Chattergoon D S, Saunders E F, Klein J, Calderwood S, Doyle J, Freedman M H, Koren G
Division of Hematology/Oncology, Hospital for Sick Children, and University of Toronto, Ontario, Canada.
Bone Marrow Transplant. 1997 Sep;20(5):347-54. doi: 10.1038/sj.bmt.1700891.
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.
对接受骨髓移植的儿童进行的白消安（BU）药代动力学（PK）研究表明，可能需要根据个体情况调整BU剂量，以优化BU的全身暴露量。优化BU的全身暴露量可能会改善骨髓移植的治疗效果并降低毒性。由于从儿童身上采血存在实际限制且出于经济原因，需要一种有限采样方法（LSM）。然而，此类针对BU的方法尚未在儿童中得到验证。在本研究中，我们根据40mg/m²的BU试验剂量后测得的9个血清BU浓度计算出的BU曲线下面积（BU AUC），对10名儿童的口服BU剂量进行个体化调整，以使BU AUC达到900 - 1400微摩尔/分钟。我们使用3个BU浓度来验证一种LSM以确定AUC。在研究的9名患者中（1名患者不可评估），有6名患者需要调整剂量（3名降低；3名增加）。平均剂量变化百分比为26.2%（范围为 - 33.3%至 + 45.3%）。我们的三个样本LSM计算出的BU AUC(0 - ∞)（1098 ± 344，平均值 ± 1标准差）与我们的九个样本计算出的BU AUC(0 - ∞)（1132 ± 389）高度相关（Pearson相关系数r = 0.98，P = 0.0001），并且经t检验无显著差异（P = 0.3）。在我们的每位患者中，三个样本LSM AUC与九个样本AUC之间的平均百分比差异为7.5%（范围为 - 10.九九%至 + 9.4%）。谷浓度与AUC的相关性非常好（r = 0.95，P = 0.0001）。在大多数儿童中，基于AUC进行个体化BU给药对于达到靶向的BU治疗水平是必要的。在BU试验剂量后0.5小时、1小时和6小时进行的三个BU浓度的LSM能密切预测由九个采样点计算出的AUC。
