Identification

Name
Delafloxacin
Accession Number
DB11943
Type
Small Molecule
Groups
Approved, Investigational
Description

Delafloxacin is a fluoroquinolone antibiotic which has been used in trials studying the treatment and basic science of Gonorrhea, Hepatic Impairment, Bacterial Skin Diseases, Skin Structure Infections, and Community Acquired Pneumonia, among others. It was approved in June 2017 under the trade name Baxdela for use in the treatment of acute bacterial skin and skin structure infections.

Structure
Thumb
Synonyms
Not Available
External IDs
ABT-492 / RX-3341 / WQ-3034
Product Ingredients
IngredientUNIICASInChI Key
Delafloxacin meglumineN7V53U4U4T352458-37-8AHJGUEMIZPMAMR-WZTVWXICSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BaxdelaTablet450 mg/1OralMelinta Therapeutics, Inc2017-06-19Not applicableUs
BaxdelaInjection, powder, lyophilized, for solution300 mg/10.5mLIntravenousMelinta Therapeutics, Inc2017-06-19Not applicableUs
Categories
UNII
6315412YVF
CAS number
189279-58-1
Weight
Average: 440.76
Monoisotopic: 440.0499171
Chemical Formula
C18H12ClF3N4O4
InChI Key
DYDCPNMLZGFQTM-UHFFFAOYSA-N
InChI
InChI=1S/C18H12ClF3N4O4/c19-12-13-7(1-9(20)14(12)25-3-6(27)4-25)15(28)8(18(29)30)5-26(13)17-11(22)2-10(21)16(23)24-17/h1-2,5-6,27H,3-4H2,(H2,23,24)(H,29,30)
IUPAC Name
1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
SMILES
NC1=NC(N2C=C(C(O)=O)C(=O)C3=CC(F)=C(N4CC(O)C4)C(Cl)=C23)=C(F)C=C1F

Pharmacology

Indication

Delafloxacin is indicated for the treatment of acute bacterial skin and skin structure infections caused by the Gram-positive organisms Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis as well as the Gram-negative organisms Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa [FDA Label].

Structured Indications
Pharmacodynamics

Delafloxacin is a fluoroquinolone antibacterial drug which kills bacterial cells [FDA Label].

Mechanism of action

Delafloxacin inhibits the activity of bacterial DNA topoisomerase IV and DNA gyrase (topoisomerase II) [FDA Label]. This interferes with bacterial DNA replication by preventing the relaxation of positive supercoils introduced as part of the elongation process [1]. The resultant strain inhibits further elongation. Delafloxacin exerts concentration-dependent bacteriocidal activity [FDA Label].

TargetActionsOrganism
ADNA topoisomerase 4 subunit A
inhibitor
Escherichia coli (strain K12)
ADNA gyrase subunit A
inhibitor
Escherichia coli (strain K12)
Absorption

The median time to peak plasma concentration for orally administered Delafloxacin is 0.75 (0.5-4.0) hours after a single dose and 1.00 (0.5-6.0) hours for steady state dosing [FDA Label]. The median time to peak plasma concentration for intravenously administered Delafloxacin is 1.00 (1.0-1.2) hours for a single dose and 1.0 (1.0-1.0) hour for steady state dosing. The absolute bioavailability for orally administed Delafloxacin is 58.8%.

Volume of distribution

The steady sate volume of distrubution of Delafloxacin is 30-48 liters [FDA Label].

Protein binding

Delafloxacin is 84% bound to human plasma proteins [FDA Label]. It primarily binds to serum albumin.

Metabolism

Delafoxacin is primarily metabolized via glucuronidation mediated by UDP glucuronosyltransferase 1-1, UDP-glucuronosyltransferase 1-3, and UDP-glucuronosyltransferase 2B15 [FDA Label]. Less than 1% is metabolized via oxidation.

Route of elimination

After a single intravenous dose, 65% of Delafloxacin was excreted in the urine either unchanged or as glucuronide metabolites with 28% excreted unchanged in the feces [FDA Label]. After a single oral dose, 50% of Delafloxacin was excreted in the urine either unchanged or as glucuronide metabolites with 48% excreted unchanged in the feces.

Half life

The mean half life of elimination of Delafloxacin is 3.7 hours after a single intravenous administration [FDA Label]. The mean half life of elimination for multple oral administrations is 4.2-8.5 hours.

Clearance

The mean total clearance of Delafloxacin is 16.3 liters per hour [FDA Label]. Renal clearance accounts for 35-45% of total clearance.

Toxicity

The most common adverse reactions noted with Delafloxacin were nausea (8%), diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%) [FDA Label]. Fluoroquinolones are associated with increased frequency of tendon rupture and tendonitis, increased risk of peipheral neuropathy, excacerbation of myasthenia gravis, and development of Clostridium difficile-associated diarrhea. Fluoroquinolones are also associated with an increased risk of central nervous system reactions (CNS), including: convulsions and increased intracranial pressure (including pseudotumor cerebri) and toxic psychosis. Fluoroquinolones may also cause CNS reactions of nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and suicidal thoughts or acts.

