Identification

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Name
Eravacycline
Accession Number
DB12329
Type
Small Molecule
Groups
Approved, Investigational
Description

Eravacycline, known as Xerava by Tetraphase Pharmaceuticals, is a fully synthetic fluorocycline antibiotic of the tetracycline class with activity against clinically significant gram-negative, gram-positive aerobic, and facultative bacteria. This includes most of those bacteria resistant to cephalosporins, fluoroquinolones, β-lactam/β-lactamase inhibitors, multidrug-resistant strains, and carbapenem-resistant Enterobacteriaceae, and the majority of anaerobic pathogens 1. It was first approved by the FDA on August 27, 2018 4. Eravacycline has demonstrated superior potency to that of antibiotics that are currently being marketed for intraabdominal infections 3.

Structure
Thumb
Synonyms
  • Eravacycline
External IDs
TP-434
Product Ingredients
IngredientUNIICASInChI Key
Eravacycline dihydrochlorideWK1NMH89VJ1334714-66-7JYCNMRVZELJVAW-RZVFYPHASA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
XeravaInjection, powder, lyophilized, for solution50 mg/1IntravenousTetraphase Pharmaceuticals, Inc.2018-09-10Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
07896928ZC
CAS number
1207283-85-9
Weight
Average: 558.563
Monoisotopic: 558.212592137
Chemical Formula
C27H31FN4O8
InChI Key
HLFSMUUOKPBTSM-ISIOAQNYSA-N
InChI
InChI=1S/C27H31FN4O8/c1-31(2)20-13-8-11-7-12-14(28)9-15(30-16(33)10-32-5-3-4-6-32)21(34)18(12)22(35)17(11)24(37)27(13,40)25(38)19(23(20)36)26(29)39/h9,11,13,20,34,36-37,40H,3-8,10H2,1-2H3,(H2,29,39)(H,30,33)/t11-,13-,20-,27-/m0/s1
IUPAC Name
(4S,4aS,5aR,12aS)-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[2-(pyrrolidin-1-yl)acetamido]-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide
SMILES
[H][C@@]12CC3=C(C(O)=C(NC(=O)CN4CCCC4)C=C3F)C(=O)C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@]([H])(N(C)C)[C@]1([H])C2

Pharmacology

Indication

This drug is a tetracycline class antibacterial indicated for the treatment of complicated intra-abdominal infections in patients 18 years of age and older Label.

Associated Conditions
Pharmacodynamics

Eravacycline is an antibiotic that disrupts bacterial protein synthesis, treating complicated intraabdominal infections Label.

Mechanism of action

Eravacycline is a fluorocycline antibacterial of the tetracycline class of antibacterial drugs. Eravacycline disrupts bacterial protein synthesis by binding to the 30S ribosomal subunit, preventing the incorporation of amino acid residues into elongating peptide chains. In general, eravacycline is bacteriostatic against gram-positive bacteria (e.g., Staphylococcus aureus and Enterococcus faecalis); however, in vitro bactericidal activity has been shown against certain strains of Escherichia coli and Klebsiella pneumoniae Label.

TargetActionsOrganism
A30S ribosomal protein S4
inhibitor
Escherichia coli (strain K12)
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

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Absorption

Following single-dose intravenous administration, eravacycline AUC (area under the curve) and Cmax (maximum concentration) increase dose-proportionally for doses from 1 mg/kg - 3 mg/kg (3 times the approved dose). There is approximately 45% accumulation following intravenous dosing of 1 mg/kg every 12 hours Label.

Volume of distribution

The volume of distribution at steady-state is approximately 321 L Label.

Protein binding

Protein binding of eravacycline to human plasma proteins increases with increasing plasma concentrations, with 79% to 90% (bound) at plasma concentrations ranging from 100 to 10,000 ng/mL Label.

Metabolism

Eravacycline is metabolized primarily by CYP3A4- and FMO-mediated oxidation Label.

