Dorr Mary Beth, de Oliveira Carlos Fernando, van de Wetering Jeroen, Lowe Kathryn, Sabato Philip, Winchell Gregory, Chen Hongzi, McGovern Paul C
VenatoRx Pharmaceuticals Inc, Malvern, Pennsylvania, USA.
PRA Health Sciences, Groningen, the Netherlands.
Antimicrob Agents Chemother. 2025 Sep 3;69(9):e0008725. doi: 10.1128/aac.00087-25. Epub 2025 Aug 5.
Ledaborbactam etzadroxil, the prodrug of the active β-lactamase inhibitor ledaborbactam, is being developed in combination with ceftibuten to treat serious infections caused by drug-resistant Enterobacterales. This study evaluated the safety and pharmacokinetics of ceftibuten in healthy adults at anticipated higher doses required, in combination with ledaborbactam etzadroxil, to treat Enterobacterales infections. Thirty-six participants ( = 12 per cohort [ceftibuten = 9, placebo = 3]) received a single oral dose of ceftibuten (400, 800, or 1,200 mg) or matched placebo on day 1. Following a one-day washout, the same participants received repeat oral doses of ceftibuten (400 mg once daily, 400 mg every 12 hours [q12h], or 400 mg q8h) for 10 days. Of the 36 participants, 25 (ceftibuten 67%, placebo 78%) reported 65 treatment-emergent adverse events (TEAEs). Nausea (22%), headache (15%), and fatigue (15%) were the most reported TEAEs among ceftibuten-treated participants. No participant experienced serious adverse events or discontinuations due to TEAEs. In both single- and multiple-dose cohorts, cis-ceftibuten isomer exposure was dose-proportional for areas under the curve (AUCs) but less than dose-proportional for maximum concentrations (). Low levels of cis-ceftibuten accumulation were observed at steady state, with accumulation ratios of 1.06, 1.09, and 1.24 for the 400 mg once daily, q12h, and q8h cohorts, respectively. Cis-ceftibuten and trans-ceftibuten recovery in urine was 47% and 6%, respectively, following a single dose of 1,200 mg.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04314206.
活性β-内酰胺酶抑制剂来达巴坦的前药来达巴坦依扎多昔，正与头孢布烯联合开发，用于治疗由耐药肠杆菌科细菌引起的严重感染。本研究评估了在治疗肠杆菌科细菌感染所需的预期更高剂量下，头孢布烯与来达巴坦依扎多昔联合使用时在健康成年人中的安全性和药代动力学。36名参与者（每组12人[头孢布烯组9人，安慰剂组3人]）在第1天接受单次口服剂量的头孢布烯（400、800或1200毫克）或匹配的安慰剂。经过一天的洗脱期后，相同的参与者接受重复口服剂量的头孢布烯（每日一次400毫克、每12小时一次400毫克[q12h]或每8小时一次400毫克），持续10天。在36名参与者中，25人（头孢布烯组67%，安慰剂组78%）报告了65起治疗中出现的不良事件（TEAE）。在接受头孢布烯治疗的参与者中，最常报告的TEAE是恶心（22%）、头痛（15%）和疲劳（15%）。没有参与者因TEAE发生严重不良事件或停药。在单剂量和多剂量组中，顺式头孢布烯异构体的曲线下面积（AUC）暴露呈剂量比例关系，但最大浓度（）小于剂量比例关系。在稳态时观察到顺式头孢布烯有低水平的蓄积，每日一次400毫克、q12h和q8h组的蓄积比分别为1.06、1.09和1.24。单次服用1200毫克后，尿液中顺式头孢布烯和反式头孢布烯的回收率分别为47%和6%。临床试验本研究已在ClinicalTrials.gov注册为NCT04314206。
