Plasma and Intrapulmonary Concentrations of ETX2514 and Sulbactam following Intravenous Administration of ETX2514SUL to Healthy Adult Subjects [Pharmacology]

ETX2514 is a novel β-lactamase inhibitor that broadly inhibits Ambler class A, C and D β-lactamases. ETX2514 combined with sulbactam (SUL) in vitro restores sulbactam activity against Acinetobacter baumannii. ETX2514/sulbactam (ETX2514SUL) is under development for the treatment of A. baumannii infections. The objective of this study was to determine and compare plasma, epithelial lining fluid (ELF) and alveolar macrophages (AM) concentrations following intravenous (i.v.) ETX2514 and sulbactam. Plasma, ELF, and AM concentrations of ETX2514 and sulbactam were measured by LC-MS/MS in 30 healthy adult subjects following repeated dosing (ETX2514 [1 g] and sulbactam [1 g] q6h, as a 3-hour i.v. infusion, for a total of 3 doses). A bronchoalveolar lavage (BAL) was performed once in each subject at either 1, 2.5, 3.25, 4 or 6 h after the start of the last infusion. Penetration ratios were calculated from AUC_0–6 values for total plasma and ELF using mean and median concentrations at the BAL sampling times. Respective ELF AUC_0-6, based on mean and median concentrations, were 40.1 and 39.4 mg·h/liter for ETX2514 and 34.7 and 34.5 mg·h/liter for sulbactam. Respective penetration ratios of ELF to total/unbound plasma concentrations, based on mean/median AUC_0-6, of ETX2514 were 0.36/0.40 and 0.35/0.39, whereas these same ratio values were 0.5/0.81 and 0.50/0.80 for sulbactam. ETX2514 and sulbactam concentrations in AM were measurable and fairly constant throughout the dosing interval (median values of 1.31 and 1.01 mg/liter, respectively). These data support further study of ETX2514SUL for treatment of pneumonia caused by multidrug-resistant A. baumanni.

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