Indacaterol

Identification

Summary

Indacaterol is an inhaled long-acting beta-2 adrenergic agonist used to relax bronchial smooth muscle and improve symptoms and airflow obstruction caused by Chronic Obstructive Pulmonary Disease (COPD) and moderate to severe asthma.

Brand Names
Hirobriz, Onbrez, Ultibro
Generic Name
Indacaterol
DrugBank Accession Number
DB05039
Background

Indacaterol is a novel, ultra-long-acting, rapid onset β(2)-adrenoceptor agonist developed for Novartis for the once-daily management of asthma and chronic obstructive pulmonary disease. It was approved by the European Medicines Agency (EMA) on 30 November 2009 and by the FDA on 1 July 2011. It is marketed in Europe as Onbrez and in America as Arcapta Neohaler. Indacaterol is provided as its maleate salt form. Indacaterol is also a chiral molecule but only the pure R-enantiomer is dispensed.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 392.4907
Monoisotopic: 392.209992772
Chemical Formula
C24H28N2O3
Synonyms
  • Indacaterol
External IDs
  • QAB 149
  • QAB-149
  • QAB149
  • QVA-149 COMPONENT INDACATEROL

Pharmacology

Indication

For the long term, once-daily-dosing maintenance of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to manageAsthmaCombination Product in combination with: Mometasone furoate (DB14512)•••••••••••••••••••• •••••••••••• •••••••••• •••• ••••••• •••••••••••••••••••••• •••••••
Used in combination to treatAsthmaCombination Product in combination with: Glycopyrronium (DB00986), Mometasone furoate (DB14512)••••••••••••••••••• •••••••
Used in combination to manageChronic obstructive pulmonary diseaseCombination Product in combination with: Glycopyrronium (DB00986)••••••••••••
Management ofChronic obstructive pulmonary disease••••••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are β(2) -agonists and anticholinergics, either alone or in combination. Currently available β(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting β(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Furthermore, this chiral compound it is given as the R-enantiomer and acts as a full agonist. Cough was the most commonly reported adverse effect with use of indacaterol. Compared to salmeterol, it has 35% more agonist activity. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. [PMID: 22499359]

Mechanism of action

Indacaterol works by stimulating adrenergic beta-2 receptors in the smooth muscle of the airways. This causes relaxation of the muscle, thereby increasing the diameter of the airways, which become constricted in asthma and COPD. It is also long acting due to its high affinity to the lipid raft domains in the airway membrane so it slowly dissociates from the receptors. Indacaterol also has a high intrinsic efficacy so it is also very rapid acting - onset of action occurs within 5 minutes.

The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. This selectivity profile is similar to formoterol. The clinical significance of these findings is unknown.

TargetActionsOrganism
ABeta-2 adrenergic receptor
agonist
Humans
Absorption

The median time to reach peak serum concentrations of indacaterol was approximately 15 minutes after single or repeated inhaled doses. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%.

Volume of distribution

After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution.

Protein binding

The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.

Metabolism

After oral administration of radiolabeled indacaterol, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. The monohydroxylated derivative, glucuronide conjugate, and the 8-O-glucuronide were the most prominent metabolites in serum. Other metabolites identified include a diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products.

In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. CYP3A4 is the predominant isoenzyme responsible for hydroxylation of indacaterol.

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Route of elimination

Renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol. In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose).

Half-life

Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing with once daily doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12-15 days.

Clearance

Renal clearance of indacaterol is, on average, between 0.46 and 1.2 L/h. Serum clearance of indacaterol is 18.8 L/h to 23.3 L/h.

