Zidebactam Phase 1 Single Ascending Dose and Crossover Study in Healthy Subjects

Background: Zidebactam (WCK 5107) is a new chemical entity (NCE) exhibiting a novel mode of action. WCK 5222, a combination of cefepime and β-lactam enhancer zidebactam, is being developed to provide a therapeutic option for the treatment of infections caused by MDR Gram-negative pathogens harbouring metallo-β-lactamases (MBL) associated with enterics and Pseudomonas as well as carbapenem-hydrolysing (CHDL) Class D β-lactamases in Acinetobacter spp and Klebsiella. WCK 5222 is based on a novel ‘enhancer’ mechanism that involves complementary binding to essential PBPs by its constituents, cefepime and zidebactam.

Methods: 70 healthy volunteers were enrolled in 7 single ascending dose (SAD) cohorts (8 subjects on zidebactam and 2 on placebo in each cohort) to receive intravenous (IV) zidebactam ranging from 250 mg to 3000 mg in a double-blind manner. 9 subjects each in 2 crossover cohorts received 3 IV treatments in a randomized treatment order: zidebactam alone, cefepime alone, and combination of cefepime and zidebactam at 2 dose levels of zidebactam (1000 mg and 2000 mg), each followed by a 3 day washout period.

Results: In the SAD cohorts, the exposure of zidebactam (AUC_0-Inf) increased in a dose-proportional manner from 44.3 to 458 µg*h/mL and C_max from 16.5 to 174 µg/mL over the 250 mg – 3000 mg dose range. The elimination half-life ranged from 1.84 to 2.39 h. For the cross-over cohorts, AUC_0-Inf, C_max, t_1/2, and related PK parameters were consistent between 2 treatments (drugs administered alone versus in combination), and for both zidebactam and cefepime. More than 80% of the administered dose of zidebactam and cefepime was excreted as unchanged drug within 0 to 6 h postdose.

All treatment-emergent adverse events (TEAEs) were mild (except for 2 events of headache, which were moderate in severity). No deaths, SAEs or discontinuations due to AEs were reported during the study.

Conclusion:

• Zidebactam increases in PK parameters were dose proportional within the 250 mg to 3000 mg dose range.
• No significant PK interaction was observed when zidebactam and cefepime were co‑administered at two different zidebactam dose levels.
• Zidebactam was safe and well tolerated up to 3000 mg alone, or in combination with cefepime at the 2 dose levels tested for zidebactam.