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

Jurgen B. Langenhorst, Jill Boss, Charlotte van Kesteren, Arief Lalmohamed, Jürgen Kuball, Antoine C.G. Egberts, Jaap Jan Boelens, Alwin D.R. Huitema, Erik M. van Maarseveen

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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.

Original languageEnglish
Pages (from-to)1499-1509
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Issue number8
Publication statusPublished - 1 Aug 2020
Externally publishedYes


  • chemotherapy – oncology
  • drug safety – clinical pharmacology
  • pharmacokinetics
  • therapeutic drug monitoring – clinical pharmacology


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