Aclidinium

Identification

Summary

Aclidinium is an inhaled long-acting anticholinergic used as a maintenance bronchodilator in patients with chronic obstructive pulmonary disease (COPD).

Brand Names
Bretaris Genuair, Duaklir, Duaklir Genuair, Eklira Genuair, Tudorza, Tudorza Genuair
Generic Name
Aclidinium
DrugBank Accession Number
DB08897
Background

Aclidinium is an anticholinergic for the long-term management of chronic obstructive pulmonary disease (COPD). It has a much higher propensity to bind to muscarinic receptors than nicotinic receptors. FDA approved on July 24, 2012.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 484.651
Monoisotopic: 484.161624833
Chemical Formula
C26H30NO4S2
Synonyms
  • Aclidinio
External IDs
  • LAS-34273

Pharmacology

Indication

Aclidinium bromide inhalation powder is indicated for the long-term, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofChronic obstructive pulmonary disease••••••••••••
Used in combination to manageChronic obstructive pulmonary diseaseCombination Product in combination with: Formoterol (DB00983)••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Aclidinium does not prolong the QTc interval or have significant effects on cardiac rhythm.

Mechanism of action

Aclidinium is a long-acting, competitive, and reversible anticholinergic drug that is specific for the acetylcholine muscarinic receptors. It binds to all 5 muscarinic receptor subtypes to a similar affinity. Aclidinium's effects on the airways are mediated through the M3 receptor at the smooth muscle to cause bronchodilation. Prevention of acetylcholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours.

TargetActionsOrganism
AMuscarinic acetylcholine receptor M1
antagonist
Humans
AMuscarinic acetylcholine receptor M2
antagonist
Humans
AMuscarinic acetylcholine receptor M3
antagonist
Humans
AMuscarinic acetylcholine receptor M4
antagonist
Humans
AMuscarinic acetylcholine receptor M5
antagonist
Humans
Absorption

Bioavailability, healthy subjects = 6%; T max, healthy subjects = 10 minutes; Time to steady state, healthy subjects = 2 days;

Volume of distribution

Following IV administration, the volume of distribution is 300 L

Protein binding

Not Available

Metabolism

The major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases in the plasma. Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are pharmacologically inactive.

Route of elimination

Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium. Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces. The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis. After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose.

Half-life

Plasma half-life = 2.4 minutes (indicating that aclidinium is very rapidly hydrolyzed in plasma into its two inactive metabolites and has a low chance of causing systemic side effects). Effective half-life = 5-8 hours.

Clearance

Total clearance, IV dose, young healthy subjects = 170 L/h (inter-individual variability of 36%)

Adverse Effects
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Toxicity

Most common adverse reactions (≥3% incidence and greater than placebo) are headache, nasopharyngitis and cough.

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Aclidinium which could result in a lower serum level and potentially a reduction in efficacy.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Aclidinium bromideUQW7UF9N91320345-99-1XLAKJQPTOJHYDR-QTQXQZBYSA-M
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Bretaris Genuair322 μgRespiratory (inhalation)Covis Pharma Europe B.V.2016-09-08Not applicableEU flag
Bretaris Genuair322 μgRespiratory (inhalation)Covis Pharma Europe B.V.2016-09-08Not applicableEU flag
Bretaris Genuair322 μgRespiratory (inhalation)Covis Pharma Europe B.V.2016-09-08Not applicableEU flag
Eklira Genuair322 μgRespiratory (inhalation)Covis Pharma Europe B.V.2016-09-08Not applicableEU flag
Eklira Genuair322 μgRespiratory (inhalation)Covis Pharma Europe B.V.2016-09-08Not applicableEU flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
BRIMICA GENUAIRAclidinium bromide (340 mcg) + Formoterol fumarate (12 mcg)PowderRespiratory (inhalation)Covis Pharma Europe Bv2015-03-18Not applicableItaly flag
Brimica GenuairAclidinium bromide (340 μg) + Formoterol fumarate (12 μg)Respiratory (inhalation)Covis Pharma Europe B.V.2016-09-08Not applicableEU flag
BRIMICA GENUAIRAclidinium (340 mcg) + Formoterol fumarate (12 mcg)Aerosol, powderRespiratory (inhalation)Covis Pharma Europe Bv2015-03-18Not applicableItaly flag
Brimica GenuairAclidinium bromide (340 μg) + Formoterol fumarate (12 μg)Respiratory (inhalation)Covis Pharma Europe B.V.2016-09-08Not applicableEU flag
BRIMICA GENUAIRAclidinium bromide (340 mcg) + Formoterol fumarate (12 mcg)PowderRespiratory (inhalation)Astrazeneca Ab2017-01-02Not applicableItaly flag

