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Lefamulin

PubChem CID
58076382
Structure
Lefamulin_small.png
Lefamulin_3D_Structure.png
Molecular Formula
Synonyms
  • Lefamulin [INN]
  • Lefamulin [USAN:INN]
  • UNII-21904A5386
  • (+)-LEFAMULIN
  • 21904A5386
Molecular Weight
507.7 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2012-08-19
  • Modify:
    2025-01-18
Description
Lefamulin is a pleuromutilin antibiotic used for the treatment of bacterial community-acquired pneumonia. A pleuromotilin is a more recently developed type of antibiotic that is derived from the fungus, Pleurotus mutilus. Lefamulin is available in intravenous and oral preparations and was granted FDA approval in August 2019. This drug is the first semi-synthetic pleuromutilin that has been designed for systemic administration. Lefamulin features a novel mechanism of action that shows benefit against resistant bacteria that cause pneumonia. The chemical structure of lefamulin contains a tricyclic mutilin core that is necessary for some of its antimicrobial activity.
Lefamulin is a Pleuromutilin Antibacterial. The mechanism of action of lefamulin is as a Cytochrome P450 3A Inhibitor, and Cytochrome P450 3A4 Inhibitor.
Lefamulin is a new and relatively unique antibiotic used for treatment of community acquired pneumonia. Lefamulin has not been linked to an increased rate of transient serum liver test abnormalities during treatment or to instances of clinically apparent liver injury.
See also: Lefamulin Acetate (active moiety of).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Lefamulin.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

[(1S,2R,3S,4S,6R,7R,8R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxo-6-tricyclo[5.4.3.01,8]tetradecanyl] 2-[(1R,2R,4R)-4-amino-2-hydroxycyclohexyl]sulfanylacetate
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C28H45NO5S/c1-6-26(4)14-22(34-23(32)15-35-21-8-7-18(29)13-20(21)31)27(5)16(2)9-11-28(17(3)25(26)33)12-10-19(30)24(27)28/h6,16-18,20-22,24-25,31,33H,1,7-15,29H2,2-5H3/t16?,17-,18+,20+,21+,22+,24-,25-,26+,27-,28-/m0/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

KPVIXBKIJXZQJX-CSOZIWFHSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C[C@H]1[C@@H]([C@](C[C@H]([C@]2([C@H]3[C@@]1(CCC2C)CCC3=O)C)OC(=O)CS[C@@H]4CC[C@H](C[C@H]4O)N)(C)C=C)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C28H45NO5S
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

1061337-51-6

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 DrugBank ID

2.3.5 Metabolomics Workbench ID

2.3.6 NCI Thesaurus Code

2.3.7 RXCUI

2.3.8 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • BC-3781
  • lefamulin
  • Xenleta

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
507.7 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
4.3
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
6
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
507.30184471 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
507.30184471 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
135 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
35
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
851
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
10
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Boiling Point

3.2.2 LogP

3.72
618.6±55.0

3.2.3 Dissociation Constants

3.3 Chemical Classes

3.3.1 Drugs

3.3.1.1 Human Drugs
Breast Feeding; Lactation; Anti-Bacterial Agents; Anti-Infective Agents
Paediatric drug

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug Indication

Lefamulin is indicated to treat adults diagnosed with community-acquired bacterial pneumonia (CABP) that is caused by susceptible bacteria. Its use should be reserved for confirmed susceptible organisms or a high probability of infection with susceptible organisms. The list of susceptible bacteria includes Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible), Legionella pneumophila, Haemophilus influenza, Chlamydophila pneumoniae, and Mycoplasma pneumoniae.
Treatment of community-acquired pneumonia

6.2 LiverTox Summary

Lefamulin is a new and relatively unique antibiotic used for treatment of community acquired pneumonia. Lefamulin has not been linked to an increased rate of transient serum liver test abnormalities during treatment or to instances of clinically apparent liver injury.

6.3 Drug Classes

Breast Feeding; Lactation; Anti-Bacterial Agents; Anti-Infective Agents
Antiinfective Agents

6.4 Clinical Trials

6.4.1 ClinicalTrials.gov

6.4.2 EU Clinical Trials Register

6.5 EMA Drug Information

Type
Paediatric investigation
Active Substance
Therapeutic Area
Infectious diseases
Drug Form
Concentrate for solution for infusion, Age-appropriate oral solid dosage form, Coated tablet
Administration Route
Intravenous use, Oral use
Decision Type
PM: decision on the application for modification of an agreed PIP
Decision Date
2022-12-30

