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

Abstract

Nacubactam is a novel β-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine β-lactamases (classes A and 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 of 50 to 8,000 mg, multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for up to 7 days, or nacubactam of 2,000 mg plus meropenem of 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. Coadministration 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. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].).

Keywords: beta-lactam; beta-lactamase inhibitor; meropenem; multiple ascending dose; nacubactam; pharmacokinetics; phase I; single ascending dose.

Copyright © 2020 Mallalieu et al.

Figures

FIG 1

Overview of the SAD and MAD study designs. Symbols: *, dosing q8h for 7 days; †, single dose on day 1, with the option to extend to q8h dosing for 7 days after confirmation of pharmacokinetics, safety, and tolerability; ‡, single dose of either nacubactam or meropenem, allocated in a crossover manner on days 1 and 2; §, single dose of both drugs in combination; **, single dose on days 1 to 3. q8h, dosing on days 4 to 9. q8h, every 8 h.

FIG 2

Log-linear overlay plot of mean nacubactam plasma concentrations over time after nacubactam q8h dosing for 7 days in the MAD study. Data are arithmetic means ± standard deviations from day 7 (part 1) or day 9 (part 2).

FIG 3

Mean nacubactam (A) and meropenem (B) plasma concentration-time profiles after dosing with nacubactam alone or nacubactam coadministered with meropenem.

FIG 4

Placebo-adjusted change in QTcF as a function of concentration (with 90% confidence intervals) from linear model.