Identification

Name
Relebactam
Accession Number
DB12377
Description

Relebactam is a diazabicyclooctane beta-lactamase inhibitor, similar in structure to avibactam.5,6 It includes a piperidine ring which reduces export from bacterial cells by producing a positive charge.6 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.Label It is considered to be a last-line treatment option and gained FDA approval as part of the combination product RecarbrioⓇ in July 2019.9

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 348.37
Monoisotopic: 348.110355554
Chemical Formula
C12H20N4O6S
Synonyms
  • Relebactam anhydrous
External IDs
  • MK-7655

Pharmacology

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.Label

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

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

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.Label,3,4,5 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.2,5,7 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.5

TargetActionsOrganism
ABeta-lactamase TEM
inhibitor
Escherichia coli
ABeta-lactamase SHV-1
inhibitor
Escherichia coli
ABeta-lactamase CTX-M
inhibitor
Escherichia coli
ABeta-lactamase (KPC-2)
inhibitor
Klebsiella pneumoniae
ABeta-lactamase
inhibitor
Enterobacter cloacae
Absorption

Currently, relebactam is only available as an intravenous product; therefore, there is no relevant absorption data in the literature.

Volume of distribution

Relebactam has a volume of distribution of approximately 19 L with both single and steady state dosing.Label,1,2

Protein binding

Relebactam is approximately 22% plasma protein bound.Label,8

Metabolism

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

Route of elimination

Approximately 90-100% of relebactam is renally eliminated.Label,1,2

Half-life

Relebactam has a half-life of 1.2 hours as per official FDA labeling.Label Values reported in pharmacokinetic studies vary from 1.35-1.8 hours.1,2

Clearance

Relebactam has a reported total clearance of approximately 130-150 mL/min (8 L/h).Label,1,2 About 30% of the total drug clearance can be attributed to active tubular secretion.Label

Adverse Effects
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Toxicity

If overdose with the combination product which includes relebactam, imipenem and cilastatin occurs, the drug should be stopped immediately and the patient should be provided with supportive care.Label Relebactam, imipenem, and cilastatin may be removed via hemodialysis; however, the use of hemodialysis to manage cases of overdose has not been studied.Label

Affected organisms
  • Pseudomonas aeruginosa
  • Escherichia coli
  • Bacteroides fragilis
  • Enterobacter cloacae
  • Klebsiella pneumoniae
  • Klebsiella oxytoca
  • Citrobacter freundii
  • Bacteroides thetaiotaomicron
  • Klebsiella aerogenes
  • Bacteroides caccae
  • Bacteroides ovatus
  • Bacteroides stercoris
  • Bacteroides uniformis
  • Bacteroides vulgatus
  • Fusobacterium nucleatum
  • Parabacteroides distasonis
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbemaciclibThe excretion of Abemaciclib can be decreased when combined with Relebactam.
Acetylsalicylic acidThe excretion of Relebactam can be decreased when combined with Acetylsalicylic acid.
AcyclovirThe excretion of Relebactam can be decreased when combined with Acyclovir.
Aminohippuric acidThe excretion of Relebactam can be decreased when combined with Aminohippuric acid.
ApalutamideThe excretion of Relebactam can be decreased when combined with Apalutamide.
AtalurenThe excretion of Relebactam can be decreased when combined with Ataluren.
AvatrombopagThe excretion of Relebactam can be decreased when combined with Avatrombopag.
BaricitinibThe excretion of Baricitinib can be decreased when combined with Relebactam.
Benzoic acidThe excretion of Relebactam can be decreased when combined with Benzoic acid.
BenzylpenicillinThe excretion of Relebactam can be decreased when combined with Benzylpenicillin.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

Product Ingredients
IngredientUNIICASInChI Key
Relebactam sodiumEX0546AJ8R1502858-91-4MMUZXOWPDRLGBD-UXQCFNEQSA-M
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
RecarbrioRelebactam (250 mg/100mL) + Cilastatin (500 mg/100mL) + Imipenem (500 mg/100mL)Injection, powder, for solutionIntravenousMerck Sharp & Dohme Corp.2020-01-06Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as alpha amino acid amides. These are amide derivatives of alpha amino acids.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acid amides
Alternative Parents
Piperidinecarboxamides / 1,3-diazepanes / Imidazolidinones / Organic sulfuric acids and derivatives / Secondary carboxylic acid amides / Dialkylamines / Azacyclic compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
1,3-diazepane / 2-piperidinecarboxamide / Aliphatic heteropolycyclic compound / Alpha-amino acid amide / Amine / Azacycle / Carbonyl group / Carboxamide group / Diazepane / Hydrocarbon derivative
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
1OQF7TT3PF
CAS number
1174018-99-5
InChI Key
SMOBCLHAZXOKDQ-ZJUUUORDSA-N
InChI
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
IUPAC Name
[(1R,2S,5R)-7-oxo-2-[(piperidin-4-yl)carbamoyl]-1,6-diazabicyclo[3.2.1]octan-6-yl]oxidanesulfonic acid
SMILES
OS(=O)(=O)ON1[[email protected]]2C[[email protected]]([[email protected]@H](CC2)C(=O)NC2CCNCC2)C1=O

