Evaluation of busulfan stability in infusion bags and biological matrix: Application to routine therapeutic drug monitoring with adaptive dosing in children

Purpose: High Dose Busulfan is administered using pharmacokinetically guided dosing for conditioning protocols before hematopoietic stem cell transplantation. To be reliable, this strategy requires that administered doses and drug levels measured from samples are not affected by degradation before being assayed. Methods: Busulfan stability at clinically meaningful concentrations was monitored by liquid chromatography/mass spectrometry in infusion bags as well as in human blood and plasma, using various storage conditions. Next, TDM (Therapeutic Drug Monitoring) with adaptive dosing was implemented in routine setting to customize the dosing in a child scheduled for High dose Busulfan. Results: Busulfan was stable up to 72h in 0.25 mg/mL infusion bags, up to 24 hours in plasma regardless of the storage condition, and up to 16 hours in whole blood at 4°C. Conversely, blood samples of Busulfan left at room temperature showed a rapid degradation, suggesting that they should be rapidly proceeded in a temperature-controlled fashion. When applied next to children treated with High Dose Busulfan following 8 to 16 administrations over 4 consecutive days, TDM with PK-guided dosing was successfully performed to tailor the dosing and reached the desired target exposure. Upon initial standard dosing, deviation from the target AUC ranged from -52.3% to +11.5%. Busulfan dosing was subsequently adapted from Dose-9 for the 7 remaining administrations) and final cumulative AUCs showed deviation from the target from -22% to +13.6%. Conclusion: Busulfan blood samples must be rapidly proceeded in refrigerated condition upon sampling to allow reliable TDM and adaptive dosing in paediatric oncology.