Identification

Name
Umeclidinium
Accession Number
DB09076
Type
Small Molecule
Groups
Approved
Description

Umeclidinium is a long-acting muscarinic antagonist (LAMA) used as maintenance treatment for symptoms of chronic obstructive pulmonary disease (COPD). It is available as a once-daily inhalation monotherapy or as a fixed-dose combination product with the long-acting beta2-agonist vilanterol. COPD is a progressive obstructive lung disease characterized by shortness of breath, cough, sputum production, and chronically poor airflow with a forced expiratory volume in 1 second (FEV1) of less than 80%. By blocking the M3 muscarinic receptor which is highly expressed in airway smooth muscle of the lungs, umeclidinium inhibits the binding of acetylcholine and thereby opens up the airways by preventing bronchoconstriction. Its use has been shown to provide clinically significant, sustained improvements in lung function.

Structure
Thumb
Synonyms
  • 1-[2-(benzyloxy)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane
External IDs
GSK-573719 / GSK573719 / GSK573719A
Product Ingredients
IngredientUNIICASInChI Key
Umeclidinium bromide7AN603V4JV869113-09-7PEJHHXHHNGORMP-UHFFFAOYSA-M
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
IncrusePowder, metered55 μgRespiratory (inhalation)Glaxo Group Limited2014-04-28Not applicableEu
IncrusePowder, metered55 μgRespiratory (inhalation)Glaxo Group Limited2014-04-28Not applicableEu
IncrusePowder, metered55 μgRespiratory (inhalation)Glaxo Group Limited2014-04-28Not applicableEu
Incruse ElliptaPowder62.5 mcgRespiratory (inhalation)Glaxosmithkline Inc2015-04-27Not applicableCanada
Incruse ElliptaAerosol, powder62.5 ug/1OralGlaxosmithkline Inc2014-04-30Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
AnoroUmeclidinium bromide (55 micrograms) + Vilanterol Trifenatate (22 micrograms)Powder, meteredRespiratory (inhalation)Glaxo Group Limited2014-05-08Not applicableEu
AnoroUmeclidinium bromide (55 micrograms) + Vilanterol Trifenatate (22 micrograms)Powder, meteredRespiratory (inhalation)Glaxo Group Limited2014-05-08Not applicableEu
AnoroUmeclidinium bromide (55 micrograms) + Vilanterol Trifenatate (22 micrograms)Powder, meteredRespiratory (inhalation)Glaxo Group Limited2014-05-08Not applicableEu
Anoro ElliptaUmeclidinium (62.5 mcg) + Vilanterol (25 mcg)PowderRespiratory (inhalation)Glaxosmithkline Inc2014-03-14Not applicableCanada
Anoro ElliptaUmeclidinium bromide (62.5 ug/1) + Vilanterol Trifenatate (25 ug/1)PowderRespiratory (inhalation)Glaxosmithkline Inc2014-01-31Not applicableUs
Trelegy ElliptaUmeclidinium (62.5 mcg) + Fluticasone furoate (100 mcg) + Vilanterol (25 mcg)PowderRespiratory (inhalation)Glaxosmithkline IncNot applicableNot applicableCanada
Trelegy ElliptaUmeclidinium bromide (62.5 ug/1) + Fluticasone furoate (100 ug/1) + Vilanterol Trifenatate (25 ug/1)PowderRespiratory (inhalation)Glaxosmithkline Inc2017-09-18Not applicableUs
Categories
UNII
GE2T1418SV
CAS number
869185-19-3
Weight
Average: 428.595
Monoisotopic: 428.258405759
Chemical Formula
C29H34NO2
InChI Key
FVTWTVQXNAJTQP-UHFFFAOYSA-N
InChI
InChI=1S/C29H34NO2/c31-29(26-12-6-2-7-13-26,27-14-8-3-9-15-27)28-16-19-30(20-17-28,21-18-28)22-23-32-24-25-10-4-1-5-11-25/h1-15,31H,16-24H2/q+1
IUPAC Name
1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azabicyclo[2.2.2]octan-1-ium
SMILES
OC(C1=CC=CC=C1)(C1=CC=CC=C1)C12CC[N+](CCOCC3=CC=CC=C3)(CC1)CC2

Pharmacology

Indication

Indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Umeclidinium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through the inhibition of M3 receptor at the smooth muscle leading to bronchodilation.

TargetActionsOrganism
NMuscarinic acetylcholine receptor M1
antagonist
Human
AMuscarinic acetylcholine receptor M2
antagonist
Human
AMuscarinic acetylcholine receptor M3
antagonist
Human
NMuscarinic acetylcholine receptor M4
antagonist
Human
NMuscarinic acetylcholine receptor M5
antagonist
Human
Absorption

Cmax occurred at 5 to 15 minutes, with steady state concentrations arriving in 14 days with 1.8-fold accumulation.

