This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

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Name
Lefamulin
Accession Number
DB12825
Type
Small Molecule
Groups
Approved, Investigational
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.6 Lefamulin is available in intravenous and oral preparations and was granted FDA approval in August 2019.11 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.1 The chemical structure of lefamulin contains a tricyclic mutilin core that is necessary for some of its antimicrobial activity.3

Structure
Thumb
Synonyms
  • Lefamulin
External IDs
BC-3781
Product Ingredients
IngredientUNIICASInChI Key
Lefamulin acetateHDN0B924X41350636-82-6WSMXIQXWHPSVDE-ZPJPNJFZSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
XenletaTablet, coated600 mg/1OralNabriva Therapeutics US, Inc.2019-09-09Not applicableUs
XenletaInjection, solution150 mg/15mLIntravenousNabriva Therapeutics US, Inc.2019-09-09Not 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
21904A5386
CAS number
1061337-51-6
Weight
Average: 507.73
Monoisotopic: 507.301844727
Chemical Formula
C28H45NO5S
InChI Key
KPVIXBKIJXZQJX-FCEONZPQSA-N
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+/m1/s1
IUPAC Name
(1S,2R,3S,4S,6R,7R,8R,14R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxotricyclo[5.4.3.0^{1,8}]tetradecan-6-yl 2-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexyl]sulfanyl}acetate
SMILES
[H][C@@]12C(=O)CC[C@]11CC[C@@H](C)[C@@]2(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]1C)OC(=O)CS[C@@H]1CC[C@@H](N)C[C@H]1O

Pharmacology

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.11

Associated Conditions
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.1,3 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.11 During in vitro studies, drug has also has demonstrated activity against Neisseria gonorrhoeae and Mycoplasma genitalium.11

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.5,11

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.6 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.10 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.3 Because of its mechanism of action that differs from that of other antimicrobials, cross-resistance to other antibiotic classes is less likely.2

TargetActionsOrganism
A50S ribosomal protein L22
binder
Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
Additional Data Available
Adverse Effects

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Contraindications

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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.7At steady-state doses, the Cmax of oral lefamulin is 37.1 mcg/mL.11 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.3 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.11

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.11 During clinical studies, lefamulin has been shown to significantly concentrate in the lung tissue, likely increasing its effectiveness in treating pneumonia.3 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.8 Animal studies demonstrate that lefamulin crosses the placenta.11

Protein binding

The average plasma protein binding of lefamulin is between 94.8 to 97.1% in healthy adults.11 A systematic review identifies the plasma protein binding at 80-87%.3

Metabolism

CYP3A4 is the main enzyme responsible for the metabolism of lefamulin.3,11

Route of elimination

Lefamulin is largely excreted by the gastrointestinal tract and about 14% excreted by the kidneys.9 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.11

Half life

The average elimination half-life of lefamulin is about 8 hours in patients diagnosed with community-acquired bacterial pneumonia.11 One pharmacokinetic study of healthy volunteers revealed a mean half-life of 13.2 hours after an intravenous infusion of lefamulin.7

Clearance

The total body clearance of lefamulin has been determined to range from 2.94 to 30.0 L/h after an injected dose.11

Toxicity

In the case of overdose with lefamulin, the patient should be monitored closely and provided with supportive treatment, according to symptoms and signs. This drug and its active metabolite are not removable by dialysis.11

Affected organisms
Not Available
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
4-hydroxycoumarinThe serum concentration of 4-hydroxycoumarin can be increased when it is combined with Lefamulin.
AbemaciclibAbemaciclib may decrease the excretion rate of Lefamulin which could result in a higher serum level.
AbexinostatLefamulin may increase the QTc-prolonging activities of Abexinostat.
AcebutololLefamulin may increase the QTc-prolonging activities of Acebutolol.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Lefamulin.
AceprometazineLefamulin may increase the QTc-prolonging activities of Aceprometazine.
AcetaminophenAcetaminophen may decrease the excretion rate of Lefamulin which could result in a higher serum level.
AcetyldigoxinLefamulin may increase the QTc-prolonging activities of Acetyldigoxin.
Acetylsalicylic acidAcetylsalicylic acid may increase the excretion rate of Lefamulin which could result in a lower serum level and potentially a reduction in efficacy.
AcrivastineLefamulin may increase the QTc-prolonging activities of Acrivastine.
Additional Data Available
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Food Interactions
Not Available

