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

Abstract

Relebactam is a small-molecule β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin. The pharmacokinetics of relebactam and imipenem across 10 clinical studies were analyzed using data from adult healthy volunteers and patients with bacterial infections. Renal function estimated by creatinine clearance significantly affected the clearance of both compounds, whereas weight and health status were of less clinical significance. Simulations were used to calculate probability of joint target attainment (ratio of free drug area under the curve from 0 to 24 hours to minimum inhibitory concentration (MIC) for relebactam and percentage of time the free drug concentration exceeded the MIC for imipenem) for the proposed imipenem/relebactam dose of 500/250 mg, with adjustments for patients with renal impairment, administered as a 30-minute intravenous infusion four times daily. These dosing regimens provide sufficient antibacterial coverage (MIC ≤ 4 μg/mL) for all renal groups.Relebactam is a small-molecule β-lactamase inhibitor active against classes A and C β-lactamases that is being developed as a fixed-dose combination with imipenem/cilastatin (PRIMAXIN, Whitehouse Station, NJ). 1,2 Imipenem is an approved carbapenem β-lactam antibacterial agent that covers many gram-negative organisms and certain gram-positive organisms and anaerobes. 2 Cilastatin alone has no antibacterial activity, but prevents the metabolism of imipenem by renal dehydropeptidase produced in vivo.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. [3][4][5] 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. 6,7 From these

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

“…When evaluating the pharmacokinetics of IMI‐REL IMI 500 mg–REL 250 mg every 6 hours in available patient data, the authors suggested that the f AUC/MIC 0–24 hr of 7.5 would have been achieved in all patients with bacterial isolates with MIC values ≤ 4 µg/ml. In the pharmacokinetic model performed by researchers, the probability of attaining this target was > 90% for isolates with IMI‐REL MIC values ≤ 4 µg/ml, including patients with dose reductions based on their renal function …”

“…76 Recently, researchers pooled pharmacokinetic data from 10 IMI-REL studies, including patients with cIAI, cUTI, and hospital-acquired or ventilator-associated bacterial pneumonia (HABP/ VABP). 77 These patients also had varying levels of renal function, including some who underwent hemodialysis, allowing for estimation of pharmacokinetics in these important patient populations. The authors evaluated the effects of several covariates, and renal function had the most important impact on IMI-REL concentrations.…”

“…In the pharmacokinetic model performed by researchers, the probability of attaining this target was > 90% for isolates with IMI-REL MIC values ≤ 4 µg/ml, including patients with dose reductions based on their renal function. 77…”

Augmented Renal Clearance and How to Augment Antibiotic Dosing

“…The exposures from this increased regimen were confirmed to be adequate upon completion of this study [ 71 ]. A population pharmacokinetic analysis that took ARC into consideration was performed for imipenem/relebactam [ 72 ]. It found a more than 90% probability of target attainment (PTA) when using a 500/250 mg dose against an imipenem MIC of 4 mg/L when creatinine clearance is 90 to 250 mL/min.…”

The Strategies of Pathogen-Oriented Therapy on Circumventing Antimicrobial Resistance

“…Relebactam-imipenem is currently being evaluated for the treatment of Gram-negative bacterial infections, including hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, complex intraperitoneal infection, and urinary tract infection caused by MDR pathogens, especially P. aeruginosa and carbapenemase-producing E. coli , K. pneumoniae , and Enterobacter [ 74 – 76 ]. Prescription of imipenem combined with relebactam for the treatment of Gram-negative bacterial infections is currently in phase III of a clinical trial [ 41 ].…”