Background and Aim: Busulfan, is a bifunctional alkylating agent, commonly administered to children as a component of conditioning therapy prior to haematopoietic stem cell transplantation (HSCT). Dosing regimens vary from six hourly (QID) to once daily (OD) with individualisation of the dose considered standard practice as recommended within product information leaflets (PI)[1,2]. However, practices around the timing and number of samples taken for drug monitoring, the technique for estimating exposure and the method to calculate subsequent doses vary from centre to centre[3]. There is an established relationship between busulfan exposure and patient outcomes, with too high drug exposure increasing the risk of toxicity and treatment-related mortality and too low drug exposure increasing the risk of graft failure and relapse[4,5]. An optimal cumulative exposure (AUCcum) range for busulfan of 78-101mg.h.L-1, estimated using model-based methods, has been published[4]. There is increasing evidence that busulfan clearance (CL) reduces with time over a four day treatment course[5]. This study aimed to evaluate different practices for sampling, methods for estimating exposure and calculating subsequent doses in achieving an individualised target AUCcum for once daily intravenous dosing.
Methods: To evaluate techniques to predict busulfan AUCcum, we compared exposure estimated through use of two model-based dosing tools (InsightRX and NextDose) under various sampling scenarios and exposure estimated using non-compartmental analysis (NCA) based on intensive pharmacokinetic profiling. Each individual patient had a pre-defined AUCcum exposure target which was used for comparison to the estimated AUCcum. To compare AUCcum based on drug monitoring and dosage adjustment across all four days of busulfan treatment versus drug monitoring and dosage adjustment on day 1 only, simulations were performed using RxODE® in the RStudio® program based on the exposure estimation methods. To examine how the method for calculating dose adjustment influences the success of attaining target AUCcum, proportional dose adjustments as recommended in the PI were compared to dose adjustments utilising a model calculated individual CL immediately prior to the next dose. In both scenarios, model-based methods were used to estimate actual AUCcum attained from samples taken at hour 0, 1, 2, and 4 post-infusion completion.
Results: Sampling from 95 subjects from 379 dosing days (2491 busulfan plasma concentration-time measurements) were collected. In a portion of subjects (n=19) data were used for the initial analysis, where both InsightRX and NextDose were able to estimate AUCcum exposure for busulfan accurately and precisely under several limited sampling strategies, with some tendency to over-estimate AUCcum compared to NCA. Application of the target concentration approach with daily sampling achieved 84.2% of patients within +/-5mg.h.L-1 of their individual pre-defined AUCcum target. Simulations based on a population pharmacokinetic model for once daily busulfan dosing in paediatric transplant patients (two-compartment model with empirical time-associated CL) showed that when NCA was used to estimate exposure this resulted in actual AUCcum being above the target in all patients regardless of whether sampling was performed daily or following dose 1 only. In comparison, utilising model-based methods to estimate AUCcum achieved more patients within +/-5mg.h.L-1 of target when a model calculated individual CL was used to calculate the subsequent dose, with increased success with daily sampling (100%) compared to following dose 1 only (0%). More subjects attained target AUCcum when utilising a model calculated individual CL to adjust the next dose/s compared to when the proportional equation from the PI was used when sampling was performed on day 1 only (100% vs 0%) however both methods performed well when daily sampling was performed (100% in both groups).
Conclusions: Study findings suggest model-based tools, such as InsightRX and NextDose, should be utilised in clinical practice for optimisation of busulfan exposure in paediatric HSCT patients. Use of these tools would allow for application of model predicted individual CL (when the model implemented allows for reduction in CL over course of treatment) to calculate subsequent doses which is preferred over the proportional calculation recommended in the busulfan PI based on linear pharmacokinetics. Performing busulfan target concentration intervention after each dose increases the success of attaining target AUCcum and is preferable over dose adjustment based on day 1 monitoring only.
1. Otsuka.America.Pharmaceutical, 2015.
2. Otsuka.Australia.Pharmaceutical.Pty.Ltd., 2018.
3. Ruutu T, van der Werf S, van Biezen A, Backman JT, Peczynski C, Kroger N, et al., 2019.
4. Bartelink IH, Lalmohamed A, van Reij EM, Dvorak CC, Savic RM, Zwaveling J, et al., 2016.
5. Lawson R, Staatz CE, Fraser CJ, Hennig S, 2021.