An improved limited sampling method for individualised busulphan dosing in bone marrow transplantation in children

Busulphan (BU) pharmacokinetic (PK) studies in children undergoing bone marrow transplantation suggest that individual BU dosing may be necessary to optimise BU systemic exposure. Optimising BU systemic exposure may improve outcome and decrease toxicity in BMT. Because of practical limitations in obtaining blood from children and for financial reasons, a limited sampling method (LSM) is needed. However, such methods for BU have not been validated in children. In the present study, we individualized oral BU dosing in 10 children to target an area under the curve of BU (BU AUC) of 900-1400 microM/min based on BU AUC(0-infinity) calculated from nine serum BU concentrations performed after a BU test dose of 40 mg/m2. We validated a LSM using 3 BU concentrations to determine AUC. Six of nine patients studied (one patient non-evaluable), required their doses modified (3, lower; 3, higher). The mean percent dose change was 26.2% (range -33.3% to +45.3%). Our three sample LSM BU AUC(0-infinity) (1098 +/- 344, mean +/- 1 s.d.) correlated highly with our nine sample BU AUC(0-infinity) (1132 +/- 389, Pearson r = 0.98, P = 0.0001) and was not significantly different by t-test (P = 0.3). The mean percentage difference between the three sample LSM AUCs and the nine sample AUCs in each of our patients was 7.5%, (range -10.99% to +9.4%). Trough levels correlated extremely well with AUC (r = 0.95, P = 0.0001). Individual BU dosing, based on AUC, is necessary in most children to achieve targeted levels of BU therapy. An LSM of three BU concentrations performed at 0.5 h, 1 h and 6 h post-BU test dose closely predicts the AUC calculated from nine sampling points.