Identification

Name
Fidaxomicin
Accession Number
DB08874
Type
Small Molecule
Groups
Approved
Description

One of the first narrow spectrum macrocyclic antibiotic, it is a natural compound and is structurally similar to compounds in lipiarmycin-a fermentation mixture. FDA approved on May 27, 2011.

Structure
Thumb
Synonyms
  • Difimicin
  • Lipiarmicin
  • Lipiarmycin
  • Lipiarrmycin
  • Tiacumicin B
External IDs
OPT 80 / OPT-80 / PAR 101 / PAR-101
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DificidTablet, film coated200 mg/1OralMerck Sharp & Dohme Limited2011-05-27Not applicableUs
DificidTablet, film coated200 mg/1OralAvera Mc Kennan Hospital2015-04-17Not applicableUs
DificidTablet200 mgOralMerck Ltd.2012-06-21Not applicableCanada
DificlirTablet, film coated200 mgOralAstellas Pharma Europe Bv2011-12-05Not applicableEu
DificlirTablet, film coated200 mgOralAstellas Pharma Europe Bv2011-12-05Not applicableEu
DificlirTablet, film coated200 mgOralAstellas Pharma Europe Bv2011-12-05Not applicableEu
DificlirTablet, film coated200 mgOralAstellas Pharma Europe Bv2011-12-05Not applicableEu
Categories
UNII
Z5N076G8YQ
CAS number
873857-62-6
Weight
Average: 1058.039
Monoisotopic: 1056.425220978
Chemical Formula
C52H74Cl2O18
InChI Key
ZVGNESXIJDCBKN-KFGPIHIUSA-N
InChI
InChI=1S/C52H74Cl2O18/c1-13-30-22-26(6)33(56)18-16-15-17-31(23-66-51-45(65-12)42(61)44(29(9)67-51)69-49(64)35-32(14-2)36(53)39(58)37(54)38(35)57)48(63)68-34(28(8)55)20-19-25(5)21-27(7)43(30)70-50-41(60)40(59)46(52(10,11)72-50)71-47(62)24(3)4/h15-17,19,21-22,24,28-30,33-34,40-46,50-51,55-61H,13-14,18,20,23H2,1-12H3/b16-15+,25-19+,26-22+,27-21+,31-17+/t28-,29-,30+,33+,34?,40-,41+,42+,43+,44-,45+,46+,50-,51-/m1/s1
IUPAC Name
(2R,3S,4S,5S,6R)-6-{[(3E,5E,8S,9E,11S,12R,13E,15E)-12-{[(2R,3S,4R,5S)-3,4-dihydroxy-6,6-dimethyl-5-[(2-methylpropanoyl)oxy]oxan-2-yl]oxy}-11-ethyl-8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-2-oxo-1-oxacyclooctadeca-3,5,9,13,15-pentaen-3-yl]methoxy}-4-hydroxy-5-methoxy-2-methyloxan-3-yl 3,5-dichloro-2-ethyl-4,6-dihydroxybenzoate
SMILES
CC[[email protected]]1\C=C(C)\[[email protected]@H](O)C\C=C\C=C(CO[[email protected]@H]2O[[email protected]](C)[[email protected]@H](OC(=O)C3=C(CC)C(Cl)=C(O)C(Cl)=C3O)[[email protected]](O)[[email protected]@H]2OC)\C(=O)OC(C\C=C(/C)\C=C(C)\[[email protected]@H]1O[[email protected]@H]1OC(C)(C)[[email protected]@H](OC(=O)C(C)C)[[email protected]](O)[[email protected]@H]1O)[[email protected]@H](C)O

Pharmacology

Indication

Treatment of Clostridium difficile-associated diarrhea

Structured Indications
Pharmacodynamics

The minimum inhibitory concentration for 90% of organisms for fidaxomicin against C. difficile is 0.9978 to 2 µg/mL.