References

General References
  1. Rhee EG, Rizk ML, Calder N, Nefliu M, Warrington SJ, Schwartz MS, Mangin E, Boundy K, Bhagunde P, Colon-Gonzalez F, Jumes P, Liu Y, Butterton JR: Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a beta-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants. Antimicrob Agents Chemother. 2018 Aug 27;62(9). pii: AAC.00280-18. doi: 10.1128/AAC.00280-18. Print 2018 Sep. [PubMed:29914955]
  2. Crass RL, Pai MP: Pharmacokinetics and Pharmacodynamics of beta-Lactamase Inhibitors. Pharmacotherapy. 2019 Feb;39(2):182-195. doi: 10.1002/phar.2210. Epub 2019 Jan 20. [PubMed:30589457]
  3. Papp-Wallace KM, Barnes MD, Alsop J, Taracila MA, Bethel CR, Becka SA, van Duin D, Kreiswirth BN, Kaye KS, Bonomo RA: Relebactam Is a Potent Inhibitor of the KPC-2 beta-Lactamase and Restores Imipenem Susceptibility in KPC-Producing Enterobacteriaceae. Antimicrob Agents Chemother. 2018 May 25;62(6). pii: AAC.00174-18. doi: 10.1128/AAC.00174-18. Print 2018 Jun. [PubMed:29610205]
  4. Barnes MD, Bethel CR, Alsop J, Becka SA, Rutter JD, Papp-Wallace KM, Bonomo RA: Inactivation of the Pseudomonas-Derived Cephalosporinase-3 (PDC-3) by Relebactam. Antimicrob Agents Chemother. 2018 Apr 26;62(5). pii: AAC.02406-17. doi: 10.1128/AAC.02406-17. Print 2018 May. [PubMed:29530851]
  5. Zhanel GG, Lawrence CK, Adam H, Schweizer F, Zelenitsky S, Zhanel M, Lagace-Wiens PRS, Walkty A, Denisuik A, Golden A, Gin AS, Hoban DJ, Lynch JP 3rd, Karlowsky JA: Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-beta-Lactamase Inhibitor Combinations. Drugs. 2018 Jan;78(1):65-98. doi: 10.1007/s40265-017-0851-9. [PubMed:29230684]
  6. Jones JA, Virga KG, Gumina G, Hevener KE: Recent Advances in the Rational Design and Optimization of Antibacterial Agents. Medchemcomm. 2016 Sep 1;7(9):1694-1715. doi: 10.1039/C6MD00232C. Epub 2016 Jul 7. [PubMed:27642504]
  7. Wong D, van Duin D: Novel Beta-Lactamase Inhibitors: Unlocking Their Potential in Therapy. Drugs. 2017 Apr;77(6):615-628. doi: 10.1007/s40265-017-0725-1. [PubMed:28303449]
  8. Rizk ML, Rhee EG, Jumes PA, Gotfried MH, Zhao T, Mangin E, Bi S, Chavez-Eng CM, Zhang Z, Butterton JR: Intrapulmonary Pharmacokinetics of Relebactam, a Novel beta-Lactamase Inhibitor, Dosed in Combination with Imipenem-Cilastatin in Healthy Subjects. Antimicrob Agents Chemother. 2018 Feb 23;62(3). pii: AAC.01411-17. doi: 10.1128/AAC.01411-17. Print 2018 Mar. [PubMed:29311084]
  9. FDA: Recarbrio Label [Link]
PubChem Compound
44129647
PubChem Substance
347828625
ChemSpider
31137585
BindingDB
1858
RxNav
2268500
ChEMBL
CHEMBL3112741
ZINC
ZINC000043206319
Wikipedia
Relebactam
MSDS
Download (211 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentBacterial Infections1
3CompletedTreatmentComplicated Intra-Abdominal Infections / Complicated Urinary Tract Infection1
3CompletedTreatmentPneumonia, Bacterial1
2CompletedTreatmentIntra-Abdominal Infections1
2CompletedTreatmentPyelonephritis / Urinary Tract Infection1
1CompletedTreatmentInfectious Diseases1
1Not Yet RecruitingOtherSepsis1
1RecruitingOtherSepsis1
Not AvailableRecruitingNot AvailableCeftolozane/Tazobactam / Hematology and Oncology / Imipenem/Relebactam1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous
Powder, for solutionIntravenous500 MG
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8487093No2013-07-162029-11-19US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.91 mg/mLALOGPS
logP-2ALOGPS
logP-3.1ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)-2ChemAxon
pKa (Strongest Basic)10.03ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area128.28 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity77.54 m3·mol-1ChemAxon
Polarizability32.83 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
TEM-type are the most prevalent beta-lactamases in enterobacteria; they hydrolyze the beta-lactam bond in susceptible beta-lactam antibiotics, thus conferring resistance to penicillins and cephalosporins. TEM-3 and TEM-4 are capable of hydrolyzing cefotaxime and ceftazidime. TEM-5 is capable of hydrolyzing ceftazidime. TEM-6 is capable of hydrolyzing ceftazidime and aztreonam. TEM-8/CAZ-2, TEM-16/CAZ-7 and TEM-24/CAZ-6 are markedly active against ceftazidime. IRT-4 shows resistance to beta-lactamase inhibitors.
Specific Function
Beta-lactamase activity
Gene Name
bla
Uniprot ID
P62593
Uniprot Name
Beta-lactamase TEM
Molecular Weight
31514.865 Da
References
  1. Zhanel GG, Lawrence CK, Adam H, Schweizer F, Zelenitsky S, Zhanel M, Lagace-Wiens PRS, Walkty A, Denisuik A, Golden A, Gin AS, Hoban DJ, Lynch JP 3rd, Karlowsky JA: Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-beta-Lactamase Inhibitor Combinations. Drugs. 2018 Jan;78(1):65-98. doi: 10.1007/s40265-017-0851-9. [PubMed:29230684]
Kind
Protein
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
Not Available
Gene Name
bla
Uniprot ID
P0AD63
Uniprot Name
Beta-lactamase SHV-1
Molecular Weight
31223.635 Da
References
  1. Zhanel GG, Lawrence CK, Adam H, Schweizer F, Zelenitsky S, Zhanel M, Lagace-Wiens PRS, Walkty A, Denisuik A, Golden A, Gin AS, Hoban DJ, Lynch JP 3rd, Karlowsky JA: Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-beta-Lactamase Inhibitor Combinations. Drugs. 2018 Jan;78(1):65-98. doi: 10.1007/s40265-017-0851-9. [PubMed:29230684]
Kind
Protein group
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Beta-lactamase activity

