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

Abstract

Relebactam (REL [MK-7655]) is a novel class A/C β-lactamase inhibitor intended for use with imipenem for the treatment of Gram-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.

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Figures

FIG 1

Profile of study enrollment and subject populations analyzed. MITT, microbiological intent to treat; ME, microbiologically evaluable; DCIV, discontinuation of i.v. study therapy.

FIG 2

Probability of target attainment for imipenem at a dose of 500 mg q6h and distribution of KPC and P. aeruginosa strains as a function of imipenem MIC (as determined in the presence of 4 μg/ml REL). CLcr, creatinine clearance.

FIG 3

REL exposures (AUC0–24) in adults at a dose of 250 mg q6h across different body weight ranges. Boxes represent the median and 25th and 75th percentiles. Whiskers represent the 5th and 95th percentiles. Data points represent individual outlier values. The dashed horizontal line represents the upper bound of the therapeutic window for the median. The solid horizontal line represents the lower bound for the median.