Clinical Impact of Maximum Plasma Concentration of Busulfan in Pediatric Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation

Busulfan's narrow therapeutic index and high pharmacokinetic (PK) variability warrant investigation of its exposure–toxicity relationship. We retrospectively analyzed 334 pediatric and young adult patients who underwent allogeneic hematopoietic stem cell transplantation at Seoul National University Children's Hospital between 2009 and 2020 and received once‐daily intravenous busulfan over four days (3‐hour infusion, n = 122; 6‐hour infusion, n = 212). Factors associated with toxicities were identified using multivariable logistic regression, and overall survival (OS) was evaluated by Kaplan–Meier and Cox regression analyses. Despite comparable exposures, the 3‐hour infusion group showed higher C max (4,260.2 vs 3,028.6 μg/L, P < 0.0001) and more frequent liver function test elevations (13.1% vs 0.5%, P < 0.0001). Receiver operating characteristic analysis identified a C max cut‐off of 4269.6 μg/L as a factor for hepatotoxicity. The 4‐year OS was superior in the 6‐hour infusion group (82.3% vs 71.9%, P = 0.02) and in the low C max group (80.8% vs 66.5%, P = 0.01). Cox regression revealed C max as an independent predictor of OS. A population PK model was developed using NONMEM. A 1‐compartment model incorporating enzyme turnover auto‐inhibition successfully described the busulfan PK profile. Simulations of published once‐daily dosing regimens showed that extending the infusion to 6 hours successfully maintained C max below the cut‐off threshold. These results show that maintaining busulfan C max below 4269.6 μg/L is associated with improved safety and survival. Prolonged infusion should be considered when adopting the busulfan once‐daily regimen.