Department of Blood and Marrow Transplantation, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.
Biol Blood Marrow Transplant. 2012 Jul;18(7):1099-107. doi: 10.1016/j.bbmt.2011.12.584. Epub 2011 Dec 23.
Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 μM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status ≥70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 μM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 μM-min (level 2) and 220 mg/m(2)/day for AUC 9,000 μM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P < .01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 μM-min × 4 days) was the maximally tolerated AUC. Within the confines of the trial's small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 μM-min × 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse.
全身暴露于高剂量白消安与恶性血液病造血细胞移植后的疗效和毒性相关。我们采用浓度-时间曲线下面积（AUC）来前瞻性确定在氟达拉滨 40mg/m² 连续 4 天后每天静脉给予白消安时的最大耐受全身暴露量。计划了 3 个目标 AUC 水平：6000、7500 和 9000μM-min。纳入标准为年龄 16-65 岁、血液恶性肿瘤、HLA A、B 或 C、DRB1 8/8 或 7/8 匹配供体、卡氏功能状态评分≥70%和足够的器官功能。对于 1 级患者，静脉给予白消安剂量 1 和 2 为 170mg/m²/天，然后根据首次剂量药代动力学模型调整剂量 3 和 4，以达到 6000μM-min 的平均日 AUC。随后队列的剂量 1 和 2 基于 1 级数据：AUC 为 7500μM-min（2 级）的 180mg/m²/天和 AUC 为 9000μM-min（3 级）的 220mg/m²/天，剂量 3 和 4 进行药代动力学靶向。最后一剂后的药代动力学分析显示，88%的患者暴露于目标值 10%以内的平均 AUC。40 名患者接受了 1 级治疗，29 名患者接受了 2 级治疗，3 名患者接受了 3 级治疗。剂量限制性毒性为肝静脉闭塞性疾病，1 级 40 名患者中无（0%）发生，2 级 29 名患者中 2 名（7%）发生，3 级 3 名患者中 3 名（100%）发生。更高 AUC 水平时还会出现皮疹（P<.01）和肺部毒性（P=.01）。2 级（7500μM-min×4 天）是最大耐受 AUC。在试验样本量小的范围内，没有证据表明从 6000 增加到 7500μM-min×4 天的白消安 AUC 会增加非复发死亡率。评估更高的白消安 AUC 对预防复发的作用需要在复发风险同质的患者中进行试验。
