Telavancin

Identification

Name
Telavancin
Accession Number
DB06402
Type
Small Molecule
Groups
Approved
Description

Telavancin is a semi-synthetic derivative of vanocymycin that has bactericidal activity against Methicillin-resistant Staphylococcus aureus (MRSA) and other gram-positive bacteria. MRSA is an important pathogen capable of causing hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and skin and subcutaneous tissue infections among others.

Structure
Thumb
Synonyms
  • Telavancina
  • Télavancine
  • Telavancinum
Product Ingredients
IngredientUNIICASInChI Key
Telavancin hydrochloride0701472ZG0560130-42-9GSSIWSIRBWAZHG-ACOPVEIWSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VibativInjection, powder, lyophilized, for solution15 mg/1mLIntravenousTheravance, Inc.2009-11-05Not applicableUs
VibativPowder, for solution250 mgIntravenousPendopharm Division Of De Pharmascience IncNot applicableNot applicableCanada
VibativInjection, powder, lyophilized, for solution750 mg/1IntravenousAstellas Pharma Inc2009-11-052015-05-31Us
VibativInjection, powder, lyophilized, for solution15 mg/1mLIntravenousTheravance, Inc.2009-11-05Not applicableUs
VibativInjection, powder, lyophilized, for solution15 mg/1mLIntravenousTheravance Biopharma R&d, Inc.2009-11-05Not applicableUs
VibativInjection, powder, lyophilized, for solution250 mg/1IntravenousAstellas Pharma Inc2009-11-052015-05-31Us
VibativPowder, for solution750 mgIntravenousPendopharm Division Of De Pharmascience Inc2016-01-06Not applicableCanada
VibativInjection, powder, lyophilized, for solution15 mg/1mLIntravenousTheravance Biopharma R&d, Inc.2009-11-05Not applicableUs
Categories
UNII
XK134822Z0
CAS number
372151-71-8
Weight
Average: 1755.65
Monoisotopic: 1753.6374296
Chemical Formula
C80H106Cl2N11O27P
InChI Key
ONUMZHGUFYIKPM-MXNFEBESSA-N
InChI
InChI=1S/C80H106Cl2N11O27P/c1-7-8-9-10-11-12-13-14-21-85-22-23-87-80(5)32-57(115-37(4)71(80)103)119-70-68(102)67(101)55(34-94)118-79(70)120-69-53-28-41-29-54(69)117-52-20-17-40(27-46(52)82)65(99)63-77(109)91-61(78(110)111)43-30-50(96)44(33-86-35-121(112,113)114)66(100)58(43)42-25-38(15-18-49(42)95)59(74(106)93-63)90-75(107)60(41)89-73(105)48(31-56(83)97)88-76(108)62(92-72(104)47(84-6)24-36(2)3)64(98)39-16-19-51(116-53)45(81)26-39/h15-20,25-30,36-37,47-48,55,57,59-65,67-68,70-71,79,84-87,94-96,98-103H,7-14,21-24,31-35H2,1-6H3,(H2,83,97)(H,88,108)(H,89,105)(H,90,107)(H,91,109)(H,92,104)(H,93,106)(H,110,111)(H2,112,113,114)/t37-,47+,48-,55+,57-,59+,60+,61-,62+,63-,64+,65+,67+,68-,70+,71+,79-,80-/m0/s1
IUPAC Name
(1S,2R,18R,19R,22S,25R,28R,40S)-22-(carbamoylmethyl)-5,47-dichloro-48-{[(2S,3R,4S,5S,6R)-3-{[(2S,4S,5S,6S)-4-{[2-(decylamino)ethyl]amino}-5-hydroxy-4,6-dimethyloxan-2-yl]oxy}-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-2,18,32,35,37-pentahydroxy-19-[(2R)-4-methyl-2-(methylamino)pentanamido]-20,23,26,42,44-pentaoxo-36-{[(phosphonomethyl)amino]methyl}-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2^{3,6}.2^{14,17}.1^{8,12}.1^{29,33}.0^{10,25}.0^{34,39}]pentaconta-3,5,8,10,12(48),14,16,29(45),30,32,34,36,38,46,49-pentadecaene-40-carboxylic acid
SMILES
CCCCCCCCCCNCCN[C@@]1(C)C[C@H](O[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]2OC2=C3OC4=CC=C(C=C4Cl)[C@@H](O)[C@@H](NC(=O)[C@@H](CC(C)C)NC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]4C(C=C2OC2=C(Cl)C=C(C=C2)[C@@H](O)[C@@H]2NC(=O)[C@H](NC4=O)C4=CC(=C(O)C=C4)C4=C(O)C(CNCP(O)(O)=O)=C(O)C=C4[C@H](NC2=O)C(O)=O)=C3)O[C@@H](C)[C@H]1O

Pharmacology

Indication

For the treatment of complicated skin and skin structure infections (cSSSI) caused by gram-positive bacteria like methicillin-susceptible or -resistant Staphylococcus aureus, vancomycin-susceptible Enterococcus faecalis, and Streptococcus pyogenes, Streptococcus agalactiae, or Streptococcus anginosus group. Also for the treatment of adult patients with hospital-acquired bacterial pneumonia (HAP) and ventilator-associated bacterial pneumonia (VAP), known or suspected to be caused by susceptible isolates of Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant S. aureus).

