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

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 transp...

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Autores principales: Langenhorst, Jurgen B., Boss, Jill, van Kesteren, Charlotte, Lalmohamed, Arief, Kuball, Jürgen, Egberts, Antoine C. G., Boelens, Jaap Jan, Huitema, Alwin D. R., van Maarseveen, Erik M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373715/
https://www.ncbi.nlm.nih.gov/pubmed/32067250
http://dx.doi.org/10.1111/bcp.14256
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author Langenhorst, Jurgen B.
Boss, Jill
van Kesteren, Charlotte
Lalmohamed, Arief
Kuball, Jürgen
Egberts, Antoine C. G.
Boelens, Jaap Jan
Huitema, Alwin D. R.
van Maarseveen, Erik M.
author_facet Langenhorst, Jurgen B.
Boss, Jill
van Kesteren, Charlotte
Lalmohamed, Arief
Kuball, Jürgen
Egberts, Antoine C. G.
Boelens, Jaap Jan
Huitema, Alwin D. R.
van Maarseveen, Erik M.
author_sort Langenhorst, Jurgen B.
collection PubMed
description 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.
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spelling pubmed-73737152020-07-22 A semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance Langenhorst, Jurgen B. Boss, Jill van Kesteren, Charlotte Lalmohamed, Arief Kuball, Jürgen Egberts, Antoine C. G. Boelens, Jaap Jan Huitema, Alwin D. R. van Maarseveen, Erik M. Br J Clin Pharmacol Original Articles 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. John Wiley and Sons Inc. 2020-03-10 2020-08 /pmc/articles/PMC7373715/ /pubmed/32067250 http://dx.doi.org/10.1111/bcp.14256 Text en © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Langenhorst, Jurgen B.
Boss, Jill
van Kesteren, Charlotte
Lalmohamed, Arief
Kuball, Jürgen
Egberts, Antoine C. G.
Boelens, Jaap Jan
Huitema, Alwin D. R.
van Maarseveen, Erik M.
A semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance
title A semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance
title_full A semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance
title_fullStr A semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance
title_full_unstemmed A semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance
title_short A semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance
title_sort semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373715/
https://www.ncbi.nlm.nih.gov/pubmed/32067250
http://dx.doi.org/10.1111/bcp.14256
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