Route of elimination

Following a single intravenous dose of radiolabeled eravacycline 60 mg, approximately 34% of the dose is excreted in urine and 47% in feces as unchanged eravacycline (20% in urine and 17% in feces) and metabolites Label.

Half life

The mean elimination half-life is 20 hours Label.

Clearance

17.82 L/min (standard deviation of 3.4) 2.

Toxicity

The most common adverse reactions (incidence ≥ 3%) are infusion site reactions, nausea, and vomiting Label. Less common (incidence ≥ 1%) adverse effects are palpitations, chest pain, acute pancreatitis, pancreatic necrosis, hypocalcemia, dizziness, dysgeusia, anxiety, insomnia, depression, pleural effusion, dyspnea, rash and hyperhidrosis Label.

The following are various side effects that may occur due to eravacycline use Label:

Hypersensitivity: Life-threatening anaphylaxis has been reported with the administration of eravacycline. Antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-class antibacterial drugs Label.

Tooth Discoloration/enamel hypoplasia: The use of this drug during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may lead to the permanent discoloration of teeth (yellow-grey-brown) Label.

Inhibition of bone growth: The use of eravacycline during the second and third trimester of pregnancy, infancy and childhood until the age of 8 years old may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in bone-forming tissue Label.

Clostridium difficile-Associated diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of the majority of antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents changes the normal flora of the colon, leading to an overgrowth of C. difficile.

Tetracycline class adverse reactions: This drug is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial agents, and may occur with eravacycline. Discontinue eravacycline if any of these adverse reactions are suspected or observed Label.

Potential for microbial overgrowth: The use of eravacycline may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue eravacycline and manage with appropriate therapy Label.

Development of drug-resistant bacteria: Prescribing eravacycline in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria Label.

Affected organisms
  • Humans and other mammals
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
(R)-warfarinThe risk or severity of bleeding can be increased when Eravacycline is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Eravacycline is combined with (S)-Warfarin.
4-MethoxyamphetamineThe metabolism of Eravacycline can be decreased when combined with 4-Methoxyamphetamine.
4-OxoretinolThe risk or severity of pseudotumor cerebri and elevated intracranial pressure can be increased when 4-Oxoretinol is combined with Eravacycline.
Acetylcysteine zincAcetylcysteine zinc can cause a decrease in the absorption of Eravacycline resulting in a reduced serum concentration and potentially a decrease in efficacy.
AcetyldigoxinEravacycline can cause an increase in the absorption of Acetyldigoxin resulting in an increased serum concentration and potentially a worsening of adverse effects.
AcitretinThe risk or severity of pseudotumor cerebri and elevated intracranial pressure can be increased when Acitretin is combined with Eravacycline.
AlitretinoinThe risk or severity of pseudotumor cerebri and elevated intracranial pressure can be increased when Alitretinoin is combined with Eravacycline.
AllylestrenolThe serum concentration of Allylestrenol can be decreased when it is combined with Eravacycline.
AltrenogestThe serum concentration of Altrenogest can be decreased when it is combined with Eravacycline.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
Not Available

