Exploring the Pharmacokinetic/Pharmacodynamic Relationship of Relebactam (MK-7655) in Combination with Imipenem in a Hollow-Fiber Infection Model

Abstract

Resistance to antibiotics among bacterial pathogens is rapidly spreading, and therapeutic options against multidrug-resistant bacteria are limited. There is an urgent need for new drugs, especially those that can circumvent the broad array of resistance pathways that bacteria have evolved. In this study, we assessed the pharmacokinetic/pharmacodynamic relationship of the novel β-lactamase inhibitor relebactam (REL; MK-7655) in a hollow-fiber infection model. REL is intended for use with the carbapenem β-lactam antibiotic imipenem for the treatment of Gram-negative bacterial infections. In this study, we used an hollow-fiber infection model to confirm the efficacy of human exposures associated with the phase 2 doses (imipenem at 500 mg plus REL at 125 or 250 mg administered intravenously every 6 h as a 30-min infusion) against imipenem-resistant strains of and Dose fractionation experiments confirmed that the pharmacokinetic parameter that best correlated with REL activity is the area under the concentration-time curve, consistent with findings in a murine pharmacokinetic/pharmacodynamic model. Determination of the pharmacokinetic/pharmacodynamic relationship between β-lactam antibiotics and β-lactamase inhibitors is complex, as there is an interdependence between their respective exposure-response relationships. Here, we show that this interdependence could be captured by treating the MIC of imipenem as dynamic: it changes with time, and this change is directly related to REL levels. For the strains tested, the percentage of the dosing interval time that the concentration remains above the dynamic MIC for imipenem was maintained at the carbapenem target of 30 to 40%, required for maximum efficacy, for imipenem at 500 mg plus REL at 250 mg.

Population Pharmacokinetic Analysis for Imipenem–Relebactam in Healthy Volunteers and Patients With Bacterial Infections

“…For selected dosing regimens ( Table ), joint PTA was assessed based on the established imipenem efficacy target criteria of 6.5% f T > MIC and the relebactam efficacy target criteria of f AUC 0–24 hours /MIC ≥ 5.2 . Imipenem and relebactam free fractions in human plasma (0.80 and 0.78, respectively) were used to simulate unbound concentrations.…”

“…In vitro susceptibility and hollow fiber (HF) time‐kill studies found that relebactam restored the activity of subinhibitory concentrations of imipenem against imipenem‐resistant isolates . Animal studies further confirmed the activity of relebactam, and integrated translational pharmacokinetic/pharmacodynamic (PK/PD) modeling suggested that the combination of imipenem/relebactam would be efficacious against the majority of imipenem‐resistant strains at clinically achievable doses and concentrations .…”

“…For imipenem and other carbapenem antibiotics, the primary PK/PD driver is the percent of the dosing interval during which the free drug concentration exceeds MIC ( f T > MIC) . Based on the HF data, an imipenem efficacy target criteria of 6.5% f T > MIC was established as needed to achieve 2‐log kill of Pseudomonas aeruginosa and Enterobacteriaceae in the presence of relebactam …”

Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

“…78,79 Researchers studied the pharmacokinetics and pharmacodynamics of IMI-REL against K. pneumoniae, E. coli, S. marcescens, and P. aeruginosa in an in vitro hollow-fiber model. 79 In their model, they determined that the best marker of IMI-REL efficacy was imipenem time above dynamic imipenem MIC. Dynamic MIC values for imipenem were calculated by determining imipenem MIC values in the presence of varying levels of relebactam based on their simulated dosing regimens.…”

An Appraisal of the Pharmacokinetic and Pharmacodynamic Properties of Meropenem-Vaborbactam

“…As our understanding of the mechanism of action and PD parameters that govern BLI continues to improve, it is crucial that each newly developed BLI undergo a thorough PK/PD evaluation in combination with several potential BL agents of interest in order to establish the PK/PD driver of efficacy and determine thresholds for bactericidality and suppression of resistance for that specific BL-BLI combination. This is highlighted by the discordance in PK/PD drivers observed for avibactam compared to vaborbactam and relebactam [32] despite their similar spectrums of activity and may contribute, in part, to the emergence of resistance observed, albeit infrequently, during clinical use of ceftazidime-avibactam [33]. As use of meropenem-vaborbactam increases, future real-world clinical outcomes data will help determine if these PK/PD advantages translate into improved outcomes for these difficult-to-treat infections.…”