de Oliveira Carlos Fernando, Dorr Mary Beth, 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):e0021025. doi: 10.1128/aac.00210-25. Epub 2025 Aug 5.
Ledaborbactam etzadroxil (LED-E), a novel oral prodrug that converts to the active β-lactamase inhibitor (BLI) ledaborbactam (LED), is being developed in combination with ceftibuten (CTB) to address a need for oral treatments against drug-resistant Enterobacterales infections. Two Phase 1 studies were conducted to (i) evaluate the safety and pharmacokinetics of single doses of LED-E 100 to 1000 mg and multiple doses of LED-E 75 to 500 mg every 8 h (q8h) for 10 days, (ii) assess potential drug interactions between CTB and LED, and (iii) evaluate safety and pharmacokinetics following multiple doses of LED-E 300 or 500 mg with CTB 400 mg or placebo q8h for 10 days. Treatment-emergent adverse events (TEAEs) were reported for 82% LED-E ± CTB ( = 109) and 78% placebo (=27) participants, respectively. TEAEs of gastrointestinal disorders were reported for 28% of the LED-E ± CTB and 15% of placebo participants. Following single doses, LED-E AUC was less than 2% of LED exposures, demonstrating extensive conversion to active BLI. LED AUC increased dose proportionally following single LED doses and less than proportionally following multiple LED-E doses. After 10 days of q8h dosing, the LED terminal half-life in plasma was approximately 11 to 12 h. Steady-state urinary excretion of LED-E-derived material (comprised almost entirely of unchanged LED) was 84%. No clinically relevant CTB and LED PK interactions occurred with the CTB + LED-E combination. These results support further development of the CTB + LED-E combination for the treatment of complicated urinary tract infections caused by drug-resistant Enterobacterales.CLINICAL TRIALSThese studies are registered with ClinicalTrials.gov as NCT04243863 and NCT04877379.
来达硼巴坦依扎多昔（LED-E）是一种新型口服前药，可转化为活性β-内酰胺酶抑制剂（BLI）来达硼巴坦（LED），目前正与头孢布烯（CTB）联合开发，以满足口服治疗耐药肠杆菌科细菌感染的需求。进行了两项1期研究，目的是：（i）评估单剂量100至1000mg LED-E以及每8小时（q8h）多次服用75至500mg LED-E，持续10天的安全性和药代动力学；（ii）评估CTB与LED之间的潜在药物相互作用；（iii）评估多次服用300或500mg LED-E与400mg CTB或安慰剂q8h，持续10天的安全性和药代动力学。分别有82%接受LED-E±CTB治疗的参与者（n = 109）和78%接受安慰剂治疗的参与者（n = 27）报告了治疗期间出现的不良事件（TEAE）。28%接受LED-E±CTB治疗的参与者和15%接受安慰剂治疗的参与者报告了胃肠道疾病的TEAE。单剂量给药后，LED-E的AUC小于LED暴露量的2%，表明其广泛转化为活性BLI。单剂量LED给药后，LED的AUC与剂量成比例增加，而多次服用LED-E后增加幅度小于剂量比例。每8小时给药10天后，血浆中LED的终末半衰期约为11至12小时。LED-E衍生物质（几乎完全由未变化的LED组成）的稳态尿排泄率为84%。CTB与LED的联合用药未发生临床相关的药代动力学相互作用。这些结果支持进一步开发CTB + LED-E联合用药，用于治疗由耐药肠杆菌科细菌引起的复杂性尿路感染。临床试验这些研究已在ClinicalTrials.gov注册，注册号为NCT04243863和NCT04877379。