Adverse Effects
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Toxicity

The expected signs and symptoms associated with overdosage of indacaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of indacaterol.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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
AbametapirThe serum concentration of Indacaterol can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Indacaterol.
AbrocitinibThe serum concentration of Indacaterol can be increased when it is combined with Abrocitinib.
AcebutololThe therapeutic efficacy of Indacaterol can be decreased when used in combination with Acebutolol.
AceclofenacThe risk or severity of hypertension can be increased when Indacaterol is combined with Aceclofenac.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Indacaterol acetateRYI4401DTM1000160-96-2HZHXFIDENGBQFQ-FTBISJDPSA-N
Indacaterol maleate2JEC1ITX7R753498-25-8IREJFXIHXRZFER-PCBAQXHCSA-N
International/Other Brands
Arcapta (Novartis) / Hirobriz / Onbrez (Novartis) / Onbrize
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Arcapta NeohalerCapsule75 ug/1Oral; Respiratory (inhalation)Novartis2011-07-012018-08-31US flag
Arcapta NeohalerCapsule75 ug/1Oral; Respiratory (inhalation)Sunovion Pharmaceuticals Inc.2011-07-012021-01-31US flag
Hirobriz BreezhalerCapsule300 μgRespiratory (inhalation)Novartis Europharm Limited2016-09-07Not applicableEU flag
Hirobriz BreezhalerCapsule150 μgRespiratory (inhalation)Novartis Europharm Limited2016-09-07Not applicableEU flag
Hirobriz BreezhalerCapsule150 μgRespiratory (inhalation)Novartis Europharm Limited2016-09-07Not applicableEU flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ATECTURA BREEZHALERIndacaterol acetate (125 MCG) + Mometasone furoate (260 MCG)Powder, meteredRespiratory (inhalation)Novartis Europharm Limited2020-09-10Not applicableItaly flag
Atectura BreezhalerIndacaterol acetate (125 mcg) + Mometasone furoate (260 mcg)CapsuleRespiratory (inhalation)Novartis Europharm Limited2023-02-08Not applicableEU flag
ATECTURA BREEZHALERIndacaterol acetate (125 MCG) + Mometasone furoate (127.5 MCG)Powder, meteredRespiratory (inhalation)Novartis Europharm Limited2020-09-10Not applicableItaly flag
Atectura BreezhalerIndacaterol acetate (125 mcg) + Mometasone furoate (260 mcg)CapsuleRespiratory (inhalation)Novartis Europharm Limited2020-12-16Not applicableEU flag
Atectura BreezhalerIndacaterol acetate (150 mcg) + Mometasone furoate (320 mcg)CapsuleRespiratory (inhalation)Novartis2020-08-19Not applicableCanada flag

Categories

ATC Codes
R03AC18 — IndacaterolR03AL04 — Indacaterol and glycopyrronium bromideR03AL12 — Indacaterol, glycopyrronium bromide and mometasoneR03AK14 — Indacaterol and mometasone
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as hydroxyquinolones. These are compounds containing a quinoline moiety bearing a hydroxyl group and a ketone. Quinoline or benzo[b]pyridine is a bicyclic compound that consists of benzene fused to a pyridine.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Quinolones and derivatives
Direct Parent
Hydroxyquinolones
Alternative Parents
8-hydroxyquinolines / Hydroxyquinolines / Hydroquinolones / Hydroquinolines / Indanes / 1-hydroxy-2-unsubstituted benzenoids / Pyridinones / Aralkylamines / Heteroaromatic compounds / 1,2-aminoalcohols
show 8 more
Substituents
1,2-aminoalcohol / 1-hydroxy-2-unsubstituted benzenoid / 8-hydroxyquinoline / Alcohol / Amine / Aralkylamine / Aromatic alcohol / Aromatic heteropolycyclic compound / Azacycle / Benzenoid
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
secondary alcohol, secondary amino compound, indanes, quinolone, monohydroxyquinoline (CHEBI:68575)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
8OR09251MQ
CAS number
312753-06-3
InChI Key
QZZUEBNBZAPZLX-QFIPXVFZSA-N
InChI
InChI=1S/C24H28N2O3/c1-3-14-9-16-11-18(12-17(16)10-15(14)4-2)25-13-22(28)19-5-7-21(27)24-20(19)6-8-23(29)26-24/h5-10,18,22,25,27-28H,3-4,11-13H2,1-2H3,(H,26,29)/t22-/m0/s1
IUPAC Name
5-[(1R)-2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxy-1,2-dihydroquinolin-2-one
SMILES
CCC1=C(CC)C=C2CC(CC2=C1)NC[C@H](O)C1=C2C=CC(=O)NC2=C(O)C=C1