Components:
References
  1. Zhanel GG, Lawrence CK, Adam H, Schweizer F, Zelenitsky S, Zhanel M, Lagace-Wiens PRS, Walkty A, Denisuik A, Golden A, Gin AS, Hoban DJ, Lynch JP 3rd, Karlowsky JA: Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-beta-Lactamase Inhibitor Combinations. Drugs. 2018 Jan;78(1):65-98. doi: 10.1007/s40265-017-0851-9. [PubMed:29230684]
Kind
Protein
Organism
Klebsiella pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Beta-lactamase activity
Gene Name
KPC-2
Uniprot ID
Q93LQ9
Uniprot Name
Beta-lactamase
Molecular Weight
31114.99 Da
References
  1. Zhanel GG, Lawrence CK, Adam H, Schweizer F, Zelenitsky S, Zhanel M, Lagace-Wiens PRS, Walkty A, Denisuik A, Golden A, Gin AS, Hoban DJ, Lynch JP 3rd, Karlowsky JA: Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-beta-Lactamase Inhibitor Combinations. Drugs. 2018 Jan;78(1):65-98. doi: 10.1007/s40265-017-0851-9. [PubMed:29230684]
Kind
Protein
Organism
Enterobacter cloacae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
Gene Name
ampC
Uniprot ID
P05364
Uniprot Name
Beta-lactamase
Molecular Weight
41301.33 Da
References
  1. Zhanel GG, Lawrence CK, Adam H, Schweizer F, Zelenitsky S, Zhanel M, Lagace-Wiens PRS, Walkty A, Denisuik A, Golden A, Gin AS, Hoban DJ, Lynch JP 3rd, Karlowsky JA: Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-beta-Lactamase Inhibitor Combinations. Drugs. 2018 Jan;78(1):65-98. doi: 10.1007/s40265-017-0851-9. [PubMed:29230684]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. Chan G, Houle R, Lin M, Yabut J, Cox K, Wu J, Chu X: Role of transporters in the disposition of a novel beta-lactamase inhibitor: relebactam (MK-7655). J Antimicrob Chemother. 2019 Jul 1;74(7):1894-1903. doi: 10.1093/jac/dkz101. [PubMed:30891606]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates saturable uptake of estrone sulfate, dehydroepiandrosterone sulfate and related compounds.
Gene Name
SLC22A11
Uniprot ID
Q9NSA0
Uniprot Name
Solute carrier family 22 member 11
Molecular Weight
59970.945 Da
References
  1. Chan G, Houle R, Lin M, Yabut J, Cox K, Wu J, Chu X: Role of transporters in the disposition of a novel beta-lactamase inhibitor: relebactam (MK-7655). J Antimicrob Chemother. 2019 Jul 1;74(7):1894-1903. doi: 10.1093/jac/dkz101. [PubMed:30891606]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. Chan G, Houle R, Lin M, Yabut J, Cox K, Wu J, Chu X: Role of transporters in the disposition of a novel beta-lactamase inhibitor: relebactam (MK-7655). J Antimicrob Chemother. 2019 Jul 1;74(7):1894-1903. doi: 10.1093/jac/dkz101. [PubMed:30891606]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. Chan G, Houle R, Lin M, Yabut J, Cox K, Wu J, Chu X: Role of transporters in the disposition of a novel beta-lactamase inhibitor: relebactam (MK-7655). J Antimicrob Chemother. 2019 Jul 1;74(7):1894-1903. doi: 10.1093/jac/dkz101. [PubMed:30891606]

Drug created on October 20, 2016 16:08 / Updated on June 12, 2020 10:53

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