Olodaterol

Identification

Summary

Olodaterol is a long-acting beta2-adrenergic agonist used in the management of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Brand Names
Inspiolto Respimat, Stiolto, Striverdi Respimat
Generic Name
Olodaterol
DrugBank Accession Number
DB09080
Background

Olodaterol is a novel, long-acting beta2-adrenergic agonist (LABA) that exerts its pharmacological effect by binding and activating beta2-adrenergic receptors located primarily in the lungs. Beta2-adrenergic receptors are membrane-bound receptors that are normally activated by endogenous epinephrine whose signalling, via a downstream L-type calcium channel interaction, mediates smooth muscle relaxation and bronchodilation. Activation of the receptor stimulates an associated G protein which then activates adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevation of these two molecules induces bronchodilation by relaxation of airway smooth muscles. It is by this mechanism that olodaterol is used for the treatment of chronic obstructive pulmonary disease (COPD) and the progressive airflow obstruction that is characteristic of it. Treatment with bronchodilators helps to mitigate associated symptoms such as shortness of breath, cough, and sputum production. Single doses of olodaterol have been shown to improve forced expiratory volume in 1 sec (FEV1) for 24 h in patients with COPD, allowing once daily dosing. A once-a-day treatment with a LABA has several advantages over short-acting bronchodilators and twice-daily LABAs including improved convenience and compliance and improved airflow over a 24-hour period. Despite similarities in symptoms, olodaterol is not indicated for the treatment of acute exacerbations of COPD or for the treatment of asthma.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 386.448
Monoisotopic: 386.184171945
Chemical Formula
C21H26N2O5
Synonyms
  • Olodaterol
External IDs
  • BI 1744
  • BI-1744
  • BI1744

Pharmacology

Indication

Olodaterol is indicated for use in chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. It is not indicated for the treatment of acute exacerbations of COPD or for the treatment of asthma.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Olodaterol is a potent agonist of the human beta2-adrenergic receptor in vitro, and is highly selective for this receptor, with much lower levels of activity at the b1- and b3-adrenergic receptors that are commonly expressed on cardiac smooth muscle and adipose tissue, respectively. Binding to the receptor causes smooth muscle relaxation in the lungs and bronchodilation. It has also been shown to potently reverse active bronchoconstriction.

Mechanism of action

Olodaterol is a long-acting beta2-adrenergic agonist (LABA) that exerts its pharmacological effect by binding and activating beta2-adrenergic receptors located primarily in the lungs. Beta2-adrenergic receptors are membrane-bound receptors that are normally activated by endogenous epinephrine whose signalling, via a downstream L-type calcium channel interaction, mediates smooth muscle relaxation and bronchodilation. Activation of the receptor stimulates an associated G protein which then activates adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevation of these two molecules induces bronchodilation by relaxation of airway smooth muscles.

TargetActionsOrganism
ABeta-2 adrenergic receptor
agonist
Humans
Absorption

Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers, the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to systemic exposure.

Volume of distribution

The volume of distribution is high (1110 L), suggesting extensive distribution into tissue.

Protein binding

In vitro binding of olodaterol to human plasma proteins is independent of concentration and is approximately 60%.

Metabolism

Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product binds to beta2-receptors. This metabolite, however, is not detectable in plasma after chronic inhalation of the recommended therapeutic dose. Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides.

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Route of elimination

Following intravenous administration of [14C]-labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of olodaterol and/or its metabolites was recovered in urine, while the major portion was recovered in feces (84%).

Half-life

The terminal half-life following intravenous administration is 22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination processes.

Clearance

Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min.

Adverse Effects
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Toxicity

Adverse drug reactions that occurred at a frequency greater than 2% include nasopharyngitis (11.3%), upper respiratory tract infection (8.2%), bronchitis (4.7%), urinary tract infection (2.5%), cough (4.2%), dizziness (2.3%), rash (2.2%), diarrhea (2.9%), back pain (3.5%), and arthralgia (2.1%).

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
AbataceptThe metabolism of Olodaterol can be increased when combined with Abatacept.
AbirateroneThe metabolism of Olodaterol can be decreased when combined with Abiraterone.
AcebutololThe therapeutic efficacy of Olodaterol can be decreased when used in combination with Acebutolol.
AceclofenacThe risk or severity of hypertension can be increased when Aceclofenac is combined with Olodaterol.
AcemetacinThe risk or severity of hypertension can be increased when Olodaterol is combined with Acemetacin.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Olodaterol.
AcetohexamideThe metabolism of Olodaterol can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazoleThe metabolism of Olodaterol can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidThe risk or severity of hypertension can be increased when Acetylsalicylic acid is combined with Olodaterol.
AclidiniumThe risk or severity of Tachycardia can be increased when Aclidinium is combined with Olodaterol.
Interactions
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Food Interactions
No interactions found.

