β-lactamase

Relebactam and imipenem together show efficacy against multidrug-resistant P. aeruginosa and KPC-producing Enterobacteriaceae[1].
Relebactam has antipseudomonal activity and exhibits a limited inhibition of Class D-producing bacteria[2].

Imipenem with relebactam was active against Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp., including K. pneumoniae carbapenemase (KPC)-producing isolates. Loss of OmpK36 in KPC-producing K. pneumoniae isolates affected the susceptibility of this combination. Enhanced activity was evident against Pseudomonas aeruginosa, including isolates with depressed oprD and increased ampC expression. However, the addition of relebactam to imipenem did not provide added benefit against Acinetobacter baumannii. The combination of imipenem with relebactam demonstrated activity against KPC-producing Enterobacteriaceae and multidrug-resistant P. aeruginosa[1].

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β-Lactamase inhibitors (BLIs) have played an important role in combatting β-lactam resistance in Gram-negative bacteria, but their effectiveness has diminished with the evolution of diverse and deleterious varieties of β-lactamases. In this review, a new generation of BLIs and inhibitor combinations is presented, describing epidemiological information, pharmacodynamic studies, resistance identification and current clinical status. Novel serine BLIs of major interest include the non-β-lactams of the diazabicyclo[3.2.1]octanone (DBO) series. The DBOs avibactam, relebactam and RG6080 inhibit most class A and class C β-lactamases, with selected inhibition of class D enzymes by avibactam. The novel boronic acid inhibitor RPX7009 has a similar inhibitory profile. All of these inhibitors are being developed in combinations that are targeting primarily carbapenemase-producing Gram-negative pathogens. Two BLI combinations (ceftolozane/tazobactam and ceftazidime/avibactam) were recently approved by the US Food and Drug Administration (FDA) under the designation of a Qualified Infectious Disease Product (QIDP). Other inhibitor combinations that have at least completed phase 1 clinical trials are ceftaroline fosamil/avibactam, aztreonam/avibactam, imipenem/relebactam, meropenem/RPX7009 and cefepime/AAI101. Although effective inhibitor combinations are in development for the treatment of infections caused by Gram-negative bacteria with serine carbapenemases, better options are still necessary for pathogens that produce metallo-β-lactamases (MBLs). The aztreonam/avibactam combination demonstrates inhibitory activity against MBL-producing enteric bacteria owing to the stability of the monobactam to these enzymes, but resistance is still an issue for MBL-producing non-fermentative bacteria. Because all of the inhibitor combinations are being developed as parenteral drugs, an orally bioavailable combination would also be of interest.[2]

Two pharmacodynamic studies have been conducted for the imipenem/relebactam combination. Although the efficacy of imipenem is related to the time the drug concentration exceeds a defined threshold, efficacy of the combination with relebactam (and cilastatin) is less well established. Hollow-fibre studies based on the results from mathematical models and computer simulations defined a novel pharmacodynamic index, the time above instantaneous MIC, or T > MICi. This study showed that different imipenem/relebactam dosing regimens correlated with comparable bacterial killing when T > MICi was 69%. In a murine thigh model, the index defining the effect of relebactam was poorly related to the maximum serum drug concentration, but showed correlations that were similar for both T > MIC (when relebactam was dosed at 4 mg/L) and area under the concentration–time curve (AUC)/MIC ratio [130]. Efficacy in dose-escalating studies in the thigh model was related to the imipenem MIC of the strain, the dose of imipenem/cilastatin and the AUC for the unbound fraction of relebactam (mean fAUC of 26 mg h/L).[2]

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Clinical development has utilised the imipenem/cilastatin combination together with relebactam for phase 2 and phase 3 trials. This triple combination completed a phase 2 dose-ranging trial that studied the safety, tolerability and efficacy of the combination to treat cIAI, utilising two relebactam doses (125 mg and 250 mg) with a standard dose of 500 mg imipenem/cilastatin dosed intravenously every 6 h. Two randomised, double-blind, active comparator-controlled phase 3 clinical trials are being initiated. One is studying the efficacy and safety of the triple combination to treat imipenem-resistant bacterial infection compared with imipenem/cilastatin plus colistin, and the second is comparing the safety and efficacy of the combination against piperacillin/tazobactam for the treatment of pneumonia. In these studies, imipenem/cilastatin and relebactam will be dosed in a 2:1 ratio. In the first study there is an option for an open-label arm for patients to be treated with the relebactam triple combination if pathogens are deemed to be resistant to both sets of study drugs.[2]