Affected organisms
  • Pseudomonas aeruginosa
  • Streptococcus pyogenes
  • Streptococcus agalactiae
  • Escherichia coli
  • Staphylococcus aureus
  • Enterococcus faecalis
  • Staphylococcus lugdunensis
  • Streptococcus anginosus
  • Proteus mirabilis
  • Enterobacter cloacae
  • Klebsiella pneumoniae
  • Staphylococcus haemolyticus
  • Streptococcus dysgalactiae
  • Enterobacter aerogenes
  • Haemophilus parainfluenzae
  • Klebsiella oxytoca
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AripiprazoleThe serum concentration of Aripiprazole can be decreased when it is combined with Delafloxacin.Approved, Investigational
EltrombopagThe serum concentration of Delafloxacin can be increased when it is combined with Eltrombopag.Approved
RilpivirineThe serum concentration of Rilpivirine can be decreased when it is combined with Delafloxacin.Approved
RolapitantThe serum concentration of Delafloxacin can be increased when it is combined with Rolapitant.Approved
SaxagliptinThe serum concentration of Saxagliptin can be decreased when it is combined with Delafloxacin.Approved
TeriflunomideThe serum concentration of Delafloxacin can be increased when it is combined with Teriflunomide.Approved
VemurafenibThe serum concentration of Vemurafenib can be decreased when it is combined with Delafloxacin.Approved
Food Interactions
Not Available

References

General References
  1. 49. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 612-614). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
External Links
PubChem Compound
487101
PubChem Substance
347828270
ChemSpider
427049
ChEMBL
CHEMBL2105637
FDA label
Download (1.37 MB)
MSDS
Download (23.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceVA Drug Interactions / VA Drug Interactions [VA Drug Interaction]1
1CompletedTreatmentHepatic Impairment1
2CompletedTreatmentBacterial Skin Diseases / Skin Structure Infections / Staphylococcal Skin Infections1
2CompletedTreatmentSkin and Subcutaneous Tissue Bacterial Infections1
3CompletedTreatmentSkin and Subcutaneous Tissue Bacterial Infections / Skin Structures and Soft Tissue Infections1
3CompletedTreatmentSkin and Subcutaneous Tissue Bacterial Infections1
3RecruitingTreatmentCommunity Acquired Bacterial Pneumonia / Community Acquired Pneumonia (CAP)1
3TerminatedTreatmentGonorrhea1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous300 mg/10.5mL
TabletOral450 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8969569No2005-10-072025-10-07Us
US8252813No2006-10-022026-10-02Us
US9539250No2005-10-072025-10-07Us
US8648093No2005-10-072025-10-07Us
US8871938No2009-09-232029-09-23Us
US7728143No2007-11-202027-11-20Us
US8273892No2006-08-062026-08-06Us
US8497378No2009-12-282029-12-28Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0699 mg/mLALOGPS
logP1.67ALOGPS
logP2.56ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)5.62ChemAxon
pKa (Strongest Basic)-1.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area119.99 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity101.33 m3·mol-1ChemAxon
Polarizability38.42 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 quinoline carboxylic acids. These are quinolines in which the quinoline ring system is substituted by a carboxyl group at one or more positions.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Quinoline carboxylic acids
Direct Parent
Quinoline carboxylic acids
Alternative Parents
Fluoroquinolones / Chloroquinolines / Aminoquinolines and derivatives / Hydroquinolones / Hydroquinolines / Pyridinecarboxylic acids / Dialkylarylamines / Polyhalopyridines / Aminopyridines and derivatives / Benzenoids
show 18 more
Substituents
Quinoline-3-carboxylic acid / Fluoroquinolone / Dihydroquinolone / Haloquinoline / Aminoquinoline / Chloroquinoline / Dihydroquinoline / Pyridine carboxylic acid / Pyridine carboxylic acid or derivatives / Polyhalopyridine
show 35 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Dna topoisomerase type ii (atp-hydrolyzing) activity
Specific Function
Topoisomerase IV is essential for chromosome segregation. It relaxes supercoiled DNA. Performs the decatenation events required during the replication of a circular DNA molecule. MukB stimulates th...
Gene Name
parC
Uniprot ID
P0AFI2
Uniprot Name
DNA topoisomerase 4 subunit A
Molecular Weight
83830.455 Da
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Identical protein binding
Specific Function
DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, inc...
Gene Name
gyrA
Uniprot ID
P0AES4
Uniprot Name
DNA gyrase subunit A
Molecular Weight
96962.63 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGTs are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isozyme displays activity toward several classes of xeno...
Gene Name
UGT2B15
Uniprot ID
P54855
Uniprot Name
UDP-glucuronosyltransferase 2B15
Molecular Weight
61035.815 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
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

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Efflux transmembrane transporter activity
Specific Function
Drug efflux transporter present in a number of stem cells that acts as a regulator of cellular differentiation. Able to mediate efflux from cells of the rhodamine dye and of the therapeutic drug do...
Gene Name
ABCB5
Uniprot ID
Q2M3G0
Uniprot Name
ATP-binding cassette sub-family B member 5
Molecular Weight
138639.48 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da

Drug created on October 20, 2016 15:03 / Updated on December 01, 2017 17:37