Safety and Pharmacokinetic Characterization of Nacubactam, a Novel β-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers



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).

[img] Text
Nacubactam SAD MAD_AAC_bioanalytical comments 8 Jan 2020_zwe.docx - Accepted Version

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
Uncontrolled Keywords: Beta-lactam, Beta-lactamese inhibitor, Meropenem, Multiple ascending dose
Depositing User: Symplectic Admin
Date Deposited: 28 Apr 2020 09:45
Last Modified: 17 Oct 2021 00:11
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