Evaluation of safety and pharmacokinetics of administering intravenous busulfan in a twice-daily or daily schedule to patients with advanced hematologic malignant disease undergoing stem cell transplantation
Evaluation of safety and pharmacokinetics of administering intravenous busulfan in a twice-daily or daily schedule to patients with advanced hematologic malignant disease undergoing stem cell transplantation
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DOI：
10.1053/bbmt.2002.v8.pm12374453
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发表时间：
2002-01-01
影响因子：
4.3
通讯作者：
Goodman, MS
中科院分区：
文献类型：
--
作者：
Fernandez, HF;Tran, HT;Goodman, MS
静脉注射白消安（IV BU）已证明在每剂量0.8 mg/kg IV每6小时X 16次给药时具有安全性。我们评价了接受造血干细胞移植（HSCT）的患者接受相同的每日IV BU总剂量（3.2 mg/kg）每日两次输注或单次输注的安全性和药代动力学（PK）。12例恶性血液病患者接受了治疗，其中7例为非霍奇金淋巴瘤，4例为急性髓细胞性白血病，1例为慢性髓细胞性白血病。第一个队列（A组）根据实际体重接受IV BU，剂量为1.6 mg/kg/剂，持续4小时，每12小时一次，持续4天（第-7天至第-4天）。第二队列（组B）接受每剂3.2 mg/kg IV BU（总剂量与A组相同）单次输注，每天4小时，持续4天。在两组中，W BU之后是环磷酰胺60 mg/kg/天，持续2天（第-3天和第-2天）。A组在第1、5和7次给药时采集血样，B组在第1和4次给药时采集血样，以确定IV BU的分布。在环磷酰胺给药完成后2天（第0天）给予外周血干细胞（7例为自体，5例为HLA匹配的同种异体），并在同一天开始粒细胞集落刺激因子5 μ g/kg。移植物抗宿主病的预防包括他克莫司加甲氨蝶呤的异基因干细胞受体。1例患者发生假定的真菌性肺炎，并在第+21天死于多系统器官功能障碍，之后才能评价血液学重建。另一名患者于第40天在家中猝死，原因不明。其余患者在中位11天时植入（中性粒细胞绝对计数>500/穆尔），并且在中位14天时持续血小板计数> 20，000/穆尔。显著的方案相关毒性（III-IV级）仅限于肝毒性（2例）、导管感染（2例）、鼻出血（3例）、腹泻（1例）、厌食（1例）、粘膜炎（1例）、高血糖症（1例）、肺炎（1例）和败血症（1例）。B组有1例轻度静脉闭塞疾病，已消退，无后遗症。未观察到中枢神经系统或肺毒性。药代动力学参数（包括清除率、半衰期、最大浓度和曲线下面积）表明，首次给药曲线高度预测后续给药PK曲线。未观察到药物蓄积。尽管血浆浓度-时间较高，但给药方案的变化并未增加毒性或终末器官损伤。虽然需要进一步研究长期疗效，但对于接受HSCT的患者，IV BU可以安全地给予，每日两次分次或每日一次给药方案的结果可重现。
Intravenous busulfan (IV BU) has demonstrated safety when administered at 0.8 mg/kg per dose IV every 6 hours X 16 doses. We evaluated the safety and pharmacokinetics (PK) of giving the same total daily IV BU dose (3.2 mg/kg) either divided as a twice-daily infusion or as a single infusion to patients undergoing hematopoietic stem cell transplantation (HSCT). Twelve patients with hematologic malignant disease were treated; 7 patients had non-Hodgkin's lymphoma, 4 patients had acute myeloid leukemia, and 1 patient had chronic myelogenous leukemia. The first cohort (group A) received, on the basis of actual body weight, IV BU at 1.6 mg/kg per dose over 4 hours every 12 hours for 4 days (day -7 to day -4). The second cohort (group B) received 3.2 mg/kg per dose of IV BU (same total dose as group A) as a single infusion over 4 hours daily for 4 days. In both groups the W BU was followed by cyclophosphamide 60 mg/kg daily for 2 days (day -3 and day -2). Blood specimens were collected on the first, fifth, and seventh doses for group A and on the first and fourth doses for group B to determine the disposition of IV BU. Peripheral blood stem cells (autologous in 7 cases and HLA-matched allogeneic in 5 cases) were given 2 days after completion of cyclophosphamide administration (day 0), and granulocyte colony-stimulating factor 5 mug/kg was started on the same day. GVHD prophylaxis consisted of tacrolimus plus methotrexate for recipients of allogeneic stem cells. One patient developed presumed fungal pneumonia and died of multisystem organ dysfunction on day +21 before hematologic reconstitution could be evaluated. Another was reported to have sudden death of undetermined cause at home on day 40. The remaining patients had engraftment (absolute neutrophil count >500/muL) at a median of 11 days and sustained platelet counts >20,000/muL at a median of 14 days. Significant regimen-related toxicity (grade III-IV) was limited to hepatic toxicity (2 cases) catheter infection (2 cases), epistaxis (3 cases), diarrhea (1 case), anorexia (I case), mucositis (I case), hyperglycemia (I case), pneumonia (1 case), and sepsis (1). In group B there was 1 case of mild venoocclusive disease, which resolved without sequelae. No central nervous system or pulmonary toxicity was noted. Pharmacokinetic parameters, including clearance, half-life, maximum concentration, and area under the curve, demonstrated that the first dose profile was highly predictive of later dose PK profiles. No accumulation of the drug was noted. The change in dosing schedule did not increase toxicity or end-organ damage despite higher plasma concentration-times. Although further study for long-term efficacy is warranted, IV BU can be given safely with reproducible results on a twice-daily divided or single-daily dosing schedule to patients undergoing HSCT.