Identification

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Name
Revefenacin
Accession Number
DB11855
Type
Small Molecule
Groups
Approved, Investigational
Description

Revefenacin is a novel biphenyl carbamate tertiary amine agent that belongs to the family of the long-acting muscarinic antagonists (LABA). The labile primary amide in the structure produces a "soft-drug" site that allows rapid systemic clearance and minimizing of the systemically mediated adverse reactions. The LABA group falls into a parent category known as long-acting inhaled bronchodilators and this type of agents are recommended as a maintenance therapy for chronic obstructive pulmonary disease (COPD).1 From the LABA group, revefenacin is the first once-daily nebulized LAMA treatment.2 It was developed by Theravance Biopharma and FDA approved on November 9, 2018.8

Structure
Thumb
Synonyms
  • Revefenacin
External IDs
GSK-1160724 / GSK1160724 / TD-4208
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
YupelriSolution175 ug/3mLRespiratory (inhalation)Mylan Specialty L.P.2018-12-03Not applicableUs
YupelriSolution175 ug/3mLRespiratory (inhalation)The Ritedose Corporation2018-12-03Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
G2AE2VE07O
CAS number
864750-70-9
Weight
Average: 597.76
Monoisotopic: 597.331504885
Chemical Formula
C35H43N5O4
InChI Key
FYDWDCIFZSGNBU-UHFFFAOYSA-N
InChI
InChI=1S/C35H43N5O4/c1-38(34(42)29-13-11-26(12-14-29)25-40-19-15-28(16-20-40)33(36)41)23-24-39-21-17-30(18-22-39)44-35(43)37-32-10-6-5-9-31(32)27-7-3-2-4-8-27/h2-14,28,30H,15-25H2,1H3,(H2,36,41)(H,37,43)
IUPAC Name
1-[2-(1-{4-[(4-carbamoylpiperidin-1-yl)methyl]phenyl}-N-methylformamido)ethyl]piperidin-4-yl N-{[1,1'-biphenyl]-2-yl}carbamate
SMILES
CN(CCN1CCC(CC1)OC(=O)NC1=CC=CC=C1C1=CC=CC=C1)C(=O)C1=CC=C(CN2CCC(CC2)C(N)=O)C=C1

Pharmacology

Indication

Revefenacin is indicated as an inhalation solution for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).9

COPD is a growing disease being the third leading cause of death in the US. This disease is characterized by not fully reversible airflow limitation.10

Associated Conditions
Pharmacodynamics

Revefenacin has been reported to produce a sustained, long-acting bronchodilation with lower anti-muscarinic-related side effects. In clinical trials, revefenacin demonstrated to be of a long duration of action and low systemic exposure in patients with COPD. Also, it was reported that a dose of 88 mcg can produce a clinically effective bronchodilation measured by through forced expiratory volume in 1s and serial spirometric assessments.3

In placebo-controlled trials, revefenacin showed a decrease in the use of albuterol rescue inhalers and sustained increases in the peak expiratory flow rate that reached a steady state at a maximum in day 7. As well, there was a reported superior lung selectivity index when compared with other LABAs such as glycopyrronium and tiotropium which produced a decreased sialagogue effect.1

Mechanism of action

Revefenacin is an inhaled bronchodilator muscarinic antagonist with a long-acting bronchodilation activity.4 It has been shown to present a high affinity and behaved as a competitive antagonist of the five muscarinic cholinergic receptors. Studies have indicated that revefenacin dissociates significantly slower from the muscarinic receptor M3 (hM3) when compared to the receptor M2 (hM2) which indicates a kinetic selectivity for this subtype. This competitive antagonism produces a suppressive action of the acetylcholine-evoked calcium mobilization and contractile responses in the airway tissue.5 Lastly, due to the duration of the bronchodilation, revefenacin is considered a long-acting muscarinic antagonist which allows it to be dosed once daily.7

This response is very important for the therapy of COPD as the main goal is the reduce the frequency and severity of exacerbations which are normally driven by the presence of elevated cholinergic bronchoconstrictor tone mediated by muscarinic receptors on parasympathetic ganglia and airway smooth muscle.6 Hence, the activity of revefenacin produces a potent and long-lasting protection against the bronchoconstrictor response to acetylcholine or methacholine.5

TargetActionsOrganism
AMuscarinic acetylcholine receptor
antagonist
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

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Absorption

In pharmacokinetic studies, revefenacin was absorbed very rapidly and presented a linear increase in plasma exposure with Cmax, tmax and AUC that ranged between 0.02-0.15 ng/ml, 0.48-0.51 hours and 0.03-0.36 ng.h/ml, respectively.1 The bioaccumulation of revefenacin was very limited and the steady-state was achieved by day 7.11

Volume of distribution

After intravenous administration of revefenacin, the reported volume of distribution is 218 L which suggests an extensive distribution to the tissues.Label

Protein binding

The protein binding of revefenacin and its active metabolite is of 71% and 42% respectively.Label

Metabolism

Revefenacin presents a high metabolic liability producing a rapid metabolic turnover after being distributed from the lung. This metabolic process is done primarily via enzymatic hydrolysis via CYP2D6 to its major hydrolytic metabolite THRX-195518.1

Route of elimination

After reaching maximum concentration, revefenacin concentrations decline in a biphasic manner.1 This elimination kinetics is observed by a rapid declining plasma concentration followed by a slow apparent bi-exponential elimination. Renal elimination of revefenacin is limited and it presents a mean cumulative amount excreted in urine as the unchanged drug of < 0.2% of the administered dose.4

Following intravenous revefenacin administration, 54% of the dose is recovered in feces and 27% was recovered in urine which confirms a high hepatobiliary processing.12

Half life

The apparent terminal half-life of a dose of 350 mcg of revefenacin was 22.3-70 hours.1

Clearance

The renal clearance of revefenacin is negligible and thus, the clearance rate is not a major parameter for this drug.