Associated Conditions
Pharmacodynamics

Telavancin is a semi-synthetic derivative of vancomycin, therefore the mode of bactericidal action is similar to vancomycin in which both antibiotics inhibit cell wall synthesis. Not only that, it displays concentration-dependent bactericidal action. Furthermore, telavancin is a more potent inhibitor (10-fold) of peptidoglycan synthesis and, unlike vancomycin, disrupts cell membrane integrity via its interaction with lipid II. AUC/MIC ratio best predicts the extent of in-vivo response in which the higher the ratio, the greater the bactericidal activity. The smallest ratio in which one would be able to observe no bacterial growth at 24 hours is 50. Maximal bactericidal activity is observed at a AUC/MIC ratio of 404.

Mechanism of action

Telavancin is a bactericidal lipoglycopeptide that is active against a broad range of gram-positive bacteria. Telavancin prevents polymerization of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) and cross-linking of peptidoglycan by binding to D-Ala-D-Ala. As a result, inhibition of bacterial cell wall synthesis occurs. Furthermore, telavancin disrupts membrane potential and cell permeability as a result of the lipophillic side chain moiety. This additional bactericidal mechanism is what sets telavancin apart from vancomycin.

Absorption

Telavancin demonstrates linear pharmacokinetics at doses between 1 and 12.5 mg/kg. Furthermore, 24 hours post-infusion of a dose of 7.5 to 15 mg/kg, activity against MRSA and penicillin-resistant Streptococcus pneumonia can still be observed. The trough concentration at this point of time is approximately 10 μg/mL. Telavancin also has poor bioavailability and must be administered over 30-120 minutes IV. Cmax, healthy subjects, 10 mg/kg = 93.6 ± 14.2 μg/mL; AUC (0- ∞), healthy subjects, 10 mg/kg = 747 ± 129 μg · h/mL; AUC (0-24h), healthy subjects, 10 mg/kg = 666± 107 μg · h/mL; Time to steady state = 3 days;

Volume of distribution

Vss, healthy subjects, 10 mg/kg = 0.14 L/kg

Protein binding

>90% to serum albumin in a concentration independent manner (despite being highly protein bound, antimicrobial activity of telavancin is not affected)

Metabolism

Metabolism of telavancin does not involve the cytochrome P450 enzyme system. Primary metabolite is called THRX-651540, but the metabolite pathway has not been identified.

Route of elimination

Urine with >80% as unchanged drug and <20% as hydroxylated metabolites (with dose of 10mg/kg); Feces (<1%)

Half life

Terminal elimination half-life = 8 ± 1.5 hours (with normal renal function)

Clearance

Cl, healthy subjects, 10 mg/kg = 13.9 ± 2.9 mL/h/kg

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

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Telavancin which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Telavancin which could result in a higher serum level.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Telavancin.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Telavancin.
AlprazolamAlprazolam may decrease the excretion rate of Telavancin which could result in a higher serum level.
AmantadineAmantadine may increase the QTc-prolonging activities of Telavancin.
AmilorideAmiloride may increase the excretion rate of Telavancin which could result in a lower serum level and potentially a reduction in efficacy.
AmiodaroneThe risk or severity of QTc prolongation can be increased when Telavancin is combined with Amiodarone.
AmitriptylineTelavancin may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
AmlodipineThe risk or severity of QTc prolongation can be increased when Amlodipine is combined with Telavancin.
Food Interactions
Not Available