Absorption, Distribution and Excretion
Currently, relebactam is only available as an intravenous product; therefore, there is no relevant absorption data in the literature.
Approximately 90-100% of relebactam is renally eliminated.
Relebactam has a volume of distribution of approximately 19 L with both single and steady state dosing.
Relebactam has a reported total clearance of approximately 130-150 mL/min (8 L/h). About 30% of the total drug clearance can be attributed to active tubular secretion.

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Metabolism / Metabolites
Relebactam does not undergo significant metabolism and can be found mostly unchanged in human plasma.

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Biological Half-Life
Relebactam has a half-life of 1.2 hours as per official FDA labeling. Values reported in pharmacokinetic studies vary from 1.35-1.8 hours.

Protein Binding
Relebactam is approximately 22% plasma protein bound.

[1]. Activity of Imipenem with Relebactam against Gram-Negative Pathogens from New York City. Antimicrob Agents Chemother. 2015 Aug;59(8):5029-31.

[2]. Bush K. A resurgence of β-lactamase inhibitor combinations effective against multidrug-resistant Gram-negative pathogens. Int J Antimicrob Agents. 2015 Nov;46(5):483-93.

Relebactam is a diazabicyclooctane beta-lactamase inhibitor, similar in structure to [avibactam]. It includes a piperidine ring which reduces export from bacterial cells by producing a positive charge. It is currently available in a combination product which includes [imipenem] and [cilastatin] to treat complicated urinary tract infections (UTIs), pyelonephritis, and complicated intra-abdominal infections in adults. It is considered to be a last-line treatment option and gained FDA approval as part of the combination product RecarbrioⓇ in July 2019.
Relebactam anhydrous is a beta Lactamase Inhibitor. The mechanism of action of relebactam anhydrous is as a beta Lactamase Inhibitor.

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Drug Indication
Relebactam is indicated in combination with [imipenem] and [cilastatin] for the treatment of complicated urinary tract infections (including pyelonephritis), and complicated intra-abdominal infections caused by susceptible organisms in adults.

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Mechanism of Action
Relebactam is a beta-lactamase inhibitor known to inhibit many types of beta-lactamases including Ambler class A and Ambler class C enzymes, helping to prevent [imipenem] from degrading in the body. Similar to the structurally-related [avibactam], first, relebactam binds non-covalently to a beta-lactamase binding site, then, it covalently acylates the serine residue in the active site of the enzyme. In contrast to some other beta-lactamase inhibitors, once relebactam de-acylates from the active site, it can reform it's 5 membered ring and is capable of rebinding to target enzymes.

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Pharmacodynamics
Relebactam prevents the hydrolysis of [imipenem], allowing it to exert its bactericidal effect.

C12H20N4O6S

348.3754

348.11

41.37; H, 5.79; N, 16.08; O, 27.55; S, 9.20

1174018-99-5

1174020-13-3 (hydrate); 1502858-91-4 (sodium); 1174018-99-5 (free acid);

44129647

White to off-white solid powder.

0.533

3

7

4

23

585

2

S(=O)(=O)(O[H])ON1C(N2C([H])([H])[C@@]1([H])C([H])([H])C([H])([H])[C@@]2([H])C(N([H])C1([H])C([H])([H])C([H])([H])N([H])C([H])([H])C1([H])[H])=O)=O

SMOBCLHAZXOKDQ-ZJUUUORDSA-N

InChI=1S/C12H20N4O6S/c17-11(14-8-3-5-13-6-4-8)10-2-1-9-7-15(10)12(18)16(9)22-23(19,20)21/h8-10,13H,1-7H2,(H,14,17)(H,19,20,21)/t9-,10+/m1/s1

(1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate

MK-7655; Relebactam; MK 7655; Relebactam anhydrous; (-)-Relebactam anhydrous; Relebactam [INN]; 1OQF7TT3PF; CHEMBL3112741;MK7655

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 70~125 mg/mL (200.93~358.80 mM ) H2O : ~50 mg/mL (~143.52 mM )

Solubility in Formulation 1: 25 mg/mL (71.76 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)