Pharmacokinetics, safety, and tolerability of nacubactam (OP0595) after intravenous infusion: a randomized, double-blind, placebo-controlled phase I clinical trial in healthy Chinese male subjects.

The rise of carbapenem-resistant Enterobacteriaceae (CRE) has posed a major clinical challenge, with limited treatment options. Nacubactam, a novel β-lactamase inhibitor, combined with cefepime or aztreonam, effectively supports CRE infection treatment. A randomized, double-blind, placebo-controlled clinical trial was conducted for the first time in healthy male Chinese subjects, including both single and multiple doses 60 ± 5-min intravenous infusion. Twenty participants were randomly assigned to nacubactam or placebo in two dosage groups (1 g and 2 g, 10 subjects each) to evaluate pharmacokinetics, safety, and tolerability. Nacubactam demonstrated good safety and tolerability in healthy male Chinese subjects after single and multiple doses intravenous infusion with no adverse events leading to study withdrawal. Nacubactam reached peak concentration immediately after infusion, had a short half-life, and showed dose-proportional exposure. At steady state, drug accumulation was minimal. The cumulative urinary excretion rates of nacubactam were 91.8% and 87.1% in the two dose groups, indicating primary renal elimination. Exposure to metabolites M1 and M2 was minimal. Nacubactam generally exhibited good safety and tolerability in healthy Chinese male subjects after single and multiple doses of 1 g/2 g intravenous doses. It was primarily excreted renally with minimal accumulation. Carbapenem-resistant Enterobacteriaceae (CRE) have become a growing global health threat due to limited treatment options and high morbidity and mortality. Nacubactam is a novel β-lactamase inhibitor that exerts dual inhibition on β-lactamases and penicillin-binding proteins. Its combination with ceftazidime or aztreonam is promising for treating multidrug-resistant Gram-negative bacterial infections. To support clinical development and future therapeutic applications, pharmacokinetic and safety data in different populations are crucial. In this work, we conducted a phase I randomized, double-blind, placebo-controlled trial to clinically evaluate nacubactam for the first time in healthy Chinese male subjects, demonstrating its good safety profile, dose-proportional pharmacokinetics, and mainly renal excretion. These data provide insights into the clinical application of nacubactam.Trial registration This trial was registered on the Chinese Clinical Trial Registration website, registration number ChiCTR2500103582.