Identification

Name
Aclidinium
Accession Number
DB08897
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
Synonyms
  • Aclidinium
External IDs
LAS-34273
Product Ingredients
IngredientUNIICASInChI Key
Aclidinium BromideUQW7UF9N91320345-99-1XLAKJQPTOJHYDR-QTQXQZBYSA-M
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Bretaris Genuair322 μgRespiratory (inhalation)Astra Zeneca Ab2012-07-20Not applicableEu
Bretaris Genuair322 μgRespiratory (inhalation)Astra Zeneca Ab2012-07-20Not applicableEu
Bretaris Genuair322 μgRespiratory (inhalation)Astra Zeneca Ab2012-07-20Not applicableEu
Eklira Genuair322 μgRespiratory (inhalation)Astra Zeneca Ab2012-07-20Not applicableEu
Eklira Genuair322 μgRespiratory (inhalation)Astra Zeneca Ab2012-07-20Not applicableEu
Eklira Genuair322 μgRespiratory (inhalation)Astra Zeneca Ab2012-07-20Not applicableEu
Tudorza GenuairPowder, metered400 mcgRespiratory (inhalation)Astra Zeneca2013-09-13Not applicableCanada
Tudorza PressairInhalant400 ug/1Respiratory (inhalation)Allergan2012-07-232017-10-20Us
Tudorza PressairInhalant400 ug/1Respiratory (inhalation)Astra Zeneca Lp2015-07-01Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Duaklir GenuairAclidinium Bromide (400 mcg) + Formoterol fumarate (12 mcg)Powder, meteredRespiratory (inhalation)Astra Zeneca2015-07-09Not applicableCanada
Duaklir GenuairAclidinium Bromide (340 μg) + Formoterol fumarate (12 μg)Respiratory (inhalation)Astra Zeneca Ab2014-11-19Not applicableEu
Duaklir GenuairAclidinium Bromide (340 μg) + Formoterol fumarate (12 μg)Respiratory (inhalation)Astra Zeneca Ab2014-11-19Not applicableEu
Duaklir GenuairAclidinium Bromide (340 μg) + Formoterol fumarate (12 μg)Respiratory (inhalation)Astra Zeneca Ab2014-11-19Not applicableEu
International/Other Brands
Bretaris Genuair / Eklira Genuair
Categories
UNII
K17VY42F6C
CAS number
727649-81-2
Weight
Average: 484.651
Monoisotopic: 484.161624833
Chemical Formula
C26H30NO4S2
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

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.

Associated Conditions
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
Human
AMuscarinic acetylcholine receptor M2
antagonist
Human
AMuscarinic acetylcholine receptor M3
antagonist
Human
AMuscarinic acetylcholine receptor M4
antagonist
Human
AMuscarinic acetylcholine receptor M5
antagonist
Human
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%)

Toxicity

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

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

Interactions

Drug Interactions
DrugInteraction
1,10-PhenanthrolineThe therapeutic efficacy of Aclidinium can be decreased when used in combination with 1,10-Phenanthroline.
AcetaminophenAcetaminophen may decrease the excretion rate of Aclidinium which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Aclidinium which could result in a higher serum level.
Adefovir DipivoxilAdefovir Dipivoxil may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AgmatineThe risk or severity of adverse effects can be increased when Aclidinium is combined with Agmatine.
AlcuroniumAlcuronium may increase the anticholinergic activities of Aclidinium.
AlfentanilThe risk or severity of adverse effects can be increased when Aclidinium is combined with Alfentanil.
AlmotriptanAlmotriptan may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AlphacetylmethadolThe risk or severity of adverse effects can be increased when Aclidinium is combined with Alphacetylmethadol.
Food Interactions
Not Available

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. [PubMed:23641160]
  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. [PubMed:23566013]
  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. [PubMed:23553509]
External Links
KEGG Drug
D08837
PubChem Compound
11434515
PubChem Substance
175427140
ChemSpider
9609381
BindingDB
50296331
ChEBI
65346
ChEMBL
CHEMBL1194325
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Aclidinium_bromide
ATC Codes
R03AL05 — Formoterol and aclidinium bromideR03BB05 — Aclidinium bromide
AHFS Codes
  • 12:08.08 — Antimuscarinics Antispasmodics
FDA label
Download (1.25 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Not Yet RecruitingTreatmentPulmonary Disease, Chronic Obstructive1
2CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)5
2CompletedTreatmentPulmonary Disease, Chronic Obstructive1
3CompletedNot AvailableChronic Obstructive Pulmonary Disease (COPD)1
3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)13
3CompletedTreatmentPulmonary Disease, Chronic Obstructive1
3RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
3RecruitingTreatmentSmoking1
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)2
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD) / Moderate to Very Severe COPD1
4CompletedTreatmentPulmonary Disease, Chronic Obstructive3
4Not Yet RecruitingOtherPulmonary Disease, Chronic Obstructive1
4RecruitingBasic ScienceChronic Obstructive Pulmonary Disease (COPD)1
4RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
4WithdrawnTreatmentChronic Obstructive Pulmonary Disease (COPD)1
Not AvailableCompletedNot AvailablePulmonary Disease, Chronic Obstructive2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Powder, meteredRespiratory (inhalation)
Powder, meteredRespiratory (inhalation)400 mcg
InhalantRespiratory (inhalation)400 ug/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6750226No2000-09-052020-09-05Us
US7078412No2000-07-162020-07-16Us
US9056100No2000-07-072020-07-07Us
US6681768No2002-08-072022-08-07Us
US8051851No2007-04-222027-04-22Us
US6071498No1996-06-212016-06-21Us
US5840279No1996-06-212016-06-21Us
USRE46417No2000-09-052020-09-05Us
US9333195No2000-07-072020-07-07Us

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
Not Available

Taxonomy

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
Phenoxy compound / Phenol ether / Quinuclidine / Alkyl aryl ether / Monocyclic benzene moiety / Piperidine / Benzenoid / Tetraalkylammonium salt / Quaternary ammonium salt / Heteroaromatic compound
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic ether, carboxylic ester, quaternary ammonium ion, thiophenes (CHEBI:65346)

Targets

Kind
Protein
Organism
Human
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
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
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
Kind
Protein
Organism
Human
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
Human
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
Human
Pharmacological action
Yes
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. [PubMed:23566013]

Drug created on June 04, 2013 17:58 / Updated on October 16, 2018 08:40