Mechanism of action

Fidaxomicin is a bactericidal-type antibiotic that inhibits RNA polymerase sigma subunit. RNA polymerase is responsible for transcription in the bacteria therefore fidaxomicin will inhibit protein synthesis. As a result, apoptosis is triggered in susceptible organisms such as C. difficile.

TargetActionsOrganism
ARNA polymerase sigma factor
inhibitor
Clostridium difficile (strain 630)
Absorption

Fidaxomicin is not systemically absorbed as shown by a plasma concentrations below the lower limit of quantification after single-dose or multiple-dose. In contrast, fecal concentrations of fidaxomicin are much higher and are concentration-dependent. Cmax = 2 hours; Tmax = 5.2 ng/mL; AUC = 14 ng•hr/mL

Volume of distribution

Fidaxomicin is largely confined in the gastrointestinal tract and is not distributed extensively in the systemic.

Protein binding
Not Available
Metabolism

Fidaxomicin is hydrolyzed by gastric acid or intestinal microsomes into a less active metabolite (OP-1118). The cytochrome enzyme system are not involved in the metabolism of fidaxomicin.

Route of elimination

Feces (>92% as unchanged drugs and metabolites) and urine (<1% of drug was excreted)

Half life

200 mg, healthy subjects = 11.7 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Gram-positive Bacteria
  • Peptoclostridium difficile
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Fidaxomicin.Approved
AtorvastatinThe risk or severity of adverse effects can be increased when Fidaxomicin is combined with Atorvastatin.Approved
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Fidaxomicin.Investigational
BosutinibThe serum concentration of Bosutinib can be increased when it is combined with Fidaxomicin.Approved
Brentuximab vedotinThe serum concentration of Brentuximab vedotin can be increased when it is combined with Fidaxomicin.Approved
CerivastatinThe risk or severity of adverse effects can be increased when Fidaxomicin is combined with Cerivastatin.Withdrawn
ColchicineThe serum concentration of Colchicine can be increased when it is combined with Fidaxomicin.Approved
Dabigatran etexilateThe serum concentration of the active metabolites of Dabigatran etexilate can be increased when Dabigatran etexilate is used in combination with Fidaxomicin.Approved
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Fidaxomicin.Approved, Investigational
EdoxabanThe serum concentration of Edoxaban can be increased when it is combined with Fidaxomicin.Approved
EverolimusThe serum concentration of Everolimus can be increased when it is combined with Fidaxomicin.Approved
FluvastatinThe risk or severity of adverse effects can be increased when Fidaxomicin is combined with Fluvastatin.Approved
LedipasvirThe serum concentration of Ledipasvir can be increased when it is combined with Fidaxomicin.Approved
LovastatinThe risk or severity of adverse effects can be increased when Fidaxomicin is combined with Lovastatin.Approved, Investigational
LumacaftorThe serum concentration of Fidaxomicin can be decreased when it is combined with Lumacaftor.Approved
MevastatinThe risk or severity of adverse effects can be increased when Fidaxomicin is combined with Mevastatin.Experimental
NaloxegolThe serum concentration of Naloxegol can be increased when it is combined with Fidaxomicin.Approved
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Fidaxomicin.Approved
Picosulfuric acidThe therapeutic efficacy of Picosulfuric acid can be decreased when used in combination with Fidaxomicin.Approved
PitavastatinThe risk or severity of adverse effects can be increased when Fidaxomicin is combined with Pitavastatin.Approved
PravastatinThe risk or severity of adverse effects can be increased when Fidaxomicin is combined with Pravastatin.Approved
PrucaloprideThe serum concentration of Prucalopride can be increased when it is combined with Fidaxomicin.Approved
RanolazineThe serum concentration of Ranolazine can be increased when it is combined with Fidaxomicin.Approved, Investigational
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Fidaxomicin.Approved, Investigational
RilpivirineThe serum concentration of Rilpivirine can be increased when it is combined with Fidaxomicin.Approved
RosuvastatinThe risk or severity of adverse effects can be increased when Fidaxomicin is combined with Rosuvastatin.Approved
SilodosinThe serum concentration of Silodosin can be increased when it is combined with Fidaxomicin.Approved
SimvastatinThe risk or severity of adverse effects can be increased when Fidaxomicin is combined with Simvastatin.Approved
TerfenadineFidaxomicin may increase the QTc-prolonging activities of Terfenadine.Withdrawn
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Fidaxomicin.Approved, Investigational
UbidecarenoneThe risk or severity of adverse effects can be increased when Fidaxomicin is combined with Ubidecarenone.Approved, Experimental
VincristineThe serum concentration of Vincristine can be increased when it is combined with Fidaxomicin.Approved, Investigational
Food Interactions
  • Food decreases Cmax of fidaxomicin and its metabolites however this is not considered clinically significant.