References

General References
  1. Laohavaleeson S, Kuti JL, Nicolau DP: Telavancin: a novel lipoglycopeptide for serious gram-positive infections. Expert Opin Investig Drugs. 2007 Mar;16(3):347-57. [PubMed:17302529]
  2. Rubinstein E, Corey GR, Stryjewski ME, Kanafani ZA: Telavancin for the treatment of serious gram-positive infections, including hospital acquired pneumonia. Expert Opin Pharmacother. 2011 Dec;12(17):2737-50. doi: 10.1517/14656566.2011.633511. [PubMed:22077833]
  3. Zhanel GG, Calic D, Schweizer F, Zelenitsky S, Adam H, Lagace-Wiens PR, Rubinstein E, Gin AS, Hoban DJ, Karlowsky JA: New lipoglycopeptides: a comparative review of dalbavancin, oritavancin and telavancin. Drugs. 2010 May 7;70(7):859-86. doi: 10.2165/11534440-000000000-00000. [PubMed:20426497]
  4. Wong SL, Goldberg MR, Ballow CH, Kitt MM, Barriere SL: Effect of Telavancin on the pharmacokinetics of the cytochrome P450 3A probe substrate midazolam: a randomized, double-blind, crossover study in healthy subjects. Pharmacotherapy. 2010 Feb;30(2):136-43. doi: 10.1592/phco.30.2.136. [PubMed:20099988]
External Links
PubChem Compound
3081362
PubChem Substance
175427069
ChemSpider
2338980
ChEBI
71229
ChEMBL
CHEMBL507870
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Telavancin
ATC Codes
J01XA03 — Telavancin
AHFS Codes
  • 08:12.28.16 — Glycopeptides
FDA label
Download (6.45 MB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedOtherEnd Stage Renal Disease (ESRD) / Kidney Diseases1
2CompletedTreatmentAbscesses / Cellulitis / Infections, Gram-Positive Bacterial / Minor burns / Ulcers / Wound Infections1
2CompletedTreatmentBacteremia / Infection NOS1
2CompletedTreatmentInfections, Gram-Positive Bacterial2
3CompletedTreatmentPneumonia, Bacterial2
3CompletedTreatmentStaphylococcal Skin Infections2
3TerminatedTreatmentBacteremia1
4CompletedNot AvailableEnd-Stage Renal Disease (ESRD) / Stage 5 Chronic Kidney Diseases1
4RecruitingBasic ScienceInfections, Gram-Positive Bacterial1
4RecruitingOtherCystic Fibrosis (CF)1
Not AvailableCompletedNot AvailableBone and Joint Infections / Complicated Bacteremia / Endocarditis / Gram Positive Infection / Hospital Acquired Bacterial Pneumonia / Skin and Subcutaneous Tissue Bacterial Infections / Ventilator Associated Bacterial Pneumonia1
Not AvailableRecruitingNot AvailablePregnancy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous15 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous250 mg/1
Injection, powder, lyophilized, for solutionIntravenous750 mg/1
Powder, for solutionIntravenous250 mg
Powder, for solutionIntravenous750 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6635618No2003-09-112023-09-11Us
US7008923No2001-05-062021-05-06Us
US7351691No2001-05-012021-05-01Us
US7700550No2001-05-012021-05-01Us
US6858584No2002-08-242022-08-24Us
US7531623No2007-01-012027-01-01Us
US7544364No2001-05-012021-05-01Us
US7208471No2001-05-012021-05-01Us
US6872701No2001-06-052021-06-05Us
US8101575No2001-05-012021-05-01Us
US8158580No2001-05-012021-05-01Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0148 mg/mLALOGPS
logP2.32ALOGPS
logP-6.2ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)1.55ChemAxon
pKa (Strongest Basic)9.99ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count29ChemAxon
Hydrogen Donor Count23ChemAxon
Polar Surface Area598.09 Å2ChemAxon
Rotatable Bond Count30ChemAxon
Refractivity429.41 m3·mol-1ChemAxon
Polarizability175.85 Å3ChemAxon
Number of Rings10ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9186
Blood Brain Barrier-0.9691
Caco-2 permeable-0.6403
P-glycoprotein substrateSubstrate0.9318
P-glycoprotein inhibitor INon-inhibitor0.6459
P-glycoprotein inhibitor IINon-inhibitor0.9898
Renal organic cation transporterNon-inhibitor0.946
CYP450 2C9 substrateNon-substrate0.877
CYP450 2D6 substrateNon-substrate0.8047
CYP450 3A4 substrateSubstrate0.665
CYP450 1A2 substrateNon-inhibitor0.7471
CYP450 2C9 inhibitorNon-inhibitor0.7401
CYP450 2D6 inhibitorNon-inhibitor0.8259
CYP450 2C19 inhibitorNon-inhibitor0.6898
CYP450 3A4 inhibitorInhibitor0.5291
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8482
Ames testNon AMES toxic0.5605
CarcinogenicityNon-carcinogens0.8098
BiodegradationNot ready biodegradable0.9966
Rat acute toxicity2.7064 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9196
hERG inhibition (predictor II)Inhibitor0.6147
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Oligopeptides
Alternative Parents
Cyclic peptides / Aminoglycosides / Phenolic glycosides / Leucine and derivatives / N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Diarylethers / Disaccharides / O-glycosyl compounds / 1-hydroxy-2-unsubstituted benzenoids
show 25 more
Substituents
Alpha-oligopeptide / Aminoglycoside core / Cyclic alpha peptide / Phenolic glycoside / Leucine or derivatives / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / O-glycosyl compound / Glycosyl compound / Disaccharide
show 48 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
glycopeptide (CHEBI:71229)

Drug created on March 19, 2008 10:29 / Updated on September 23, 2018 19:37