Volume of distribution

Mean volume of distribution was 86 L.

Protein binding

89%

Metabolism

In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, Odealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

Route of elimination

Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine.

Half life

The effective half-life after once daily dosing is 11 hours.

Clearance
Not Available
Toxicity

In clinical trials, the most common adverse effects of umeclidinium were nasopharyngitis, upper respiratory tract infection, cough, and arthralgia. Atrial fibrillation occurred in <1% of patients, but was more common among patients treated with umeclidinium than in those treated with placebo. Anticholinergics like umeclidinium should be used with caution in patients with narrow-angle glaucoma and in those with prostatic hyperplasia or bladder-neck obstruction. Inhaled medications can cause paradoxical bronchospasm, which can be fatal.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
1,10-PhenanthrolineThe therapeutic efficacy of Umeclidinium can be decreased when used in combination with 1,10-Phenanthroline.
AbirateroneThe serum concentration of Umeclidinium can be increased when it is combined with Abiraterone.
AcetaminophenThe serum concentration of Umeclidinium can be increased when it is combined with Acetaminophen.
AclidiniumAclidinium may increase the anticholinergic activities of Umeclidinium.
AgmatineThe risk or severity of adverse effects can be increased when Umeclidinium is combined with Agmatine.
AlcuroniumAlcuronium may increase the anticholinergic activities of Umeclidinium.
AlfentanilThe risk or severity of adverse effects can be increased when Umeclidinium is combined with Alfentanil.
AlphacetylmethadolThe risk or severity of adverse effects can be increased when Umeclidinium is combined with Alphacetylmethadol.
AlphaprodineThe risk or severity of adverse effects can be increased when Umeclidinium is combined with Alphaprodine.
AmbenoniumThe therapeutic efficacy of Umeclidinium can be decreased when used in combination with Ambenonium.
Food Interactions
Not Available

References

General References
  1. Feldman GJ, Edin A: The combination of umeclidinium bromide and vilanterol in the management of chronic obstructive pulmonary disease: current evidence and future prospects. Ther Adv Respir Dis. 2013 Dec;7(6):311-9. doi: 10.1177/1753465813499789. Epub 2013 Sep 3. [PubMed:24004659]
  2. Decramer M, Maltais F, Feldman G, Brooks J, Harris S, Mehta R, Crater G: Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients. Respir Physiol Neurobiol. 2013 Jan 15;185(2):393-9. doi: 10.1016/j.resp.2012.08.022. Epub 2012 Sep 28. [PubMed:23026438]
  3. Tal-Singer R, Cahn A, Mehta R, Preece A, Crater G, Kelleher D, Pouliquen IJ: Initial assessment of single and repeat doses of inhaled umeclidinium in patients with chronic obstructive pulmonary disease: two randomised studies. Eur J Pharmacol. 2013 Feb 15;701(1-3):40-8. doi: 10.1016/j.ejphar.2012.12.019. Epub 2012 Dec 28. [PubMed:23276660]
  4. Trivedi R, Richard N, Mehta R, Church A: Umeclidinium in patients with COPD: a randomised, placebo-controlled study. Eur Respir J. 2014 Jan;43(1):72-81. doi: 10.1183/09031936.00033213. Epub 2013 Aug 15. [PubMed:23949963]
  5. Goyal N, Beerahee M, Kalberg C, Church A, Kilbride S, Mehta R: Population pharmacokinetics of inhaled umeclidinium and vilanterol in patients with chronic obstructive pulmonary disease. Clin Pharmacokinet. 2014 Jul;53(7):637-48. doi: 10.1007/s40262-014-0143-4. [PubMed:24756395]
  6. Scott LJ, Hair P: Umeclidinium/Vilanterol: first global approval. Drugs. 2014 Mar;74(3):389-95. doi: 10.1007/s40265-014-0186-8. [PubMed:24532124]
  7. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [PubMed:23435542]
External Links
KEGG Drug
D10180
PubChem Compound
11519070
PubChem Substance
347827824
ChemSpider
9693858
BindingDB
50267614
ChEBI
79041
ChEMBL
CHEMBL1187833
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Umeclidinium_bromide
ATC Codes
R03BB07 — Umeclidinium bromideR03AL03 — Vilanterol and umeclidinium bromide
AHFS Codes
  • 12:08.08 — Antimuscarinics Antispasmodics

