High-dose weekly AmBisome antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: A pharmacokinetic study
High-dose weekly AmBisome antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: A pharmacokinetic study
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DOI：
10.1016/j.bbmt.2005.10.010
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发表时间：
2006-02-01
影响因子：
4.3
通讯作者：
Davies, S
中科院分区：
文献类型：
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作者：
Mehta, P;Vinks, A;Davies, S
在接受造血干细胞移植（HSCT）的儿童中，播散性真菌感染导致显著的发病率和死亡率。预防性口服三唑类药物的广泛使用具有吸收不良、代谢个体间差异和肝毒性的局限性。AmBisome（阿替霉素B脂质体复合物）具有比母体药物阿替霉素B更好的安全性，并产生更高的血浆和组织浓度。我们假设每周一次的高剂量AmBisome治疗可以为接受HSCT的免疫功能低下儿童提供足够的真菌预防。我们进行了一项药代动力学初步研究，以确定每周一次高剂量AmBisome给药是否会在整个给药间隔期间产生有效浓度。共14例接受HSCT的儿童（中位年龄：3岁1个月;范围：4.5个月-9岁9个月）接受每周一次AmBisome静脉注射预防（10 mg/kg，2小时输注）。在第一次和第四次每周一次给药前后采集用于药代动力学测量的血样。通过经验证的生物测定法测定血浆中非脂质复合的阿朴霉素的浓度。使用标准非房室方法计算单次给药后和稳态期间的药代动力学参数。AmBisome在该剂量下耐受良好。在12例患者中获得了第1周和第4周的完整药代动力学曲线。在该儿科人群中计算的半衰期平均短于成人中报告的半衰期（45小时vs 152小时）。分布容积与体重相关性最好（R-2 =.55），清除率最好通过初始血清肌酐水平预测（R-2 =.19）。单次给药后的平均（+/-标准差）个体血浆谷浓度为0.23（0.13）mg/L，多次给药后为0.47（0.41）mg/L。平均稳态曲线下面积在第4周高于单次给药后（P
Disseminated fungal infection causes significant morbidity and mortality in children undergoing hematopoietic stem cell transplantation (HSCT). The widespread use of prophylactic oral triazoles has limitations of poor absorption, interindividual variability in metabolism, and hepatic toxicity. AmBisome (amphotericin B liposomal complex) has a better safety profile than the parent drug amphotericin B and produces higher plasma and tissue concentrations. We hypothesized that once-weekly high-dose AmBisome therapy could provide adequate fungal prophylaxis for immunocompromised children undergoing HSCT. We performed a pharmacokinetic pilot study to determine whether once-weekly high-dose AmBisome administration would result in effective concentrations throughout the dosing interval. A total of 14 children (median age, 3 years, 1 month; range, 4.5 months-9 years, 9 months) undergoing HSCT received once-weekly intravenous AmBisome prophylaxis (10 mg/kg as a 2-hour infusion). Blood samples for pharmacokinetic measurements were drawn around the first and the fourth weekly doses. The concentration of non-lipid-complexed amphotericin in plasma was determined by a validated bioassay. Pharmacokinetic parameters after single doses and during steady state were calculated using standard noncompartmental methods. AmBisome was well tolerated at this dose. Complete pharmacokinetic profiles for weeks 1 and 4 were obtained in 12 patients. The half-life calculated in this pediatric population was shorter on average than reported in adults (45 hours vs 152 hours). The volume of distribution correlated best with body weight (R-2 =.55), and clearance was best predicted by initial serum creatinine level (R-2 =.19). Mean (+/- standard deviation) individual plasma trough concentrations were 0.23 (0.13) mg/L after single doses and 0.47 (0.41) mg/L after multiple doses. Mean steady-state area under the curve was higher at week 4 than after a single dose (P