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

Lefamulin demonstrates strong antibacterial activity against several microbes that are found to be common in both acute bacterial skin and skin structure infections as well as community-acquired bacterial pneumonia. It shows antibacterial activity against gram-positive and atypical microbes (for example, Streptococcus pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydophila pneumoniae). Lefamulin also exerts activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. It does not treat Pseudomonas aeruginosa infections. During in vitro studies, drug has also has demonstrated activity against Neisseria gonorrhoeae and Mycoplasma genitalium. **A note on QT prolongation and Clostridium difficile** According to the FDA label, lefamulin may have cardiac QT interval prolonging effects and advises against the administration of this drug in patients with diagnosed QT prolongation or ventricular arrhythmias. The administration of lefamulin should also be avoided in patients being administered antiarrhythmic agents and other drugs that prolong the QT interval. As with other antibiotics, the risk of Clostridium difficile associated diarrhea is increased with lefamulin use. Any case of diarrhea should be evaluated for C. difficile.

7.2 MeSH Pharmacological Classification

Anti-Bacterial Agents
Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)

7.3 FDA Pharmacological Classification

FDA UNII
21904A5386
Active Moiety
LEFAMULIN
Pharmacological Classes
Established Pharmacologic Class [EPC] - Pleuromutilin Antibacterial
Pharmacological Classes
Chemical Structure [CS] - Diterpenes
Pharmacological Classes
Mechanisms of Action [MoA] - Cytochrome P450 3A Inhibitors
Pharmacological Classes
Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors
FDA Pharmacology Summary
Lefamulin is a Pleuromutilin Antibacterial. The mechanism of action of lefamulin is as a Cytochrome P450 3A Inhibitor, and Cytochrome P450 3A4 Inhibitor.

7.4 ATC Code

J - Antiinfectives for systemic use

J01 - Antibacterials for systemic use

J01X - Other antibacterials

J01XX - Other antibacterials

J01XX12 - Lefamulin

7.5 Absorption, Distribution and Excretion

Absorption
In a pharmacokinetic study of healthy subjects, lefamulin was rapidly absorbed after oral administration. The median Tmax was measured at 1.00 h for the intravenous preparation and 1.76 h for the tablet preparation.At steady-state doses, the Cmax of oral lefamulin is 37.1 mcg/mL. The AUC at steady-state concentrations of this drug is 49.2 mcg·h/mL. The estimated bioavailability of the oral tablets is 25%. Clinical studies have found that the AUC of lefamulin is decreased by about 10-28% in the fed state. To optimize absorption, this drug should be administered a minimum of 1 hour before a meal or, at minimum, 2 hours after a meal with water.
Route of Elimination
Lefamulin is largely excreted by the gastrointestinal tract and about 14% excreted by the kidneys. In healthy adult volunteers during clinical trials, a radiolabeled dose of lefamulin was administered. The total radioactivity found to be excreted in the feces was 77.3% on average with 4.2% to 9.1% as unchanged drug when the drug was administered via the intravenous route. A total radioactivity of 88.5% was measured in the feces with 7.8-24.8% as unchanged drug after a dose administered via the oral route. In the urine, it was found to be 15.5% with 9.6-14.1% excretd as unchanged drug after an intravenous dose and 5.3% after an oral dose.
Volume of Distribution
The average volume of distribution of lefamulin is 86.1 L in patients with community-acquired bacterial pneumonia, but can range from 34.2 to 153 L. During clinical studies, lefamulin has been shown to significantly concentrate in the lung tissue, likely increasing its effectiveness in treating pneumonia. After lefamulin is administered, penetration into various tissues is observed, and is about 6 times greater in concentration in the fluid of the pulmonary epithelium, when compared with concentrations in the plasma. Animal studies demonstrate that lefamulin crosses the placenta.
Clearance
The total body clearance of lefamulin has been determined to range from 2.94 to 30.0 L/h after an injected dose.

7.6 Metabolism / Metabolites

CYP3A4 is the main enzyme responsible for the metabolism of lefamulin.

7.7 Biological Half-Life

The average elimination half-life of lefamulin is about 8 hours in patients diagnosed with community-acquired bacterial pneumonia. One pharmacokinetic study of healthy volunteers revealed a mean half-life of 13.2 hours after an intravenous infusion of lefamulin.

7.8 Mechanism of Action

Lefamulin inhibits prokaryotic ribosomal protein synthesis via its binding to the peptidyl transferase center (PTC) of the ribosomal bacterial 50S subunit. It inhibits protein translation through binding to both the A and P sites of the PTC via four hydrogen bonds, resulting in the interruption of peptide bond formation. Lefamulin's tricyclic mutilin core is the common moiety for binding of all members of its drug class, the pleuromutilins. Although the tricyclic motilin core doesn’t form any hydrogen bonds with the PTC nucleotides, it is stabilized or anchored by hydrophobic and Van der Waals interactions. Lefamulin exerts a selective inhibition of protein translation in eukaryotes, however, does not affect ribosomal translation of eukaryotes. Lefamulin demonstrates a unique induced-fit type of action that closes the binding pocket within a ribosome, conferring close contact of the drug to its target, therefore improving therapeutic efficacy. Because of its mechanism of action that differs from that of other antimicrobials, cross-resistance to other antibiotic classes is less likely.

