Details of the Drug

General Information of Drug (ID: DME6G97)

• Drug Name: Lefamulin
• Synonyms: UNII-21904A5386; 1061337-51-6; CHEMBL3291398; 21904A5386; Lefamulin [INN]; Acetic acid, 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; Lefamulin(BC-3781); Lefamulin [USAN:INN]; Acetic acid, 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

Indication

Disease Entry	ICD 11	Status	REF
Community-acquired pneumonia	CA40.Z	Approved	[1]
Acute bacterial skin infection	1C41	Phase 2	[2]

• #Ro5 Violations (Lipinski): 1:
  Molecular Weight (mw); 507.7
  Topological Polar Surface Area (xlogp); 4.3
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 3
  Hydrogen Bond Acceptor Count (hbondacc); 7
• ADMET Property:
  Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 49.2 mgh/L [3]
  Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 37.1 mg/L [3]
  Absorption Tmax: The time to maximum plasma concentration (Tmax) is 1 h [3]
  Clearance: The total body clearance of drug is 2.94-30.0 L/h [4]
  Elimination: Lefamulin is largely excreted by the gastrointestinal tract and about 14% excreted by the kidneys [5]
  Half-life: The concentration or amount of drug in body reduced by one-half in 8 hours [4]
  Metabolism: The drug is metabolized via the CYP3A4 [6]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.17% [7]
  Vd: The volume of distribution (Vd) of drug is 86.1 L [4]
• Chemical Identifiers:
  Formula: C28H45NO5S
  IUPAC Name: [(1S,2R,3S,4S,6R,7R,8R,14R)-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
  Canonical SMILES: C[C@@H]1CC[C@@]23CCC(=O)[C@H]2[C@@]1([C@@H](C[C@@]([C@H]([C@@H]3C)O)(C)C=C)OC(=O)CS[C@@H]4CC[C@H](C[C@H]4O)N)C
  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
  InChIKey: KPVIXBKIJXZQJX-FCEONZPQSA-N
• Cross-matching ID:
  PubChem CID: 25185057
  CAS Number: 1061337-51-6
  DrugBank ID: DB12825
  TTD ID: D0EB5N
  INTEDE ID: DR0919
  ACDINA ID: D01201

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Bacterial 23S ribosomal RNA (Bact 23S rRNA)	TTLFGBV	NOUNIPROTAC	Inhibitor	[1]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[8]

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Lefamulin (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Ivosidenib	DM8S6T7	Major	Increased risk of prolong QT interval by the combination of Lefamulin and Ivosidenib.	Acute myeloid leukaemia [2A60]	[27]
Oliceridine	DM6MDCF	Moderate	Decreased metabolism of Lefamulin caused by Oliceridine mediated inhibition of CYP450 enzyme.	Acute pain [MG31]	[28]
Levalbuterol	DM5YBO1	Moderate	Increased risk of prolong QT interval by the combination of Lefamulin and Levalbuterol.	Asthma [CA23]	[29]
Pexidartinib	DMS2J0Z	Major	Increased metabolism of Lefamulin caused by Pexidartinib mediated induction of CYP450 enzyme.	Bone/articular cartilage neoplasm [2F7B]	[30]
Avapritinib	DMK2GZX	Moderate	Decreased metabolism of Lefamulin caused by Avapritinib mediated inhibition of CYP450 enzyme.	Gastrointestinal stromal tumour [2B5B]	[28]
Ubrogepant	DM749I3	Moderate	Decreased metabolism of Lefamulin caused by Ubrogepant mediated inhibition of CYP450 enzyme.	Migraine [8A80]	[28]
Macimorelin	DMQYJIR	Major	Increased risk of prolong QT interval by the combination of Lefamulin and Macimorelin.	Pituitary gland disorder [5A60-5A61]	[31]
Upadacitinib	DM32B5U	Moderate	Decreased metabolism of Lefamulin caused by Upadacitinib mediated inhibition of CYP450 enzyme.	Rheumatoid arthritis [FA20]	[28]
Larotrectinib	DM26CQR	Moderate	Decreased metabolism of Lefamulin caused by Larotrectinib mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[28]
Fluticasone	DMGCSVF	Moderate	Decreased metabolism of Lefamulin caused by Fluticasone mediated inhibition of CYP450 enzyme.	Vasomotor/allergic rhinitis [CA08]	[28]

