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 semimechanistic 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. K E Y W O R D Schemotherapyoncology, drug safetyclinical pharmacology, pharmacokinetics, therapeutic drug monitoringclinical pharmacologyThe authors confirm that the Principal Investigator for this paper is Dr E. M. van Maarseveen and that he had direct clinical responsibility for patients.

Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study

“… 16 This intraindividual CL decrease could be explained by glutathione depletion during the course Bu conditioning. 43 , 44 Inconsistencies in the administration of Bu, such as noncontrolled infusion durations and rates, or omission of central venous catheter flushing between dose administrations, could also add to this observation. However, as several studies have consistently reported this phenomenon, 16 , 17 , 33 , 42 , 43 , 45 and considering Bu first‐order elimination implying a CL independent of the dose, this observed CL decrease is likely to have a physiological explanation.…”

“… 43 , 44 Inconsistencies in the administration of Bu, such as noncontrolled infusion durations and rates, or omission of central venous catheter flushing between dose administrations, could also add to this observation. However, as several studies have consistently reported this phenomenon, 16 , 17 , 33 , 42 , 43 , 45 and considering Bu first‐order elimination implying a CL independent of the dose, this observed CL decrease is likely to have a physiological explanation. Further mechanistic investigations should be performed to better understand the factors leading to this CL decrease.…”

αβ T-cell graft depletion for allogeneic HSCT in adults with hematological malignancies

“…20,21 The ATG dosage was aimed at a post-HSCT area under the curve of ;20 to 30 AU*day/mL. Therapeutic drug monitoring of busulfan was performed and targeted to a cumulative area under the curve of 80 to 90 mg/h per L. 22 ab T-cell reduction was performed by depletion with anti-ab T-cell receptor (TCR) antibodies, in combination with magnetic microbeads using the automated CliniMACS device (Miltenyi Biotec, Bergisch Gladbach, Germany), as described previously, 23 and according to standard operating procedures. The maximal allowed residual ab T-cell number was 5 3 10 5 cells per kg.…”

“…14,16,19 The timing and dosing of the conditioning agents has great impact on early IR. For that reason, we individualized many parameters within the ab T-cell depletion transplantation protocol, such as the number of abT cells, dose of busulfan, 22,51 and very early ATG administration, to avoid the presence of ATG at the time of transplantation. 20,21 However, early IR was still very heterogeneous.…”

Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia

“…As shown in Table 2, body size metrics (actual body weight, body surface area, fatfree mass, etc.) are covariates consistently reported to explain Busulfan PK variability in paediatric patients and are used for dose calculations (38,57,63,66,67,80,(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100).…”