Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a β-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants

Abstract

Relebactam is a novel class A and C β-lactamase inhibitor that is being developed in combination with imipenem-cilastatin for the treatment of serious infections with Gram-negative bacteria. Here we report on two phase 1 randomized, double-blind, placebo-controlled pharmacokinetics, safety, and tolerability studies of relebactam administered with or without imipenem-cilastatin to healthy participants: (i) a single-dose (25 to 1,150 mg) and multiple-dose (50 to 625 mg every 6 h [q6h] for 7 to 14 days) escalation study with men and (ii) a single-dose (125 mg) study with women and elderly individuals. Following single- or multiple-dose intravenous administration over 30 min, plasma relebactam concentrations declined biexponentially, with a terminal half-life (t_1/2) ranging from 1.35 to 1.85 h independently of the dose. Exposures increased in a dose-proportional manner across the dose range. No clinically significant differences in pharmacokinetics between men and women, or between adult and elderly participants, were observed. Urine pharmacokinetics demonstrated that urinary excretion is the major route of relebactam elimination. No drug-drug interaction between relebactam and imipenem-cilastatin was observed, and the observed t_1/2 values for relebactam, imipenem, and cilastatin were comparable, thus supporting coadministration. Relebactam administered alone or in combination with imipenem-cilastatin was well tolerated across the dose ranges studied. No serious adverse events or deaths were reported. The pharmacokinetic profile and favorable safety results supported q6h dosing of relebactam with imipenem-cilastatin in clinical treatment trials.

Keywords: pharmacokinetics; relebactam; β-lactamase inhibitor.

FIG 1

Study design. Predose baseline safety evaluations were conducted, and blood and urine samples were collected within 24 h prior to dosing. Safety assessments were conducted through the duration of dosing and continued through approximately 14 days after the last dose.

FIG 2

Plasma relebactam concentration-versus-time profiles (on a semilog scale) following administration of single doses (25 mg to 1,150 mg) of relebactam to healthy male participants in study 1. Concentrations were measured in 2 patient cohorts, indicated by black (panel A) or gray (panel B) lines. Within each cohort, participants received 250 mg relebactam during one of the study periods.

FIG 3

Arithmetic mean concentrations of relebactam (A), imipenem (B), and cilastatin (C) in plasma (on a semilog scale) over time following administration of a single 500-mg i.v. dose of relebactam, either alone or together with imipenem-cilastatin, to healthy male patients in study 1.

FIG 4

Plasma exposures and concentration-versus-time profiles following administration of a single dose of relebactam with imipenem-cilastatin. Shown are plasma exposures of relebactam (A), imipenem (C), and cilastatin (E) and plasma concentration-versus-time profiles for relebactam (B), imipenem (D), and cilastatin (F) on a semilog scale.