Tedizolid phosphate

Identification

Name
Tedizolid phosphate
Accession Number
DB09042
Type
Small Molecule
Groups
Approved
Description

Tedizolid Phosphate is an oxazolidinone-class antibiotic prodrug indicated in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of several Gram-positive bacteria. Following administration via oral or intravenous route, tedizolid phosphate prodrug is converted by plasma phosphatases to its active moiety, Tedizolid. Once activated, tedizolid exerts its bacteriostatic microbial activity through inhibition of protein synthesis by binding to the 50S ribosomal subunit of susceptible bacteria. Tedizolid is an effective and potent alternative to linezolid for the treatment of patients with Gram-positive ABSSSI due to MRSA or MSSA. Increased potency allows for once daily dosing with reduced total dosages, improving the side effect profile of this drug. Of note, the minimum inhibitory concentrations of tedizolid appear to be largely unaffected by the chloramphenicol-florfenicol resistance (cfr) gene, which has been implicated in a number of published linezolid-resistant organism outbreaks.

Structure
Thumb
Synonyms
  • [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl dihydrogen phosphate
  • Torezolid phosphate
External IDs
TR 701 / TR-701 / TR-701 FA / TR-701FA / TR701
Active Moieties
NameKindUNIICASInChI Key
Tedizolidprodrug97HLQ82NGL856866-72-3XFALPSLJIHVRKE-GFCCVEGCSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SivextroInjection, powder, for solution200 mgIntravenousMerck Sharp & Dohme B.V.2015-03-23Not applicableEu
SivextroTablet200 mgOralMerck Ltd.Not applicableNot applicableCanada
SivextroTablet, film coated200 mg/1OralMerck Sharp & Dohme Limited2014-06-20Not applicableUs
SivextroInjection, powder, for solution200 mgIntravenousMerck Sharp & Dohme B.V.2015-03-23Not applicableEu
SivextroPowder, for solution200 mgIntravenousMerck Ltd.Not applicableNot applicableCanada
SivextroTablet, film coated200 mgOralMerck Sharp & Dohme B.V.2015-03-23Not applicableEu
SivextroInjection, powder, lyophilized, for solution200 mg/4mLIntravenousMerck Sharp & Dohme Limited2014-06-20Not applicableUs
Categories
UNII
O7DRJ6R4DW
CAS number
856867-55-5
Weight
Average: 450.323
Monoisotopic: 450.08529742
Chemical Formula
C17H16FN6O6P
InChI Key
QCGUSIANLFXSGE-GFCCVEGCSA-N
InChI
InChI=1S/C17H16FN6O6P/c1-23-21-16(20-22-23)15-5-2-10(7-19-15)13-4-3-11(6-14(13)18)24-8-12(30-17(24)25)9-29-31(26,27)28/h2-7,12H,8-9H2,1H3,(H2,26,27,28)/t12-/m1/s1
IUPAC Name
{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}phosphonic acid
SMILES
CN1N=NC(=N1)C1=CC=C(C=N1)C1=CC=C(C=C1F)N1C[C@H](COP(O)(O)=O)OC1=O

Pharmacology

Indication

Tedizolid Phosphate is an oxazolidinone antibacterial drug indicated in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), and Enterococcus faecalis.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

After conversion to its active form by phosphatases, tedizolid exerts its antibacterial activity through inhibition of protein synthesis by binding to the 50S ribosomal subunit of susceptible Gram-positive bacteria. Cross-resistance between other non-oxazolidinone antibacterial drugs is unlikely as it inhibits bacterial protein synthesis through a different mechanism.

Absorption

Peak plasma tedizolid concentrations are achieved within approximately 3 hours following oral administration under fasting conditions or at the end of the 1 hour intravenous infusion of tedizolid phosphate. The absolute bioavailability is approximately 91% and no dosage adjustment is necessary between intravenous and oral administration. Oral tedizolid phosphate may be administered with or without food as total systemic exposure is unchanged between fasted and fed conditions.

Volume of distribution

Mean steady-state volume of distribution after 200 mg intravenous infusion is between 67-80 L

Protein binding

Binding to plasma protein is between 70-90%

Metabolism

Tedizolid phosphate is a prodrug that is converted by phosphatases to tedizolid, it's microbiologically active form. There are no other significant circulating metabolites beyond tedizolid which accounts for approximately 95% of the AUC. It is also unlikely to be metabolized by CYP450 enzymes in the liver.

Route of elimination

Tedizolid is excreted in feces as a non-circulating and microbiologically inactive sulfate conjugate.

Half life

12 hours

Clearance

Clearance of a single oral 200 mg dose is 6.9 L/hr, while steady state clearance is 8.4 L/hr

Toxicity

The most commonly reported adverse effects were nausea, vomiting, diarrhea, nausea, and dizziness. Other reactions that occurred during clinical trials at a rate less than 2% include anemia, tachycardia, blurred vision, oral candidiasis, colitis, decreased white blood cell count, vulvovaginal mycotic infection, paresthesia, hypertension, and urticaria. There are no adequate studies to confirm that tedizolid phosphate is safe to use during pregnancy and should be avoided as it was shown to produce fetal developmental toxicities in mice, rats, and rabbits.

