Mallalieu, Navita L, Winter, Erica, Fettner, Scott, Patel, Katie, Zwanziger, Elke, Attley, Gemma, Rodriguez, Ignacio, Kano, Akiko, Salama, Sameeh M, Bentley, Darren et al (show 1 more authors)
(2020)
Safety and Pharmacokinetic Characterization of Nacubactam, a Novel β-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers.
Antimicrobial agents and chemotherapy, 64 (5).
e02229-e02219.
Text
Nacubactam SAD MAD_AAC_bioanalytical comments 8 Jan 2020_zwe.docx - Author Accepted Manuscript Download (350kB) |
Abstract
Nacubactam is a novel, β-lactamase inhibitor with dual mechanism of action as an inhibitor of serine β-lactamases (classes A, C, and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single and multiple ascending dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam 50 to 8,000 mg, multiple ascending doses of nacubactam 1,000 to 4,000 mg every 8 hours (q8h) for up to 7 days, or nacubactam 2,000 mg plus meropenem 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild-to-moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Co-administration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential β-lactam partner for nacubactam.ClinicalTrials.gov NCT02134834 (single ascending dose study); ClinicalTrials.gov NCT02972255 (multiple ascending dose study).
Item Type: | Article |
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Uncontrolled Keywords: | Beta-lactam, Beta-lactamese inhibitor, Meropenem, Multiple ascending dose |
Depositing User: | Symplectic Admin |
Date Deposited: | 28 Apr 2020 09:45 |
Last Modified: | 18 Jan 2023 23:53 |
DOI: | 10.1128/aac.02229-19 |
Open Access URL: | https://aac.asm.org/content/64/5/e02229-19 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3084656 |