References

General References
  1. Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L, Sutcliffe JA, Horn P: Assessing the Efficacy and Safety of Eravacycline vs Ertapenem in Complicated Intra-abdominal Infections in the Investigating Gram-Negative Infections Treated With Eravacycline (IGNITE 1) Trial: A Randomized Clinical Trial. JAMA Surg. 2017 Mar 1;152(3):224-232. doi: 10.1001/jamasurg.2016.4237. [PubMed:27851857]
  2. Connors KP, Housman ST, Pope JS, Russomanno J, Salerno E, Shore E, Redican S, Nicolau DP: Phase I, open-label, safety and pharmacokinetic study to assess bronchopulmonary disposition of intravenous eravacycline in healthy men and women. Antimicrob Agents Chemother. 2014;58(4):2113-8. doi: 10.1128/AAC.02036-13. Epub 2014 Jan 27. [PubMed:24468780]
  3. Thakare R, Dasgupta A, Chopra S: Eravacycline for the treatment of patients with bacterial infections. Drugs Today (Barc). 2018 Apr;54(4):245-254. doi: 10.1358/dot.2018.54.4.2800623. [PubMed:29869646]
  4. Xerava Approval History [Link]
External Links
PubChem Compound
54726192
PubChem Substance
347828591
ChemSpider
28495485
ChEMBL
CHEMBL1951095
Wikipedia
Eravacycline
ATC Codes
J01AA13 — EravacyclineJ01AA20 — Combinations of tetracyclines
FDA label
Download (194 KB)
MSDS
Download (22 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceNormal Drug Tolerance1
1CompletedTreatmentEnd Stage Renal Disease (ESRD)1
1CompletedTreatmentImpaired Hepatic Function1
1RecruitingTreatmentBacterial Infections1
2CompletedTreatmentComplicated Intra-Abdominal Infections1
3CompletedTreatmentComplicated Appendicitis / Complicated Intra-Abdominal Infections1
3CompletedTreatmentComplicated Intra-Abdominal Infections1
3CompletedTreatmentComplicated Urinary Tract Infection2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8796245No2014-08-052029-08-07Us
US8906887No2014-12-092030-12-28Us
Additional Data Available
  • Filed On
    Filed On

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

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.838 mg/mLALOGPS
logP0.24ALOGPS
logP-3.3ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)2.62ChemAxon
pKa (Strongest Basic)8.53ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area193.73 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity144.16 m3·mol-1ChemAxon
Polarizability55.23 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as tetracyclines. These are polyketides having an octahydrotetracene-2-carboxamide skeleton, substituted with many hydroxy and other groups.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Tetracyclines
Sub Class
Not Available
Direct Parent
Tetracyclines
Alternative Parents
Naphthacenes / Anthracenecarboxylic acids and derivatives / Alpha amino acid amides / Tetralins / P-fluorophenols / Aryl ketones / N-arylamides / Aralkylamines / Cyclohexenones / Aryl fluorides
show 12 more
Substituents
Tetracycline / Naphthacene / Tetracene / Anthracene carboxylic acid or derivatives / Alpha-amino acid amide / Alpha-amino acid or derivatives / Tetralin / 4-halophenol / 4-fluorophenol / Aryl ketone
show 35 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Translation repressor activity, nucleic acid binding
Specific Function
One of two assembly initiator proteins for the 30S subunit, it binds directly to 16S rRNA where it nucleates assembly of the body of the 30S subunit.With S5 and S12 plays an important role in trans...
Gene Name
rpsD
Uniprot ID
P0A7V8
Uniprot Name
30S ribosomal protein S4
Molecular Weight
23468.915 Da
References
  1. Zhanel GG, Cheung D, Adam H, Zelenitsky S, Golden A, Schweizer F, Gorityala B, Lagace-Wiens PR, Walkty A, Gin AS, Hoban DJ, Karlowsky JA: Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent. Drugs. 2016 Apr;76(5):567-88. doi: 10.1007/s40265-016-0545-8. [PubMed:26863149]
  2. Grossman TH, Starosta AL, Fyfe C, O'Brien W, Rothstein DM, Mikolajka A, Wilson DN, Sutcliffe JA: Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob Agents Chemother. 2012 May;56(5):2559-64. doi: 10.1128/AAC.06187-11. Epub 2012 Feb 21. [PubMed:22354310]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Eravacycline [Link]
  2. Eravacycline FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
Serotonin binding
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOA
Uniprot ID
P21397
Uniprot Name
Amine oxidase [flavin-containing] A
Molecular Weight
59681.27 Da
References
  1. Eravacycline FDA label [File]

Drug created on October 20, 2016 15:57 / Updated on December 02, 2019 09:23