Busulfan disposition in children.
Busulfan disposition in children.
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DOI：
10.1182/blood.v75.8.1723.1723
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发表时间：
1990-04
期刊：
影响因子：
20.3
通讯作者：
L. Grochow;W. Krivit;C. Whitley;B. Blazar
中科院分区：
文献类型：
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作者：
L. Grochow;W. Krivit;C. Whitley;B. Blazar
儿童在恶性和非恶性骨髓移植前口服丁硫凡作为清髓治疗的一部分。据报道，儿童的严重毒性发生率很低，完全植入失败的发生率也很高。我们使用气相色谱法评估了2个月至3.6岁患有溶酶体贮积病、白血病和免疫缺陷疾病的儿童在接受口服剂量1或2mg /kg时的处理情况。峰值浓度低于先前报道的成人浓度，范围为1.4至5.2 μ mol/L。消除半衰期的谐波平均值为92分钟，仅略快于成人（140分钟）。然而，曲线下的面积从400到1,000 (715 +/- 240)μ mol不等。min/L，显著低于接受1mg /kg治疗的成人（范围：710 ~ 5100 mmol .min/L；平均+/- SD， 2180 +/- 1200）。表观分布体积（假设完全生物利用度）范围为0.28 ~ 3.53 L/kg(1.42 +/- 0.86)，是成人报告的（0.60 +/- 0.42）的两倍多。儿童（200 +/- 100 mL/min/m2）的布磺胺清除率是成人（95 +/- 54 mL/min/m2）的两倍。生物利用度（吸收或第一次消除）或实际分布量的改变可以解释药物处置的这些差异。观察到的差异表明需要在儿童中进行单独的I期剂量递增研究，并伴随药代动力学评估。
Children receive busulfan orally as part of myeloablative therapy before bone marrow transplantation for malignant and nonmalignant conditions. Children have been reported to have a low incidence of severe toxicity and significant rates of failure to achieve full engraftment. We evaluated the disposition of busulfan in children between 2 months and 3.6 years of age with lysosomal storage diseases, leukemia, and immunodeficiency disorders receiving oral doses of 1 or 2 mg/kg using a gas chromatographic assay. Peak concentrations were lower than those previously reported for adults, ranging from 1.4 to 5.2 mumol/L. The harmonic mean of the elimination half-life was 92 minutes, which is only slightly faster than that for adults (140 minutes). However, the area under the curve ranged from 400 to 1,000 (715 +/- 240) mumol.min/L, substantially lower than in adults receiving 1 mg/kg (range, 710 to 5,100 mumol.min/L; mean +/- SD, 2,180 +/- 1,200). The apparent volume of distribution (assuming complete bioavailability) ranged from 0.28 to 3.53 L/kg (1.42 +/- 0.86), which is more than twice that reported for adults (0.60 +/- 0.42). Busulfan clearance rate normalized to surface area is twice as high in children (200 +/- 100 mL/min/m2) as it is in adults (95 +/- 54 mL/min/m2). Alterations in bioavailability (absorption or first pass elimination) or in actual volume of distribution may account for these differences in drug disposition. The observed differences suggest the need for separate phase I dose escalation studies in children with accompanying pharmacokinetic assessment.