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
  • Fidaxomicin
  • Fidaxomicina
  • 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 Corp.2011-05-27Not applicableUs
DificidTablet200 mgOralMerck Ltd.2012-06-21Not applicableCanada
DificidTablet, film coated200 mg/1OralAvera McKennan Hospital2015-04-172018-07-05Us
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[C@H]1\C=C(C)\[C@@H](O)C\C=C\C=C(CO[C@@H]2O[C@H](C)[C@@H](OC(=O)C3=C(CC)C(Cl)=C(O)C(Cl)=C3O)[C@H](O)[C@@H]2OC)\C(=O)OC(C\C=C(/C)\C=C(C)\[C@@H]1O[C@@H]1OC(C)(C)[C@@H](OC(=O)C(C)C)[C@H](O)[C@@H]1O)[C@@H](C)O

Pharmacology

Indication

Treatment of Clostridium difficile-associated diarrhea

Associated Conditions
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
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Fidaxomicin is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Fidaxomicin is combined with (S)-Warfarin.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Fidaxomicin.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Fidaxomicin.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Fidaxomicin.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Fidaxomicin.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Fidaxomicin.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Fidaxomicin.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Fidaxomicin.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Fidaxomicin.
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
2CompletedTreatmentSevere or persistent diarrhea1
2Not Yet RecruitingTreatmentClostridium Difficile1
3Active Not RecruitingTreatmentClostridium Difficile Infection (CDI)2
3CompletedPreventionClostridium Difficile-Associated Diarrhea (CDAD)1
3CompletedTreatmentClostridium Difficile1
3CompletedTreatmentClostridium Difficile-Associated Diarrhea (CDAD)1
3CompletedTreatmentClostridium Infections / Severe or persistent diarrhea2
4CompletedTreatmentClostridium Difficile1
4CompletedTreatmentClostridium Difficile Infection (CDI) / Inflammatory Bowel Diseases (IBD)1
4RecruitingTreatmentClostridium Difficile Infection (CDI)1
4RecruitingTreatmentClostridium / Difficile / Fidaxomicin / Vancomycin1
4TerminatedTreatmentClostridium Difficile1
4TerminatedTreatmentClostridium Difficile / Spinal Cord Injuries (SCI)1
4Unknown StatusTreatmentClostridium Difficile Infection (CDI)1
4WithdrawnPreventionClostridium Difficile Infection (CDI)1
4WithdrawnTreatmentClostridium Difficile Infection (CDI) / Solid Organ Transplant1
Not AvailableCompletedNot AvailableC. Difficile / Enterocolitis / Severe or persistent diarrhea1
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)
US8859510No2014-10-142027-07-31Us
US7906489No2011-03-152027-03-04Us
US7378508No2008-05-272027-07-31Us
US7863249No2011-01-042027-07-31Us
US8586551No2013-11-192024-04-12Us

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]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
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. Spina E, Pisani F, Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinet. 1996 Sep;31(3):198-214. doi: 10.2165/00003088-199631030-00004. [PubMed:8877250]

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 December 14, 2018 17:11