References

Synthesis Reference

Youe-Kong Shue, Chi-Jen Frank Du, Ming-Hsi Chiou, Mei-Chiao Wu, Yuan-Ting Chen, Franklin W. Okumu, Jonathan James Duffield, "Medium for the Production of Tiacumicin B." U.S. Patent US20100028970, issued February 04, 2010.

US20100028970
General References
  1. Artsimovitch I, Seddon J, Sears P: Fidaxomicin is an inhibitor of the initiation of bacterial RNA synthesis. Clin Infect Dis. 2012 Aug;55 Suppl 2:S127-31. doi: 10.1093/cid/cis358. [PubMed:22752861]
  2. Crawford T, Huesgen E, Danziger L: Fidaxomicin: a novel macrocyclic antibiotic for the treatment of Clostridium difficile infection. Am J Health Syst Pharm. 2012 Jun 1;69(11):933-43. doi: 10.2146/ajhp110371. [PubMed:22610025]
External Links
KEGG Drug
D09394
PubChem Compound
70678896
PubChem Substance
175427128
ChemSpider
28533231
ChEBI
68590
ChEMBL
CHEMBL1255800
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Fidaxomicin
ATC Codes
A07AA12 — Fidaxomicin
AHFS Codes
  • 08:12.12.92 — Other Macrolides
FDA label
Download (207 KB)
MSDS
Download (143 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Fidaxomicin1
1CompletedBasic ScienceDrug-Drug Interaction (DDI) / Healthy Volunteers / Intestinal Absorption / Pharmacokinetics of Fidaxomicin / Pharmacokinetics of Rosuvastatin1
2CompletedTreatmentClostridium Difficile Infection (CDI)1
2CompletedTreatmentClostridium Difficile-Associated Diarrhea (CDAD)1
2CompletedTreatmentDiarrhea1
3Active Not RecruitingTreatmentClostridium Difficile Infection (CDI)1
3CompletedPreventionClostridium Difficile-Associated Diarrhea (CDAD)1
3CompletedTreatmentClostridium Difficile1
3CompletedTreatmentClostridium Infections / Diarrhea2
3RecruitingTreatmentClostridium Difficile Infection (CDI)1
3RecruitingTreatmentClostridium Difficile-Associated Diarrhea (CDAD)1
4CompletedTreatmentClostridium Difficile1
4CompletedTreatmentClostridium Difficile Infection (CDI) / Inflammatory Bowel Diseases (IBD)1
4Not Yet RecruitingTreatmentClostridium Difficile Infection (CDI)1
4Not Yet RecruitingTreatmentClostridium Difficile Infection (CDI) / Solid Organ Transplant1
4RecruitingTreatmentClostridium / Difficile / Fidaxomicin / Vancomycin1
4TerminatedTreatmentClostridium Difficile1
4TerminatedTreatmentClostridium Difficile / Spinal Cord Injuries (SCI)1
4Unknown StatusTreatmentClostridium Difficile Infection (CDI)1
4WithdrawnPreventionClostridium Difficile Infection (CDI)1
Not AvailableCompletedNot AvailableC. Difficile / Diarrhea / Enterocolitis1
Not AvailableCompletedNot AvailableClostridium Difficile Infection (CDI)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral200 mg
Tablet, film coatedOral200 mg/1
Tablet, film coatedOral200 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8859510No2007-07-312027-07-31Us
US7906489No2007-03-042027-03-04Us
US7378508No2007-07-312027-07-31Us
US7863249No2007-07-312027-07-31Us
US8586551No2004-04-122024-04-12Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0125 mg/mLALOGPS
logP5.59ALOGPS
logP8.56ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)5.87ChemAxon
pKa (Strongest Basic)-1.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count15ChemAxon
Hydrogen Donor Count7ChemAxon
