Safety, Pharmacokinetics, and Drug-Drug Interaction Potential of Intravenous Durlobactam, a β-Lactamase Inhibitor, in Healthy Subjects

• Published in: Antimicrobial agents and chemotherapy Vol. 64; no. 7
• Main Authors: Lickliter, Jason D., Lawrence, Kenneth, O’Donnell, John, Isaacs, Robin
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 23.06.2020
• Subjects: Aged; Anti-Bacterial Agents - adverse effects; beta-Lactamase Inhibitors; Cilastatin, Imipenem Drug Combination; Double-Blind Method; Drug Interactions; Healthy Volunteers; Humans; Pharmacology; β-lactamases; pharmacokinetics; drug interactions
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.00071-20

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. 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.)