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.

journal_name

Br J Clin Pharmacol

authors

Langenhorst JB,Boss J,van Kesteren C,Lalmohamed A,Kuball J,Egberts ACG,Boelens JJ,Huitema ADR,van Maarseveen EM

doi

10.1111/bcp.14256

subject

Has Abstract

pub_date

2020-08-01 00:00:00

pages

1499-1509

issue

8

eissn

0306-5251

issn

1365-2125

journal_volume

86

pub_type

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