Products

Products
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Product Ingredients
IngredientUNIICASInChI Key
Olodaterol hydrochloride65R445W3V9869477-96-3KCEHVJZZIGJAAW-FERBBOLQSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Striverdi RespimatSpray, metered2.5 ug/1Respiratory (inhalation)Boehringer Ingelheim Pharmaceuticals, Inc.2014-08-01Not applicableUS flag
Striverdi RespimatSolution2.5 mcg / actRespiratory (inhalation)Boehringer Ingelheim (Canada) Ltd LteeNot applicableNot applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Inspiolto RespimatOlodaterol hydrochloride (2.5 mcg / act) + Tiotropium (2.5 mcg / act)SolutionRespiratory (inhalation)Boehringer Ingelheim (Canada) Ltd Ltee2015-05-29Not applicableCanada flag
SPIOLTO RESPIMAT 2.5 MCG/2.5 MCG INHALASYON ÇÖZELTISI,1 ADETOlodaterol hydrochloride (2.5 mcg) + Tiotropium bromide monohydrate (2.5 mcg)SolutionRespiratory (inhalation)BOEHRİNGER INGELHEİM İLAÇ TİC. A.Ş.2020-08-14Not applicableTurkey flag
SPIOLTO�RESPIMAT�Olodaterol (2.5 mcg) + Tiotropium (2.5 mcg)SolutionRespiratory (inhalation)BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG.2015-10-19Not applicableColombia flag
Stiolto RespimatOlodaterol hydrochloride (2.736 ug/1) + Tiotropium bromide monohydrate (3.124 ug/1)Spray, meteredRespiratory (inhalation)Boehringer Ingelheim Pharmaceuticals Inc.2015-05-21Not applicableUS flag
สไปออลโต เรสพิแมท (สารละลายสำหรับพ่นสูด 2.5 ไมโครกรัม/2.5 ไมโครกรัม)Olodaterol (2.5 MCG) + Tiotropium (2.5 MCG)AerosolRespiratory (inhalation)บริษัท เบอริงเกอร์ อินเกลไฮม์ (ไทย) จำกัด2019-01-22Not applicableThailand flag

Categories

ATC Codes
R03AL06 — Olodaterol and tiotropium bromideR03AC19 — Olodaterol
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzoxazinones. These are organic compounds containing a benzene fused to an oxazine ring (a six-member aliphatic ring with four carbon atoms, one oxygen atom, and one nitrogen atom) bearing a ketone group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzoxazines
Sub Class
Benzoxazinones
Direct Parent
Benzoxazinones
Alternative Parents
Amphetamines and derivatives / Benzomorpholines / Phenylpropanes / Phenoxy compounds / Methoxybenzenes / Anisoles / 1-hydroxy-2-unsubstituted benzenoids / Alkyl aryl ethers / Aralkylamines / Secondary carboxylic acid amides
show 12 more
Substituents
1,2-aminoalcohol / 1-hydroxy-2-unsubstituted benzenoid / Alcohol / Alkyl aryl ether / Amine / Amino acid or derivatives / Amphetamine or derivatives / Anisole / Aralkylamine / Aromatic alcohol
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic ether, secondary alcohol, phenols, secondary amino compound, benzoxazine (CHEBI:82700)
Affected organisms
Not Available

Chemical Identifiers

UNII
VD2YSN1AFD
CAS number
868049-49-4
InChI Key
COUYJEVMBVSIHV-SFHVURJKSA-N
InChI
InChI=1S/C21H26N2O5/c1-21(2,10-13-4-6-15(27-3)7-5-13)22-11-18(25)16-8-14(24)9-17-20(16)28-12-19(26)23-17/h4-9,18,22,24-25H,10-12H2,1-3H3,(H,23,26)/t18-/m0/s1
IUPAC Name
6-hydroxy-8-[(1R)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino}ethyl]-3,4-dihydro-2H-1,4-benzoxazin-3-one
SMILES
COC1=CC=C(CC(C)(C)NC[C@H](O)C2=C3OCC(=O)NC3=CC(O)=C2)C=C1

