Walsh T J, Yeldandi V, McEvoy M, Gonzalez C, Chanock S, Freifeld A, Seibel N I, Whitcomb P O, Jarosinski P, Boswell G, Bekersky I, Alak A, Buell D, Barret J, Wilson W
Pediatric Oncology Branch, National Institutes of Health, Bethesda, Maryland, USA.
Antimicrob Agents Chemother. 1998 Sep;42(9):2391-8. doi: 10.1128/AAC.42.9.2391.
The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.
对36名接受癌症化疗和骨髓移植且持续发热的中性粒细胞减少成人患者，评估两性霉素B的一种小单室脂质体制剂（安必素）用于经验性抗真菌治疗时的安全性、耐受性和药代动力学。该方案是一项开放标签、序贯剂量递增、多剂量药代动力学研究，四个剂量组每组共纳入8至12名患者。每个组每日接受以安必素形式给予的两性霉素B剂量分别为1.0、2.5、5.0或7.5mg/千克体重。研究人群包括年龄在13至80岁之间、有中性粒细胞减少（绝对中性粒细胞计数<500/mm³）且有资格接受经验性抗真菌治疗的患者。通过频繁的实验室检查和监测输液相关反应来监测患者的安全性和耐受性。通过监测侵袭性真菌感染的发生来评估疗效。安必素的药代动力学参数通过高效液相色谱法作为两性霉素B的参数进行测量。采用非房室方法计算药代动力学参数。在该人群中，以1小时输注方式给予的安必素耐受性良好，很少与输液相关毒性相关。331次输注中，15次（5%）出现输液相关副作用，只有两名患者（5%）需要预处理。在任何剂量组中，血清肌酐、钾和镁水平与基线相比均无显著变化，血清转氨酶水平也没有净升高。安必素呈现出与网状内皮系统摄取和再分布一致的非线性剂量关系。在使用安必素进行经验性治疗期间，没有出现突破性真菌感染。本研究中给予发热中性粒细胞减少患者的安必素耐受性良好，很少与输液相关毒性相关，具有非线性饱和动力学特征，并且在预防突破性真菌感染方面有效。
