A Phase I, randomized, double-blind, placebo-controlled, dose escalation study to evaluate the safety, tolerability, and pharmacokinetics of intravenous ertapenem and zidebactam in combination (WCK 6777) in healthy adult subjects

Resumo

ABSTRACT WCK 6777 is a novel once-daily β-lactam enhancer combination comprising ertapenem (ERT) and zidebactam (ZID), designed to expand ERT activity against multidrug-resistant gram-negative Enterobacterales, including serine- and metallo-β-lactamase producers. This first-in-human, randomized, double-blind, placebo-controlled Phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of WCK 6777 and its individual components following once-daily intravenous administration for 7 days in healthy adults. In total, 54 participants were enrolled, of whom 52 received ERT alone (2 or 3 g), ZID alone (2 or 3 g), WCK 6777 (ERT + ZID at 1 + 1, 2 + 2, or 3 + 3 g), or placebo. Safety assessments included adverse events, clinical laboratory testing, vital signs, and electrocardiography. Plasma and urine PK of total and unbound ERT and ZID were characterized using noncompartmental methods. WCK 6777 was safe and well tolerated at all dose levels, with no deaths, serious adverse events, or treatment discontinuations. Adverse events were predominantly mild or moderate and were most commonly infusion-site reactions. Both ERT and ZID exhibited predictable, time-independent PK. Ertapenem exhibited a biphasic disposition with a terminal half-life supportive of once-daily dosing, whereas ZID displayed linear PK across the evaluated dose range. Plasma exposure, clearance, protein binding, and renal excretion were comparable between monotherapy and combination regimens, indicating no clinically meaningful PK interaction. Both drugs were eliminated predominantly unchanged in urine. In summary, WCK 6777 demonstrated a favorable safety profile and predictable PK following once-daily administration, supporting further clinical development, including evaluation in Phase II/III efficacy studies and potential application in outpatient parenteral antimicrobial therapy. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT05645757 .