References

General References
  1. Naline E, Trifilieff A, Fairhurst RA, Advenier C, Molimard M: Effect of indacaterol, a novel long-acting beta2-agonist, on isolated human bronchi. Eur Respir J. 2007 Mar;29(3):575-81. Epub 2006 Nov 29. [Article]
  2. Kagan M, Dain J, Peng L, Reynolds C: Metabolism and pharmacokinetics of indacaterol in humans. Drug Metab Dispos. 2012 Sep;40(9):1712-22. doi: 10.1124/dmd.112.046151. Epub 2012 May 30. [Article]
  3. 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]
Human Metabolome Database
HMDB0015608
KEGG Drug
D09318
PubChem Compound
6918554
PubChem Substance
175426936
ChemSpider
5293751
BindingDB
50318159
RxNav
1114326
ChEBI
68575
ChEMBL
CHEMBL1095777
ZINC
ZINC000035801098
PharmGKB
PA165958348
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Indacaterol
FDA label
Download (360 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleRespiratory (inhalation)
CapsuleOral; Respiratory (inhalation)75 ug/1
PowderBuccal
Powder, meteredRespiratory (inhalation)150 mcg
PowderBuccal0.050 mg
Powder, meteredRespiratory (inhalation)300 MCG
CapsuleRespiratory (inhalation)150 UG
CapsuleRespiratory (inhalation)75 mcg
PowderRespiratory (inhalation)
PowderRespiratory (inhalation)194 MCG
PowderRespiratory (inhalation)389 MCG
PowderRespiratory (inhalation)150 MCG
PowderRespiratory (inhalation)300 MCG
CapsuleRespiratory (inhalation)300 UG
CapsuleRespiratory (inhalation)0.150 mg
CapsuleRespiratory (inhalation)0.300 mg
Drug delivery systemBuccal389.000 mcg
PowderRespiratory (inhalation)0.15 mg
CapsuleRespiratory (inhalation)150 μg
CapsuleRespiratory (inhalation)300 μg
Drug delivery systemBuccal
PowderRespiratory (inhalation)
CapsuleBuccal
Capsule, coatedRespiratory (inhalation)
CapsuleRespiratory (inhalation)
Powder, meteredRespiratory (inhalation)
Powder, meteredRespiratory (inhalation)
CapsuleRespiratory (inhalation)150 mcg
CapsuleRespiratory (inhalation)300 mcg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6878721No2005-04-122020-10-10US flag
US8067437No2011-11-292020-06-02US flag
US8658673No2014-02-252020-06-02US flag
US8796307No2014-08-052020-06-02US flag
US8479730No2013-07-092028-10-11US flag
US7229607No2007-06-122021-04-09US flag
US7820694No2010-10-262020-06-02US flag
US8029768No2011-10-042021-04-09US flag
US8283362No2012-10-092020-06-02US flag
US7736670No2010-06-152021-06-27US flag
US8435567No2013-05-072021-06-27US flag
US8303991No2012-11-062021-06-27US flag
US8956661No2015-02-172021-06-27US flag
US8580306No2013-11-122021-06-27US flag
US6582678No2003-06-242018-04-24US flag
US8182838No2012-05-222028-10-20US flag
US6521260No2003-02-182016-01-31US flag
US8048451No2011-11-012021-06-27US flag
US9931304No2018-04-032021-06-27US flag
US9962338No2018-05-082021-06-27US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)195-202°C with decompositionNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00798 mg/mLALOGPS
logP3.31ALOGPS
logP3.26Chemaxon
logS-4.7ALOGPS
pKa (Strongest Acidic)8.51Chemaxon
pKa (Strongest Basic)9.71Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area81.59 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity118.1 m3·mol-1Chemaxon
Polarizability44.96 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9963
Blood Brain Barrier+0.5
Caco-2 permeable-0.6288
P-glycoprotein substrateSubstrate0.6953
P-glycoprotein inhibitor INon-inhibitor0.9284
P-glycoprotein inhibitor IINon-inhibitor0.9178
Renal organic cation transporterNon-inhibitor0.8838
CYP450 2C9 substrateNon-substrate0.8148
CYP450 2D6 substrateNon-substrate0.6907
CYP450 3A4 substrateSubstrate0.5896
CYP450 1A2 substrateInhibitor0.553
CYP450 2C9 inhibitorNon-inhibitor0.56
CYP450 2D6 inhibitorNon-inhibitor0.8547
CYP450 2C19 inhibitorNon-inhibitor0.5581
CYP450 3A4 inhibitorNon-inhibitor0.6546
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5888
Ames testNon AMES toxic0.7577
CarcinogenicityNon-carcinogens0.8559
BiodegradationNot ready biodegradable0.9856
Rat acute toxicity2.6531 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9657
hERG inhibition (predictor II)Inhibitor0.6406
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 GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-03fr-1954000000-ccc7de5fce46537c0912
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0009000000-cbec9d56059af437dfcf
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0fdo-0049000000-83925c1ad51999083331
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-0109000000-3baffa3c79830348e4d6
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0319000000-53ca387c3442df4ccf77
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-06y6-3936000000-a8102b2e45be875dfb5d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0w2l-0955000000-ec1a9baaec4529a79dbb
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]-221.3031722
predicted
DarkChem Lite v0.1.0
[M-H]-221.4978722
predicted
DarkChem Lite v0.1.0
[M-H]-192.33443
predicted
DeepCCS 1.0 (2019)
[M+H]+222.4347722
predicted
DarkChem Lite v0.1.0
[M+H]+222.6830722
predicted
DarkChem Lite v0.1.0
[M+H]+194.69243
predicted
DeepCCS 1.0 (2019)
[M+Na]+222.0900722
predicted
DarkChem Lite v0.1.0
[M+Na]+222.1065722
predicted
DarkChem Lite v0.1.0
[M+Na]+200.89961
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Protein homodimerization activity
Specific Function
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately ...
Gene Name
ADRB2
Uniprot ID
P07550
Uniprot Name
Beta-2 adrenergic receptor
Molecular Weight
46458.32 Da
References
  1. Cazzola M, Matera MG, Lotvall J: Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2005 Jul;14(7):775-83. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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

Drug created at October 21, 2007 22:23 / Updated at January 02, 2024 23:47