8 Use and Manufacturing

8.1 Uses

8.1.1 Use Classification

Human Drugs -> EU pediatric investigation plans

9 Safety and Hazards

9.1 Hazards Identification

9.1.1 GHS Classification

Pictogram(s)
Corrosive
Acute Toxic
Irritant
Environmental Hazard
Signal
Danger
GHS Hazard Statements

H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]

H315 (50%): Causes skin irritation [Warning Skin corrosion/irritation]

H317 (50%): May cause an allergic skin reaction [Warning Sensitization, Skin]

H318 (50%): Causes serious eye damage [Danger Serious eye damage/eye irritation]

H330 (50%): Fatal if inhaled [Danger Acute toxicity, inhalation]

H411 (50%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P260, P261, P264, P264+P265, P270, P271, P272, P273, P280, P284, P301+P317, P302+P352, P304+P340, P305+P354+P338, P316, P317, P320, P321, P330, P332+P317, P333+P317, P362+P364, P391, P403+P233, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

9.1.2 Hazard Classes and Categories

Acute Tox. 4 (50%)

Skin Irrit. 2 (50%)

Skin Sens. 1B (50%)

Eye Dam. 1 (50%)

Acute Tox. 2 (50%)

Aquatic Chronic 2 (50%)

9.2 Regulatory Information

REACH Registered Substance

10 Toxicity

10.1 Toxicological Information

10.1.1 Hepatotoxicity

Serum ALT, AST and GGT elevations above 3 times the upper limit of normal occurred in 1.2% to 3.5% of patients treated with lefamulin (n=641), but rates and severity of serum enzyme elevations were similar to those in comparator arms (moxifloxacin: n=641). These enzymes elevations were usually mild-to-moderate in severity, self-limited in duration and not accompanied by symptoms or jaundice. Instances of clinically apparent liver injury attributable to lefamulin have not been reported but this antibiotic has had limited general use.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

10.1.2 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

No information is available on the use of lefamulin during breastfeeding. The manufacturer recommends that mothers should avoid breastfeeding during treatment and for 2 days after the final dose. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

10.1.3 Protein Binding

The average plasma protein binding of lefamulin is between 94.8 to 97.1% in healthy adults. A systematic review identifies the plasma protein binding at 80-87%.

11 Literature

11.1 Consolidated References

11.2 NLM Curated PubMed Citations

11.3 Thieme References

11.4 Chemical Co-Occurrences in Literature

11.5 Chemical-Gene Co-Occurrences in Literature

11.6 Chemical-Disease Co-Occurrences in Literature

12 Patents

12.1 Depositor-Supplied Patent Identifiers

12.2 WIPO PATENTSCOPE

12.3 Chemical Co-Occurrences in Patents

13 Interactions and Pathways

13.1 Chemical-Target Interactions

13.2 Drug-Drug Interactions

13.3 Drug-Food Interactions

  • Exercise caution with grapefruit products. Grapefruit inhibits CYP3A, which may increase the serum concentration of lefamulin.
  • Exercise caution with St. John's Wort. This herb induces the CYP3A metabolism of lefamulin and may reduce its serum concentration.
  • Take on an empty stomach. This drug should be taken at least 1 hour before or 2 hours after a meal.
  • Take with a full glass of water. The tablet should be swallowed whole with water.

14 Classification

14.1 MeSH Tree

14.2 NCI Thesaurus Tree

14.3 ChemIDplus

14.4 MolGenie Organic Chemistry Ontology

15 Information Sources

  1. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  2. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  3. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    Acet i c ac id, 2- [ [ (1R,2R,4R) -4-amino-2-hydroxycyclohexyl ] thio] -, (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyldecahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3aH-cyclopentacycloocten-8-yl ester
    https://chem.echa.europa.eu/100.246.378
    Acet i c ac id, 2- [ [ (1R,2R,4R) -4-amino-2-hydroxycyclohexyl ] thio] -, (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyldecahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3aH-cyclopentacycloocten-8-yl ester (EC: 813-124-2)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/252226
  4. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  5. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  6. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  7. LiverTox
  8. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  9. Drugs and Lactation Database (LactMed)
  10. EU Clinical Trials Register
  11. Metabolomics Workbench
  12. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  13. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  14. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  15. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  16. Wikipedia
  17. PubChem
  18. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  19. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  20. PATENTSCOPE (WIPO)
CONTENTS