Categories

ATC Codes
R03BB05 — Aclidinium bromideR03AL05 — Formoterol and aclidinium bromide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as quinuclidines. These are compounds containing a 1-azabicyclo[2.2.2]octane moiety.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinuclidines
Sub Class
Not Available
Direct Parent
Quinuclidines
Alternative Parents
Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Piperidines / Thiophenes / Tetraalkylammonium salts / Tertiary alcohols / Heteroaromatic compounds / Carboxylic acid esters / Azacyclic compounds
show 9 more
Substituents
Alcohol / Alkyl aryl ether / Amine / Aromatic alcohol / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic ether, carboxylic ester, quaternary ammonium ion, thiophenes (CHEBI:65346)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
K17VY42F6C
CAS number
727649-81-2
InChI Key
ASMXXROZKSBQIH-VITNCHFBSA-N
InChI
InChI=1S/C26H30NO4S2/c28-25(26(29,23-9-4-17-32-23)24-10-5-18-33-24)31-22-19-27(14-11-20(22)12-15-27)13-6-16-30-21-7-2-1-3-8-21/h1-5,7-10,17-18,20,22,29H,6,11-16,19H2/q+1/t20?,22-,27?/m0/s1
IUPAC Name
(3R)-3-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azabicyclo[2.2.2]octan-1-ium
SMILES
OC(C(=O)O[C@H]1C[N+]2(CCCOC3=CC=CC=C3)CCC1CC2)(C1=CC=CS1)C1=CC=CS1

References

General References
  1. Reid DJ, Pham NT: Emerging Therapeutic Options for the Management of COPD. Clin Med Insights Circ Respir Pulm Med. 2013 Apr 9;7:7-15. doi: 10.4137/CCRPM.S8140. Print 2013. [Article]
  2. Cazzola M, Page CP, Matera MG: Aclidinium bromide for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother. 2013 Jun;14(9):1205-14. doi: 10.1517/14656566.2013.789021. Epub 2013 Apr 9. [Article]
  3. Jones P: Aclidinium bromide twice daily for the treatment of chronic obstructive pulmonary disease: a review. Adv Ther. 2013 Apr;30(4):354-68. doi: 10.1007/s12325-013-0019-2. Epub 2013 Apr 2. [Article]
  4. Alberti J, Martinet A, Sentellas S, Salva M: Identification of the human enzymes responsible for the enzymatic hydrolysis of aclidinium bromide. Drug Metab Dispos. 2010 Jul;38(7):1202-10. doi: 10.1124/dmd.109.031724. Epub 2010 Mar 23. [Article]
KEGG Drug
D08837
PubChem Compound
11434515
PubChem Substance
175427140
ChemSpider
9609381
BindingDB
50296331
RxNav
1303098
ChEBI
65346
ChEMBL
CHEMBL1194325
ZINC
ZINC000030691727
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Aclidinium_bromide
FDA label
Download (1.25 MB)

