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Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability. A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated. Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16–23 kg; 0.95 mg/kg for >23–34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3–17.2 years (median 5.6 years). No difference in AUC values was observed between weight strata (mean ± SD 1248 ± 205 μmol·min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900–1500 μmol·min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window. [ABSTRACT FROM AUTHOR]