Polar Surface Area266.66 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity269.66 m3·mol-1ChemAxon
Polarizability110.47 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.6628
Blood Brain Barrier-0.8559
Caco-2 permeable-0.6641
P-glycoprotein substrateSubstrate0.8975
P-glycoprotein inhibitor INon-inhibitor0.5357
P-glycoprotein inhibitor IINon-inhibitor0.902
Renal organic cation transporterNon-inhibitor0.9112
CYP450 2C9 substrateNon-substrate0.8485
CYP450 2D6 substrateNon-substrate0.8756
CYP450 3A4 substrateSubstrate0.6796
CYP450 1A2 substrateNon-inhibitor0.7059
CYP450 2C9 inhibitorNon-inhibitor0.6775
CYP450 2D6 inhibitorNon-inhibitor0.8859
CYP450 2C19 inhibitorNon-inhibitor0.6826
CYP450 3A4 inhibitorNon-inhibitor0.899
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7301
Ames testNon AMES toxic0.7118
CarcinogenicityNon-carcinogens0.928
BiodegradationNot ready biodegradable0.9721
Rat acute toxicity2.6789 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9875
hERG inhibition (predictor II)Non-inhibitor0.7335
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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 macrolides and analogues. These are organic compounds containing a lactone ring of at least twelve members.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Macrolides and analogues
Sub Class
Not Available
Direct Parent
Macrolides and analogues
Alternative Parents
p-Hydroxybenzoic acid alkyl esters / o-Hydroxybenzoic acid esters / O-glycosyl compounds / 3-halobenzoic acids and derivatives / Salicylic acid and derivatives / Tricarboxylic acids and derivatives / Benzoyl derivatives / Dichlorobenzenes / O-chlorophenols / P-chlorophenols
show 15 more
Substituents
Macrolide / P-hydroxybenzoic acid alkyl ester / P-hydroxybenzoic acid ester / O-hydroxybenzoic acid ester / Glycosyl compound / Dihydroxybenzoic acid / O-glycosyl compound / Benzoate ester / Salicylic acid or derivatives / 3-halobenzoic acid or derivatives
show 40 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
carboxylic ester, organochlorine compound, phenols, macrolide antibiotic, glycoside (CHEBI:68590)

Targets

Kind
Protein
Organism
Clostridium difficile (strain 630)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transcription factor activity, sequence-specific dna binding
Specific Function
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released.Sigma factors are initiation factors that promote the attachmen...
Gene Name
sigA1
Uniprot ID
Q18BX5
Uniprot Name
RNA polymerase sigma factor SigA
Molecular Weight
44426.185 Da
References
  1. Venugopal AA, Johnson S: Fidaxomicin: a novel macrocyclic antibiotic approved for treatment of Clostridium difficile infection. Clin Infect Dis. 2012 Feb 15;54(4):568-74. doi: 10.1093/cid/cir830. Epub 2011 Dec 7. [PubMed:22156854]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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. Crawford T, Huesgen E, Danziger L: Fidaxomicin: a novel macrocyclic antibiotic for the treatment of Clostridium difficile infection. Am J Health Syst Pharm. 2012 Jun 1;69(11):933-43. doi: 10.2146/ajhp110371. [PubMed:22610025]

Drug created on May 12, 2013 16:32 / Updated on November 19, 2017 20:33