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
FD&C blue no. 2	E00446	2723854	Colorant
Kyselina citronova	E00014	311	Acidulant; Antioxidant; Buffering agent; Complexing agent; Flavoring agent
Mannitol	E00103	6251	Diluent; Flavoring agent; Lyophilization aid; Plasticizing agent; Tonicity agent
Carmellose sodium	E00625	Not Available	Disintegrant
Ferrosoferric oxide	E00231	14789	Colorant
Magnesium stearate	E00208	11177	lubricant
Polyethylene glycol 4000	E00654	Not Available	Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Polyvinyl alcohol	E00666	Not Available	Coating agent; Emulsion stabilizing agent; Film/Membrane-forming agent
Povidone	E00667	Not Available	Binding agent; Coating agent; Disintegrant; Film/membrane-forming agent; Solubilizing agent; Suspending agent
Sodium chloride	E00077	5234	Diluent; Tonicity agent
Sodium citrate dihydrate	E00369	71474	Alkalizing agent; Buffering agent; Complexing agent; Emulsifying agent
Talc	E00520	16211421	Anticaking agent; Diluent; Glidant; lubricant
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Water	E00035	962	Solvent
Hydrophobic colloidal silica	E00285	24261	Anticaking agent; Emulsion stabilizing agent; Glidant; Suspending agent; Viscosity-controlling agent
Cellulose microcrystalline	E00698	Not Available	Adsorbent; Suspending agent; Diluent
Shellac	E00695	Not Available	Coating agent; Film/membrane-forming agent; Microencapsulating agent; Modified-release agent

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Lefamulin 600 mg tablet	600 mg	Tablet	Oral
Lefamulin 150 mg Injection	150 mg	Injection	Intravenous

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] 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.
• [4] Xenleta FDA label
• [5] 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.
• [6] Molden E, Asberg A, Christensen H: Desacetyl-diltiazem displays severalfold higher affinity to CYP2D6 compared with CYP3A4. Drug Metab Dispos. 2002 Jan;30(1):1-3.
• [7] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [8] Lefamulin: review of a promising novel pleuromutilin antibiotic. Pharmacotherapy. 2018 Sep;38(9):935-946.
• [9] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [10] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [11] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [12] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [13] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [14] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [15] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [16] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [17] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [18] Company report (JMI Laboratories)
• [19] Inhibition of peptide bond formation by pleuromutilins: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin. Mol Microbiol. 2004 Dec;54(5):1287-94.
• [20] The fused TrpEG from Streptomyces venezuelae is an anthranilate synthase, not a 2-amino-2-deoxyisochorismate [corrected] (ADIC) synthase. Ethn Dis. 2008 Spring;18(2 Suppl 2):S2-9-13.
• [21] Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance. Genome Res. 2009 Jul;19(7):1214-23.
• [22] The apicoplast as an antimalarial drug target. Drug Resist Updat. 2001 Jun;4(3):145-51.
• [23] Has nature already identified all useful antibacterial targets Curr Opin Microbiol. 2008 Oct;11(5):387-92.
• [24] How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.
• [25] Ribosomal RNA is the target for oxazolidinones, a novel class of translational inhibitors. RNA. 1999 Jul;5(7):939-46.
• [26] EDP-420, a Bicyclolide (Bridged Bicyclic Macrolide), Is Active against Mycobacterium avium. Antimicrob Agents Chemother. 2007 May; 51(5): 1666-1670.
• [27] Product Information. Fareston (toremifene). Schering Laboratories, Kenilworth, NJ.
• [28] Product Information. Xenleta (lefamulin). Nabriva Therapeutics US, Inc., King of Prussia, PA.
• [29] Product Information. Arcapta Neohaler (indacaterol). Novartis Pharmaceuticals, East Hanover, NJ.
• [30] Patel S, Robinson R, Burk M "Hypertensive crisis associated with St. John's Wort." Am J Med 112 (2002): 507-8. [PMID: 11959071]
• [31] Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.