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健康成年人中 3 克头孢他洛/他唑巴坦的安全性、耐受性和药代动力学:一项随机、安慰剂对照、多剂量研究。

Safety, Tolerability, and Pharmacokinetics of 3 g of Ceftolozane/Tazobactam in Healthy Adults: A Randomized, Placebo-Controlled, Multiple-Dose Study.

机构信息

Merck & Co, Inc, Kenilworth, NJ, USA.

出版信息

Clin Pharmacol Drug Dev. 2018 May;7(4):382-391. doi: 10.1002/cpdd.429. Epub 2018 Mar 8.

DOI:10.1002/cpdd.429
PMID:29517862
Abstract

Ceftolozane/tazobactam is an antibacterial approved at 1.5 g (1g/0.5 g) every 8 hours (q8h); higher doses may provide additional benefits in difficult-to-treat infections. We conducted a phase I trial in healthy adults evaluating safety, tolerability, and pharmacokinetics of 3 g (2 g/1 g) ceftolozane/tazobactam administered q8h for 10 days. Sixteen participants were randomized (2:1:1) to 3 g ceftolozane/tazobactam, 1.5 g ceftolozane/tazobactam, or placebo. Participants underwent regular safety and plasma drug level assessments, with a follow-up safety visit 7 days after completion. No adverse events (AEs) were reported with placebo; 75% of participants in the 1.5-g and 50% in the 3-g arm experienced AEs. AE types were similar between the ceftolozane/tazobactam groups; all AEs were mild. No participants experienced clinically meaningful laboratory assessment or electrocardiogram abnormalities. Both ceftolozane and tazobactam exhibited dose-proportional pharmacokinetics without accumulation and without substantial differences in clearance and volume of distribution between groups. In the 3-g group, mean ceftolozane parameters were: peak concentration 104 μg/mL (day 1), 112 μg/mL (day 10); half-life 3 hours (day 10); area under the concentration-time curve (AUC ) 272 μg·h/mL (day 1), 300μg·h/mL (day 10). Mean tazobactam parameters were: peak concentration 28 μg/mL (day 1), 26 μg/mL (day 10); half-life 1 hour (day 10); AUC 47μg·h/mL (day 1), 41μg·h/mL (day 10). Administration of 3 g ceftolozane/tazobactam q8h for 10 days was safe and well tolerated in healthy volunteers.

摘要

头孢洛扎/他唑巴坦批准的剂量为 1.5g(1g/0.5g),每 8 小时一次(q8h);对于治疗困难的感染,较高的剂量可能会提供额外的益处。我们在健康成年人中进行了一项 I 期临床试验,评估了 3g(2g/1g)头孢洛扎/他唑巴坦 q8h 给药 10 天的安全性、耐受性和药代动力学。16 名参与者按照 2:1:1 的比例随机分为 3g 头孢洛扎/他唑巴坦组、1.5g 头孢洛扎/他唑巴坦组和安慰剂组。参与者定期接受安全性和血浆药物水平评估,并在完成后 7 天进行随访安全性检查。安慰剂组未报告不良事件(AE);1.5g 组和 3g 组分别有 75%和 50%的参与者发生 AE。AE 类型在头孢洛扎/他唑巴坦组之间相似;所有 AE 均为轻度。没有参与者出现有临床意义的实验室评估或心电图异常。头孢洛扎和他唑巴坦均表现出剂量比例药代动力学,无蓄积,清除率和分布容积在各组之间无显著差异。在 3g 组中,头孢洛扎的平均药代动力学参数为:峰浓度 104μg/mL(第 1 天),112μg/mL(第 10 天);半衰期 3 小时(第 10 天);浓度-时间曲线下面积(AUC)272μg·h/mL(第 1 天),300μg·h/mL(第 10 天)。他唑巴坦的平均药代动力学参数为:峰浓度 28μg/mL(第 1 天),26μg/mL(第 10 天);半衰期 1 小时(第 10 天);AUC 47μg·h/mL(第 1 天),41μg·h/mL(第 10 天)。健康志愿者 q8h 给予 3g 头孢洛扎/他唑巴坦 10 天,安全性和耐受性良好。

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