Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects
Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects
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DOI：
10.1128/aac.02228-17
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发表时间：
2018-04-01
影响因子：
4.9
通讯作者：
Griffith, David C.
中科院分区：
文献类型：
--
作者：
Rubino, Christopher M.;Bhavnani, Sujata M.;Griffith, David C.
美罗培南-瓦波巴坦是新型β -内酰胺酶抑制剂瓦波巴坦和碳青霉烯类抗生素美罗培南的固定组合，用于治疗耐药革兰氏阴性菌引起的严重感染。在一项随机、安慰剂对照、双盲研究中，对76名健康成人受试者进行了维巴坦和美罗培南单次和多次递增剂量单独或联合用药后的安全性、耐受性和药代动力学（PK）的评估。受试者被纳入单独或联合使用的5个剂量队列中的1个（接受250 - 2000 mg瓦博巴坦和/或1000 - 2000 mg美罗培南）。没有受试者因不良事件（ae）而中断研究，也没有观察到严重的ae。美罗培南与瓦波巴坦单独或联合用药时药代动力学相似；所有评估的血浆PK暴露测量（峰值血浆浓度，从时间0到最后可测量的血浆浓度-时间曲线下面积[AUC]，以及从时间0到无穷远的AUC）对于研究药物单独使用与联合使用相似，表明美罗南和瓦博巴坦之间没有药代动力学相互作用。在所有治疗中，47 - 64%的美罗培南和75 - 95%的瓦博巴坦在给药后48小时内随尿排出。美罗培南和瓦波巴坦单独或联合使用时，具有相似的药代动力学特性，无血浆或尿液药代动力学相互作用，耐受性良好。这些发现支持了该联合产品的进一步临床研究。
Meropenem-vaborbactam is a fixed combination of the novel beta-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product.