Clinical Trials

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Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Aerosol, powderRespiratory (inhalation)322 mg
Aerosol, powderRespiratory (inhalation)
Drug delivery systemBuccal
Powder, meteredRespiratory (inhalation)343 mcg
Powder, meteredRespiratory (inhalation)
PowderBuccal375.000 mcg
PowderRespiratory (inhalation)
Powder, meteredRespiratory (inhalation)322 mcg
Powder, meteredRespiratory (inhalation)343 mcg
PowderRespiratory (inhalation)322 mcg
Powder, meteredRespiratory (inhalation)400 mcg / act
InhalantRespiratory (inhalation)400 ug/1
Powder, meteredRespiratory (inhalation)400 ug/1
PowderRespiratory (inhalation)
PowderRespiratory (inhalation)400 mcg/1dose
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6750226No2004-06-152020-09-05US flag
US7078412No2006-07-182020-07-16US flag
US9056100No2015-06-162020-07-07US flag
US6681768No2004-01-272022-08-07US flag
US8051851No2011-11-082027-04-22US flag
US6071498No2000-06-062016-06-21US flag
US5840279No1998-11-242016-06-21US flag
USRE46417No2017-05-302020-09-05US flag
US9333195No2016-05-102020-07-07US flag
US10085974No2018-10-022029-03-13US flag
US10034867No2018-07-312020-07-07US flag
US7750023No2010-07-062020-07-07US flag
US8129405No2012-03-062020-07-07US flag
US10588895No2020-03-172022-01-14US flag
US11000517No2021-05-112029-03-13US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityVery slightly soluble FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.00152 mg/mLALOGPS
logP3.07ALOGPS
logP0.45Chemaxon
logS-5.5ALOGPS
pKa (Strongest Acidic)10.35Chemaxon
pKa (Strongest Basic)-4.8Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area55.76 Å2Chemaxon
Rotatable Bond Count10Chemaxon
Refractivity141.33 m3·mol-1Chemaxon
Polarizability52.09 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.9907
Blood Brain Barrier+0.8883
Caco-2 permeable-0.6509
P-glycoprotein substrateSubstrate0.7017
P-glycoprotein inhibitor INon-inhibitor0.8103
P-glycoprotein inhibitor IINon-inhibitor0.6449
Renal organic cation transporterInhibitor0.6092
CYP450 2C9 substrateNon-substrate0.7784
CYP450 2D6 substrateNon-substrate0.809
CYP450 3A4 substrateNon-substrate0.5
CYP450 1A2 substrateNon-inhibitor0.8536
CYP450 2C9 inhibitorNon-inhibitor0.8817
CYP450 2D6 inhibitorNon-inhibitor0.5813
CYP450 2C19 inhibitorNon-inhibitor0.8022
CYP450 3A4 inhibitorNon-inhibitor0.7154
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.808
Ames testNon AMES toxic0.7753
CarcinogenicityNon-carcinogens0.9292
BiodegradationReady biodegradable0.6794
Rat acute toxicity2.6182 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7765
hERG inhibition (predictor II)Non-inhibitor0.6484
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 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-197.9976
predicted
DeepCCS 1.0 (2019)
[M+H]+200.3556
predicted
DeepCCS 1.0 (2019)
[M+Na]+206.86502
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
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
Kind
Protein
Organism
Humans
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
Kind
Protein
Organism
Humans
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
Kind
Protein
Organism
Humans
Pharmacological action
Yes
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
Kind
Protein
Organism
Humans
Pharmacological action
Yes
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

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Cazzola M, Page CP, Matera MG: Aclidinium bromide for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother. 2013 Jun;14(9):1205-14. doi: 10.1517/14656566.2013.789021. Epub 2013 Apr 9. [Article]
  2. Alberti J, Martinet A, Sentellas S, Salva M: Identification of the human enzymes responsible for the enzymatic hydrolysis of aclidinium bromide. Drug Metab Dispos. 2010 Jul;38(7):1202-10. doi: 10.1124/dmd.109.031724. Epub 2010 Mar 23. [Article]

Drug created at June 04, 2013 23:58 / Updated at January 02, 2024 23:48