Affected organisms
  • Bacteria
  • Streptococcus pyogenes
  • Streptococcus agalactiae
  • Staphylococcus aureus
  • Enterococcus faecalis
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Tedizolid phosphate is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Tedizolid phosphate is combined with (S)-Warfarin.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Tedizolid phosphate.
2,5-Dimethoxy-4-ethylamphetamineTedizolid phosphate may increase the hypertensive activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineTedizolid phosphate may increase the hypertensive activities of 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of serotonin syndrome can be increased when Tedizolid phosphate is combined with 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineTedizolid phosphate may increase the hypertensive activities of 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Tedizolid phosphate is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Tedizolid phosphate.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of serotonin syndrome can be increased when Tedizolid phosphate is combined with 5-methoxy-N,N-dimethyltryptamine.
Food Interactions
Not Available

References

General References
  1. Ong V, Flanagan S, Fang E, Dreskin HJ, Locke JB, Bartizal K, Prokocimer P: Absorption, distribution, metabolism, and excretion of the novel antibacterial prodrug tedizolid phosphate. Drug Metab Dispos. 2014 Aug;42(8):1275-84. doi: 10.1124/dmd.113.056697. Epub 2014 May 29. [PubMed:24875463]
  2. Michalska K, Karpiuk I, Krol M, Tyski S: Recent development of potent analogues of oxazolidinone antibacterial agents. Bioorg Med Chem. 2013 Feb 1;21(3):577-91. doi: 10.1016/j.bmc.2012.11.036. Epub 2012 Dec 5. [PubMed:23273607]
  3. Rybak JM, Roberts K: Tedizolid Phosphate: a Next-Generation Oxazolidinone. Infect Dis Ther. 2015 Feb 24. [PubMed:25708156]
  4. Gras J: Tedizolid phosphate for the treatment of acute bacterial skin and skin structure infections. Drugs Today (Barc). 2014 Nov;50(11):729-37. doi: 10.1358/dot.2014.50.11.2233783. [PubMed:25525633]
  5. Flanagan S, Fang E, Munoz KA, Minassian SL, Prokocimer PG: Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid. Pharmacotherapy. 2014 Sep;34(9):891-900. doi: 10.1002/phar.1458. Epub 2014 Jul 3. [PubMed:24989138]
External Links
KEGG Drug
D09686
PubChem Compound
11476460
PubChem Substance
310264990
ChemSpider
9651289
BindingDB
50017198
ChEBI
83326
ChEMBL
CHEMBL2105669
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tedizolid
AHFS Codes
  • 08:12.28.24 — Oxazolidinones
FDA label
Download (378 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers2
1CompletedNot AvailableHepatic Impairment1
1CompletedBasic ScienceBacterial Infections3
1CompletedBasic ScienceHealthy Volunteers3
1CompletedOtherHealthy Volunteers3
1CompletedTreatmentImpaired Renal Function1
1CompletedTreatmentSkin Diseases, Bacterial1
1Not Yet RecruitingTreatmentGram-Positive Infections1
1RecruitingOtherDiabetes Mellitus (DM) / Healthy Volunteers / Wound Infections1
1RecruitingTreatmentInfections, Gram-Positive Bacterial1
2CompletedOtherCellulitis / Erysipelas / Major Cutaneous Abscess1
2CompletedTreatmentSkin Diseases, Bacterial / Skin Diseases, Infectious1
2RecruitingTreatmentBone and Joint Infections1
3CompletedTreatmentBacterial Infections1
3CompletedTreatmentPneumonia1
3CompletedTreatmentSkin Diseases, Bacterial / Skin Diseases, Infectious1
3CompletedTreatmentSkin Diseases, Infectious1
3CompletedTreatmentSkin and Subcutaneous Tissue Bacterial Infections2
3Not Yet RecruitingTreatmentAcute acute bacterial skin and skin structure infections1
4CompletedHealth Services ResearchBMI >30 kg/m21
Not AvailableRecruitingTreatmentProsthetic Joint Infection1
Not AvailableTerminatedNot AvailableAbscesses / Cellulitis / Erysipelas / Wound Infections1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous200 mg
Injection, powder, lyophilized, for solutionIntravenous200 mg/4mL
Powder, for solutionIntravenous200 mg
TabletOral200 mg
Tablet, film coatedOral200 mg
Tablet, film coatedOral200 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7816379No2008-02-232028-02-23Us
US8420676No2008-02-232028-02-23Us
US8426389No2010-12-312030-12-31Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP4.89ChEMBL
Predicted Properties
PropertyValueSource
Water Solubility0.608 mg/mLALOGPS
logP0.82ALOGPS
logP1.97ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)1.35ChemAxon
pKa (Strongest Basic)-1.6ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area152.79 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity125.93 m3·mol-1ChemAxon
Polarizability41.46 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
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 phenylpyridines. These are polycyclic aromatic compounds containing a benzene ring linked to a pyridine ring through a CC or CN bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Phenylpyridines
Direct Parent
Phenylpyridines
Alternative Parents
Fluorobenzenes / Monoalkyl phosphates / Oxazolidinones / Aryl fluorides / Tetrazoles / Carbamate esters / Heteroaromatic compounds / Organic carbonic acids and derivatives / Azacyclic compounds / Oxacyclic compounds
show 6 more
Substituents
3-phenylpyridine / Fluorobenzene / Halobenzene / Monoalkyl phosphate / Aryl fluoride / Aryl halide / Monocyclic benzene moiety / Organic phosphoric acid derivative / Oxazolidinone / Phosphoric acid ester
show 21 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, carbamate ester, tetrazoles, pyridines, ring assembly, oxazolidinone (CHEBI:83326)

Drug created on April 27, 2015 16:15 / Updated on November 14, 2018 12:56