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedOtherPulmonary Disease, Chronic Obstructive2
1CompletedPreventionHealthy Volunteers / Pulmonary Disease, Chronic Obstructive1
1CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD) / Pulmonary Disease, Chronic Obstructive1
1CompletedTreatmentPulmonary Disease, Chronic Obstructive3
1, 2RecruitingTreatmentAsthma Bronchial / Chronic Obstructive Pulmonary Disease (COPD)1
2CompletedDiagnosticAsthma Bronchial1
2CompletedTreatmentHyperhidrosis2
2CompletedTreatmentPulmonary Disease, Chronic Obstructive6
2Not Yet RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
2RecruitingDiagnosticChronic Obstructive Pulmonary Disease (COPD)1
2WithdrawnTreatmentAsthma Bronchial1
3CompletedOtherPulmonary Disease, Chronic Obstructive1
3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)4
3CompletedTreatmentPulmonary Disease, Chronic Obstructive14
3WithdrawnTreatmentPulmonary Disease, Chronic Obstructive1
4CompletedTreatmentPulmonary Disease, Chronic Obstructive1
4Not Yet RecruitingOtherPulmonary Disease, Chronic Obstructive1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Powder, meteredRespiratory (inhalation)
PowderRespiratory (inhalation)
Powder, meteredRespiratory (inhalation)55 μg
Aerosol, powderOral62.5 ug/1
PowderRespiratory (inhalation)62.5 mcg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5873360Yes1996-08-232016-08-23Us
US7101866No2001-08-032021-08-03Us
US7439393No2002-09-112022-09-11Us
US6759398No2001-08-032021-08-03Us
USRE44874No2003-03-232023-03-23Us
US6537983No2001-08-032021-08-03Us
US8511304No2007-06-142027-06-14Us
US7629335No2001-08-032021-08-03Us
US8161968No2008-02-052028-02-05Us
US8746242No2010-10-112030-10-11Us
US8113199No2007-10-232027-10-23Us
US7776895No2002-09-112022-09-11Us
US8534281No2009-08-102029-08-10Us
US6878698No2001-08-032021-08-03Us
US8309572No2005-04-272025-04-27Us
US8183257No2005-07-272025-07-27Us
US7488827No2005-04-272025-04-27Us
US7498440No2005-04-272025-04-27Us
US8201556No2009-02-052029-02-05Us
US9333310No2007-10-022027-10-02Us
US9750726No2010-11-292030-11-29Us
US9750762No2010-11-292030-11-29Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.94e-05 mg/mLALOGPS
logP2.88ALOGPS
logP0.68ChemAxon
logS-7.4ALOGPS
pKa (Strongest Acidic)13.04ChemAxon
pKa (Strongest Basic)-3.7ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area29.46 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity141.75 m3·mol-1ChemAxon
Polarizability50.42 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Benzylethers / Quinuclidines / Aralkylamines / Piperidines / Tetraalkylammonium salts / Tertiary alcohols / Dialkyl ethers / Azacyclic compounds / Organopnictogen compounds / Organic salts
show 3 more
Substituents
Diphenylmethane / Benzylether / Quinuclidine / Aralkylamine / Piperidine / Tetraalkylammonium salt / Quaternary ammonium salt / Tertiary alcohol / Dialkyl ether / Ether
show 14 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM1
Uniprot ID
P11229
Uniprot Name
Muscarinic acetylcholine receptor M1
Molecular Weight
51420.375 Da
References
  1. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [PubMed:23435542]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
G-protein coupled acetylcholine receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM2
Uniprot ID
P08172
Uniprot Name
Muscarinic acetylcholine receptor M2
Molecular Weight
51714.605 Da
References
  1. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [PubMed:23435542]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM3
Uniprot ID
P20309
Uniprot Name
Muscarinic acetylcholine receptor M3
Molecular Weight
66127.445 Da
References
  1. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [PubMed:23435542]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Antagonist
General Function
Guanyl-nucleotide exchange factor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM4
Uniprot ID
P08173
Uniprot Name
Muscarinic acetylcholine receptor M4
Molecular Weight
53048.65 Da
References
  1. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [PubMed:23435542]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM5
Uniprot ID
P08912
Uniprot Name
Muscarinic acetylcholine receptor M5
Molecular Weight
60073.205 Da
References
  1. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [PubMed:23435542]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Feldman GJ, Edin A: The combination of umeclidinium bromide and vilanterol in the management of chronic obstructive pulmonary disease: current evidence and future prospects. Ther Adv Respir Dis. 2013 Dec;7(6):311-9. doi: 10.1177/1753465813499789. Epub 2013 Sep 3. [PubMed:24004659]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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. Feldman GJ, Edin A: The combination of umeclidinium bromide and vilanterol in the management of chronic obstructive pulmonary disease: current evidence and future prospects. Ther Adv Respir Dis. 2013 Dec;7(6):311-9. doi: 10.1177/1753465813499789. Epub 2013 Sep 3. [PubMed:24004659]

Drug created on May 19, 2015 10:00 / Updated on September 21, 2018 00:16