Phase 2, Dose-Ranging Study of Relebactam with Imipenem-Cilastatin in Subjects with Complicated Intra-abdominal Infection

Abstract

f Relebactam (REL [MK-7655]) is a novel class A/C ␤-lactamase inhibitor intended for use with imipenem for the treatment ofGram-negative bacterial infections. REL restores imipenem activity against some resistant strains of Klebsiella and Pseudomonas. In this multicenter, double-blind, controlled trial (NCT01506271), subjects who were >18 years of age with complicated intra-abdominal infection were randomly assigned (1:1:1) to receive 250 mg REL, 125 mg REL, or placebo, each given intravenously (i.v.) with 500 mg imipenem-cilastatin (IMI) every 6 h (q6h) for 4 to 14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of i.v. therapy (DCIV). A total of 351 subjects were randomized, 347 (99%) were treated, and 255 (73%) were ME at DCIV (55% male; mean age, 49 years). The most common diagnoses were complicated appendicitis (53%) and complicated cholecystitis (17%). Thirty-six subjects (13%) had imipenem-resistant Gram-negative infections at baseline. Both REL doses plus IMI were generally well tolerated and demonstrated safety profiles similar to that of IMI alone. Clinical response rates at DCIV were similar in subjects who received 250 mg REL plus IMI (96.3%) or 125 mg REL plus IMI (98.8%), and both were noninferior to IMI alone (95.2%; one-sided P < 0.001). The treatment groups were also similar with respect to clinical response at early and late follow-up and microbiological response at all visits. Pharmacokinetic/pharmacodynamic simulations show that imipenem exposure at the proposed dose of 500 mg IMI with 250 mg REL q6h provides coverage of >90% of carbapenem-resistant bacterial strains.

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

“…The appropriateness of the dosing regimen was confirmed by a probability-of-target-attainment (PTA) analysis demonstrating >90% PTA following the initial phase 2 study for patients with complicated IAIs (29). This regimen has been evaluated in a phase 3 study of patients with imipenem-resistant bacterial infections (RESTORE-IMI 1 [ClinicalTrials registration no.…”

“…pneumoniae, and P. aeruginosa, coadministration of 250 or 125 mg of relebactam with imipenem-cilastatin resulted in favorable clinical responses in 96.3% or 98.8%, respectively (29). This combination was well tolerated, and the incidence of study discontinuation due to AEs was low (29).…”

Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae

“…Relebactam is a novel ␤-lactamase inhibitor currently being evaluated for use with imipenem for the treatment of Gram-negative bacterial infections (16,17). Like avibactam, it inhibits class A and C ␤-lactamases and has no activity against MBLs.…”

Novel Beta-Lactamase Inhibitors: Unlocking Their Potential in Therapy

“…[42] However, certain models did suggest higher concentrations of relebactam may be required for highly resistant strains of Pseudomonas . [42]…”

“…In the introduction to their phase 2 data, Lucasti et al refer to phase I unpublished data that relebactam is well tolerated with intravenous administration as either a single dose of up to 1150 mg or when administered at multiple doses of625 mg every 6 hours. [42] Notably, transient liver enzyme elevation did occur in several patients who received multiple administration dosing. [42]…”