References

General References
  1. Dillon C, Guarascio AJ, Covvey JR: Lefamulin: a promising new pleuromutilin antibiotic in the pipeline. Expert Rev Anti Infect Ther. 2019 Jan;17(1):5-15. doi: 10.1080/14787210.2019.1554431. Epub 2018 Dec 7. [PubMed:30513017]
  2. Rodvold KA: Introduction: lefamulin and pharmacokinetic/pharmacodynamic rationale to support the dose selection of lefamulin. J Antimicrob Chemother. 2019 Apr 1;74(Supplement_3):iii2-iii4. doi: 10.1093/jac/dkz084. [PubMed:30949709]
  3. Veve MP, Wagner JL: Lefamulin: Review of a Promising Novel Pleuromutilin Antibiotic. Pharmacotherapy. 2018 Sep;38(9):935-946. doi: 10.1002/phar.2166. Epub 2018 Aug 20. [PubMed:30019769]
  4. Bhavnani SM, Zhang L, Hammel JP, Rubino CM, Bader JC, Sader HS, Gelone SP, Wicha WW, Ambrose PG: Pharmacokinetic/pharmacodynamic target attainment analyses to support intravenous and oral lefamulin dose selection for the treatment of patients with community-acquired bacterial pneumonia. J Antimicrob Chemother. 2019 Apr 1;74(Supplement_3):iii35-iii41. doi: 10.1093/jac/dkz089. [PubMed:30949705]
  5. Crowther GS, Wilcox MH: Antibiotic therapy and Clostridium difficile infection - primum non nocere - first do no harm. Infect Drug Resist. 2015 Sep 15;8:333-7. doi: 10.2147/IDR.S87224. eCollection 2015. [PubMed:26396535]
  6. Paukner S, Riedl R: Pleuromutilins: Potent Drugs for Resistant Bugs-Mode of Action and Resistance. Cold Spring Harb Perspect Med. 2017 Jan 3;7(1). pii: cshperspect.a027110. doi: 10.1101/cshperspect.a027110. [PubMed:27742734]
  7. Wicha WW, Prince WT, Lell C, Heilmayer W, Gelone SP: Pharmacokinetics and tolerability of lefamulin following intravenous and oral dosing. J Antimicrob Chemother. 2019 Apr 1;74(Supplement_3):iii19-iii26. doi: 10.1093/jac/dkz087. [PubMed:30949704]
  8. File TM Jr, Goldberg L, Das A, Sweeney C, Saviski J, Gelone SP, Seltzer E, Paukner S, Wicha WW, Talbot GH, Gasink LB: Efficacy and Safety of IV-to-Oral Lefamulin, a Pleuromutilin Antibiotic, for Treatment of Community-Acquired Bacterial Pneumonia: The Phase 3 LEAP 1 Trial. Clin Infect Dis. 2019 Feb 4. pii: 5306243. doi: 10.1093/cid/ciz090. [PubMed:30722059]
  9. Amalakuhan B, Echevarria KL, Restrepo MI: Managing community acquired pneumonia in the elderly - the next generation of pharmacotherapy on the horizon. Expert Opin Pharmacother. 2017 Aug;18(11):1039-1048. doi: 10.1080/14656566.2017.1340937. Epub 2017 Jun 21. [PubMed:28598693]
  10. Eyal Z, Matzov D, Krupkin M, Paukner S, Riedl R, Rozenberg H, Zimmerman E, Bashan A, Yonath A: A novel pleuromutilin antibacterial compound, its binding mode and selectivity mechanism. Sci Rep. 2016 Dec 13;6:39004. doi: 10.1038/srep39004. [PubMed:27958389]
  11. Xenleta FDA label [Link]
External Links
PubChem Compound
25185057
PubChem Substance
347828993
ChemSpider
32701544
BindingDB
50019649
ChEMBL
CHEMBL3291398
HET
62B
Wikipedia
Lefamulin
PDB Entries
5hl7

