Abstract
Durlobactam (DUR; also known as ETX2514) is a novel β-lactamase inhibitor with broad activity against Ambler class A, C, and D β-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem-cilastatin (IMI-CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In part A, subjects, including a cohort of elderly subjects (which received DUR at 1 g), received single ascending doses of DUR ranging from 0.25 to 8 g. In part B, multiple ascending doses of DUR ranging from 0.25 to 2 g were administered every 6 h (q6h) for 29 doses. In parts C and D, the drug-drug interaction (DDI) potential, including the safety, of DUR (1 g) with SUL (1 g) and/or IMI-CIL (0.5/0.5 g) was investigated after single and multiple doses. Plasma and urine concentrations of DUR, SUL, and IMI-CIL were determined. Among 124 subjects, DUR was generally safe and well tolerated when it was administered either alone or in combination with SUL and/or IMI-CIL. After single and multiple doses, DUR demonstrated linear dose-proportional exposure across the studied dose ranges. Renal excretion was a predominant clearance mechanism. No drug-drug interaction potential between DUR and SUL and/or IMI-CIL was identified. SUL-DUR at 1 g (of each component) administered q6h with a 3-h intravenous (i.v.) infusion is under development for the treatment of serious infections due to A. baumannii (This study has been registered at ClinicalTrials.gov under identifier NCT02971423.).
Highlights
Durlobactam (DUR; known as ETX2514) is a novel -lactamase inhibitor with broad activity against Ambler class A, C, and D -lactamases
Acinetobacter baumannii belongs to a cluster of bacterial species referred to as the A. baumannii-A. calcoaceticus complex (ABC), the members of which are associated with serious infections, including hospital-acquired and ventilator-associated bacterial pneumonia and bloodstream, wound, and complicated urinary tract infections [1, 2]
All 124 subjects were included in the safety population, and all 94 who received DUR were included in the PK population
Summary
Durlobactam (DUR; known as ETX2514) is a novel -lactamase inhibitor with broad activity against Ambler class A, C, and D -lactamases. The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem-cilastatin (IMI-CIL) were evaluated in healthy subjects. In parts C and D, the drug-drug interaction (DDI) potential, including the safety, of DUR (1 g) with SUL (1 g) and/or IMI-CIL (0.5/0.5 g) was investigated after single and multiple doses. Among 124 subjects, DUR was generally safe and well tolerated when it was administered either alone or in combination with SUL and/or IMI-CIL. The combination of sulbactamdurlobactam (SUL-DUR) exhibited potent in vitro and in vivo activity against ABC isolates, including carbapenem-resistant ABC and colistin-resistant isolates [17, 19,20,21,22]
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