Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects
Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects
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DOI：
10.1128/aac.47.4.1318-1323.2003
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发表时间：
2003-04-01
影响因子：
4.9
通讯作者：
Arbeit, RD
中科院分区：
文献类型：
--
作者：
Dvorchik, BH;Brazier, D;Arbeit, RD
这篇文章的目的是建立每日一次递增剂量的达托霉素的药代动力学和安全性。达托霉素是一种新型脂肽抗生素，对革兰氏阳性病原菌，包括对甲氧西林和万古霉素耐药的病原菌具有活性。这项第一阶段的多剂量双盲研究涉及24名健康受试者，分为3个剂量组(4、6和8 mg/kg体重)，随机接受达托霉素或对照组，按3：1的比例接受治疗，每24天静脉滴注30分钟，持续7~14天。血样和尿样测定达托霉素的药代动力学。安全性和耐受性通过监测不良事件和实验室参数进行评估。达托霉素的药代动力学在6 mg/kg范围内呈线性，在所研究的最高剂量(8 mg/kg)的曲线和谷浓度下的区域有轻微的非线性(类似于20%)。在研究期间的中位数天(第7天)测量的药代动力学参数为半衰期(类似于9h)、分布体积(类似于0.1L/kg)、全身清除量(类似于8.2ml/h/kg)以及在0-24小时内从尿中完整排泄的药物的百分比(类似于54%)。达托霉素蛋白结合量(平均结合量为91.7%)与药物浓度无关。未观察到性别效应。所有接受达托霉素治疗的受试者都完成了这项研究。接受达托霉素治疗的受试者和对照受试者的治疗应急性不良反应的频率和分布相似。没有严重的不良反应，也没有剂量相关事件的模式。达托霉素每日1次给药在6 mg/kg范围内呈线性关系。对于所有三种剂量，达托霉素的血浆浓度在整个给药间隔内是一致的和可预测的。达托霉素每日1次，剂量高达8 mg/kg，连续给药14天，耐受性良好。
The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 It for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight (similar to20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life (similar to9 h), volume of distribution (similar to0.1 liters/kg), systemic clearance (similar to8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h (similar to54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.