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingBasic ScienceHealthy Volunteers1
1CompletedNot AvailableHealthy Volunteers1
3CompletedTreatmentCommunity Acquired Pneumonia (CAP)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous150 mg/15mL
Tablet, coatedOral600 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)618.6±55.0 http://www.chemspider.com/Chemical-Structure.32701544.html
logP3.72618.6±55.0
pKa9.41https://patents.google.com/patent/EP3310331A1/en
Predicted Properties
PropertyValueSource
Water Solubility0.00494 mg/mLALOGPS
logP3.04ALOGPS
logP2.9ChemAxon
logS-5ALOGPS
pKa (Strongest Acidic)14.19ChemAxon
pKa (Strongest Basic)10.08ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area109.85 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity138.86 m3·mol-1ChemAxon
Polarizability56.55 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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 pleuromutilin and derivatives. These are mutilins with a hydroxyacetate derivative attached to the C8 carbon atom of the cyclopenta[8]annulene moiety.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Prenol lipids
Sub Class
Diterpenoids
Direct Parent
Pleuromutilin and derivatives
Alternative Parents
Cyclohexylamines / Cyclohexanols / Ketones / Cyclic alcohols and derivatives / Carboxylic acid esters / Amino acids and derivatives / Sulfenyl compounds / Monocarboxylic acids and derivatives / Dialkylthioethers / Organopnictogen compounds
show 3 more
Substituents
Pleuromutilin / Cyclohexanol / Cyclohexylamine / Cyclic alcohol / Amino acid or derivatives / Carboxylic acid ester / Ketone / Secondary alcohol / Carboxylic acid derivative / Dialkylthioether
show 17 more
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
Pharmacological action
Yes
Actions
Binder
Curator comments
Representative organism. This target is provided as an example lefamulin binding, although the 50S subunit of other organisms are also bound by this drug. Lefamulin targets the ribosomal 50S subunit at the peptidyl transferase center (PTC).
General Function
This protein binds specifically to 23S rRNA; its binding is stimulated by other ribosomal proteins, e.g. L4, L17, and L20. It is important during the early stages of 50S assembly. It makes multiple contacts with different domains of the 23S rRNA in the assembled 50S subunit and ribosome (By similarity).
Specific Function
Rrna binding
Gene Name
rplV
Uniprot ID
P61182
Uniprot Name
50S ribosomal protein L22
Molecular Weight
12200.055 Da
References
  1. Veve MP, Wagner JL: Lefamulin: Review of a Promising Novel Pleuromutilin Antibiotic. Pharmacotherapy. 2018 Sep;38(9):935-946. doi: 10.1002/phar.2166. Epub 2018 Aug 20. [PubMed:30019769]
  2. Eyal Z, Matzov D, Krupkin M, Paukner S, Riedl R, Rozenberg H, Zimmerman E, Bashan A, Yonath A: A novel pleuromutilin antibacterial compound, its binding mode and selectivity mechanism. Sci Rep. 2016 Dec 13;6:39004. doi: 10.1038/srep39004. [PubMed:27958389]
  3. Xenleta FDA label [Link]

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. Veve MP, Wagner JL: Lefamulin: Review of a Promising Novel Pleuromutilin Antibiotic. Pharmacotherapy. 2018 Sep;38(9):935-946. doi: 10.1002/phar.2166. Epub 2018 Aug 20. [PubMed:30019769]
  2. Xenleta FDA label [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Xenleta FDA label [Link]

Drug created on October 20, 2016 18:32 / Updated on September 02, 2019 22:13