References

General References
  1. Bouyssou T, Casarosa P, Naline E, Pestel S, Konetzki I, Devillier P, Schnapp A: Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. J Pharmacol Exp Ther. 2010 Jul;334(1):53-62. doi: 10.1124/jpet.110.167007. Epub 2010 Apr 6. [Article]
  2. Bouyssou T, Hoenke C, Rudolf K, Lustenberger P, Pestel S, Sieger P, Lotz R, Heine C, Buttner FH, Schnapp A, Konetzki I: Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. Bioorg Med Chem Lett. 2010 Feb 15;20(4):1410-4. doi: 10.1016/j.bmcl.2009.12.087. Epub 2010 Jan 4. [Article]
  3. Koch A, Pizzichini E, Hamilton A, Hart L, Korducki L, De Salvo MC, Paggiaro P: Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat(R) versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014 Jul 5;9:697-714. doi: 10.2147/COPD.S62502. eCollection 2014. [Article]
  4. Gibb A, Yang LP: Olodaterol: first global approval. Drugs. 2013 Nov;73(16):1841-6. doi: 10.1007/s40265-013-0137-9. [Article]
  5. Deeks ED: Olodaterol: a review of its use in chronic obstructive pulmonary disease. Drugs. 2015 Apr;75(6):665-73. doi: 10.1007/s40265-015-0371-4. [Article]
KEGG Drug
D10145
PubChem Compound
11504295
PubChem Substance
310265008
ChemSpider
9679097
RxNav
1546059
ChEBI
82700
ChEMBL
CHEMBL605846
ZINC
ZINC000034636383
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Olodaterol
FDA label
Download (746 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceChronic Obstructive Pulmonary Disease (COPD)2
4CompletedTreatmentAsthma1
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)7
4RecruitingOtherChronic Obstructive Pulmonary Disease (COPD)1
4RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)25
2CompletedTreatmentAsthma4
2CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)8
2WithdrawnTreatmentAsthma1
1CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
AerosolRespiratory (inhalation)
SolutionRespiratory (inhalation)
Aerosol, meteredRespiratory (inhalation)
Spray, meteredRespiratory (inhalation)
SolutionRespiratory (inhalation)2.5 UG
AerosolRespiratory (inhalation)
SolutionRespiratory (inhalation)2.5 mcg / act
Spray, meteredRespiratory (inhalation)2.5 ug/1
SolutionRespiratory (inhalation)
Spray, meteredRespiratory (inhalation)2.5 mcg/1dose
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
USRE39820Yes2007-09-042018-07-30US flag
US6453795Yes2002-09-242017-06-05US flag
US8733341Yes2014-05-272031-04-16US flag
US9027967Yes2015-05-122027-10-01US flag
US7104470Yes2006-09-122017-04-04US flag
US7246615Yes2007-07-242016-12-01US flag
US7896264Yes2011-03-012025-11-26US flag
US7988001Yes2011-08-022022-02-04US flag
US7802568Yes2010-09-282019-08-26US flag
US6149054Yes2000-11-212017-06-16US flag
US6726124Yes2004-04-272017-04-04US flag
US7396341Yes2008-07-082027-04-10US flag
US6846413Yes2005-01-252019-02-28US flag
US6176442Yes2001-01-232016-12-01US flag
US7837235Yes2010-11-232028-09-13US flag
US5964416Yes1999-10-122017-04-04US flag
US7284474Yes2007-10-232025-02-26US flag
US6977042Yes2005-12-202019-02-28US flag
US6988496Yes2006-01-242020-08-23US flag
US8044046No2011-10-252023-11-10US flag
US8034809No2011-10-112025-05-12US flag
US7220742No2007-05-222025-05-12US flag
US7491719No2009-02-172023-11-10US flag
US7056916No2006-06-062023-12-07US flag
US7727984No2010-06-012023-11-10US flag
US7786111No2010-08-312023-11-10US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0703 mg/mLALOGPS
logP2.02ALOGPS
logP1.19ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)9.22ChemAxon
pKa (Strongest Basic)9.84ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area100.05 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity106.9 m3·mol-1ChemAxon
Polarizability41.34 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets
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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. Bouyssou T, Casarosa P, Naline E, Pestel S, Konetzki I, Devillier P, Schnapp A: Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. J Pharmacol Exp Ther. 2010 Jul;334(1):53-62. doi: 10.1124/jpet.110.167007. Epub 2010 Apr 6. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Olodaterol FDA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da

Drug created on June 26, 2015 18:38 / Updated on August 05, 2021 19:40