Résumé
The objective of this First-in-Human Phase 1, double-blind, randomized, placebo-controlled study was to assess the pharmacokinetics (PK), safety, and tolerability of the dual targeting beta-lactamase inhibitor xeruborbactam (QPX7728) in healthy adults. The study included single-ascending (SAD) and multiple-ascending dose (MAD) cohorts. Subjects received intravenous xeruborbactam at doses ranging from 250 to 2,000 mg. PK parameters of total and unbound xeruborbactam were derived from plasma, ultrafiltrate, and urine samples. Adverse events (AEs) were monitored and assessed throughout the study. Fifty-two subjects participated (39 xeruborbactam and 13 placebo). Following single doses, total and unbound xeruborbactam exhibited dose-dependent increases in exposure parameters (Cmax, AUC0-24, and AUC0-INF). Mean terminal half-life ranged from 26.8 to 32.0 h for total xeruborbactam, and from 20.7 to 22.4 h for unbound xeruborbactam. The mean fraction of the administered dose excreted in the urine ranged from 82.9% to 85.0% after single doses, and from 71.5% to 81.2% after multiple doses. After repeated 8-hourly dosing in MAD cohorts 7 and 8, the mean accumulation ratios for total xeruborbactam were 5.0 and 6.1. Plasma protein binding showed a concentration-dependent trend, with increased unbound xeruborbactam concentrations at higher doses. AEs were not different between xeruborbactam and placebo participants and included headache, vascular access site bruising and pain, and self-resolving mild increases in alanine transaminases. No severe or serious AEs were observed. Xeruborbactam was primarily eliminated renally. Dose proportionality was only observed for unbound xeruborbactam. Significant accumulation was noted with 8-hourly dosing. Xeruborbactam at doses up to 1,000 mg daily for 7-10 days was well tolerated, with no serious or life-threatening AEs. Xeruborbactam was primarily eliminated renally. Dose proportionality was only observed for unbound xeruborbactam. Significant accumulation was noted with 8-hourly dosing. Xeruborbactam at doses up to 1,000 mg daily for 7-10 days was well tolerated, with no serious or life-threatening AEs.