Phase I studies assessing safety and pharmacokinetics of nacubactam administered alone or in combination with cefepime or aztreonam in Japanese healthy participants.

Nacubactam is a novel developed β-lactamase inhibitor. Two randomized, double-blind, placebo-controlled phase 1 studies (OP0595-2 and -4 studies) were conducted to evaluate its pharmacokinetics and safety in healthy Japanese male participants. In the OP0595-2 study, single ascending doses (1, 2, and 4 g) and multiple doses (1 and 2 g per dose for 7 days) of nacubactam were administered intravenously over 90 min. In the OP0595-4 study, 2 g of nacubactam was administered intravenously over 60 min for 7 days in combination with cefepime or aztreonam (2 g per dose each). In both studies, participants were randomized in a 3:1 ratio to receive nacubactam or placebo. In the OP0595-2 study, exposure to nacubactam increased in a dose-dependent manner following single infusion, with steady mean trough plasma concentrations observed after Day 4 during multiple dosing. Metabolites of nacubactam were detected at low levels compared to the parent drug. Nacubactam was predominantly excreted unchanged in the urine, indicating minimal metabolic clearance. In the OP0595-4 study, administration of cefepime or aztreonam did not alter the pharmacokinetic profile of nacubactam. In both studies, nacubactam, whether administered alone or combined with cefepime or aztreonam, was generally well tolerated. These favorable findings support further clinical development of nacubactam.