-dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi-mechanistic model could be used to further improve TDM-guided exposure target attainment of busulfan in patients undergoing HCT. © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society
Keywords: adolescent; adult; child; major clinical study; busulfan; fludarabine; drug dose reduction; protein depletion; cyclophosphamide; childhood cancer; age; simulation; hematologic malignancy; myeloablative conditioning; drug clearance; allogeneic hematopoietic stem cell transplantation; drug monitoring; drug metabolism; clofarabine; glutathione; pharmacokinetics; thymocyte antibody; fludarabine phosphate; nonbiological model; human; male; female; priority journal; article; chemotherapy – oncology; drug safety – clinical pharmacology; therapeutic drug monitoring – clinical pharmacology; semi mechanistic model
Journal Title: British Journal of Clinical Pharmacology
Volume: 86
Issue: 8
ISSN: 0306-5251
Publisher: Wiley Blackwell  
Date Published: 2020-08-01
Start Page: 1499
End Page: 1509
Language: English
DOI: 10.1111/bcp.14256
PUBMED: 32067250
PROVIDER: scopus
PMCID: PMC7373715
DOI/URL:
Notes: Article -- Export Date: 3 August 2020 -- Source: Scopus
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  1. Jaap Jan Boelens
    211 Boelens