Toxicity

Revefenacin does not produce the typical systemic effects associated with anticholinergic therapies.1 In carcinogenic studies in animals, there was no evidence of tumorigenicity. As well, there was no evidence of mutagenicity in the Ames test nor genotoxicity in in vitro mouse lymphoma assays and in vivo rat bone marrow micronucleus assays. There is no effect in the fertility.Label

In overdose situations, the common signs and symptoms are nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure, obstipation and difficulties in voiding.Label

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
4-MethoxyamphetamineThe metabolism of Revefenacin can be decreased when combined with 4-Methoxyamphetamine.
AbataceptThe metabolism of Revefenacin can be increased when combined with Abatacept.
AbemaciclibAbemaciclib may decrease the excretion rate of Revefenacin which could result in a higher serum level.
AbirateroneThe metabolism of Revefenacin can be decreased when combined with Abiraterone.
AcebutololThe serum concentration of Revefenacin can be increased when it is combined with Acebutolol.
AcetaminophenThe serum concentration of Revefenacin can be increased when it is combined with Acetaminophen.
AcetylcysteineAcetylcysteine may decrease the excretion rate of Revefenacin which could result in a higher serum level.
Acetylsalicylic acidThe serum concentration of Revefenacin can be increased when it is combined with Acetylsalicylic acid.
AdalimumabThe metabolism of Revefenacin can be increased when combined with Adalimumab.
AfatinibAfatinib may decrease the excretion rate of Revefenacin which could result in a higher serum level.
Additional Data Available
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    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
Not Available

References

General References
  1. Pudi KK, Barnes CN, Moran EJ, Haumann B, Kerwin E: A 28-day, randomized, double-blind, placebo-controlled, parallel group study of nebulized revefenacin in patients with chronic obstructive pulmonary disease. Respir Res. 2017 Nov 2;18(1):182. doi: 10.1186/s12931-017-0647-1. [PubMed:29096627]
  2. Tashkin DP: A review of nebulized drug delivery in COPD. Int J Chron Obstruct Pulmon Dis. 2016 Oct 18;11:2585-2596. doi: 10.2147/COPD.S114034. eCollection 2016. [PubMed:27799757]
  3. Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M, Fabbri LM, Frith P, Halpin DM, Lopez Varela MV, Nishimura M, Roche N, Rodriguez-Roisin R, Sin DD, Singh D, Stockley R, Vestbo J, Wedzicha JA, Agusti A: Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary. Am J Respir Crit Care Med. 2017 Mar 1;195(5):557-582. doi: 10.1164/rccm.201701-0218PP. [PubMed:28128970]
  4. Quinn D, Barnes CN, Yates W, Bourdet DL, Moran EJ, Potgieter P, Nicholls A, Haumann B, Singh D: Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies. Pulm Pharmacol Ther. 2018 Feb;48:71-79. doi: 10.1016/j.pupt.2017.10.003. Epub 2017 Oct 4. [PubMed:28987804]
  5. Hegde SS, Pulido-Rios MT, Luttmann MA, Foley JJ, Hunsberger GE, Steinfeld T, Lee T, Ji Y, Mammen MM, Jasper JR: Pharmacological properties of revefenacin (TD-4208), a novel, nebulized long-acting, and lung selective muscarinic antagonist, at human recombinant muscarinic receptors and in rat, guinea pig, and human isolated airway tissues. Pharmacol Res Perspect. 2018 Apr 30;6(3):e00400. doi: 10.1002/prp2.400. eCollection 2018 Jun. [PubMed:29736245]
  6. Melani AS: Long-acting muscarinic antagonists. Expert Rev Clin Pharmacol. 2015;8(4):479-501. doi: 10.1586/17512433.2015.1058154. [PubMed:26109098]
  7. Barnes PJ: Muscarinic receptor subtypes in airways. Life Sci. 1993;52(5-6):521-7. [PubMed:8441331]
  8. FDA approvals [Link]
  9. FDA news [Link]
  10. Respirology paper [Link]
  11. Theravance Biopharma Report Filing [Link]
  12. ATS Journals paper [Link]
External Links
PubChem Compound
11753673
PubChem Substance
347828196
ChemSpider
9928376
ChEMBL
CHEMBL3833319
Wikipedia
Revefenacin
FDA label
Download (1.44 MB)
MSDS
Download (56.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceChronic Obstructive Pulmonary Disease (COPD)1
1CompletedBasic ScienceHepatic Impairment1
1CompletedBasic ScienceImpaired Renal Function1
1CompletedTreatmentCardiac Repolarization in Healthy Subjects1
1CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
2CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)4
3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)4
3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD) / Chronic Obstructive Pulmonary Disease, COPD, Low Peak Inspiratory Flow Rate / Low Peak Inspiratory Flow Rate (PIFR)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionRespiratory (inhalation)175 ug/3mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7491736No2009-02-172025-03-10Us
US8053448No2011-11-082025-03-10Us
US7521041No2009-04-212025-03-10Us
US10106503No2018-10-232025-03-10Us
US7585879No2009-09-082025-03-10Us
US7910608No2011-03-222025-03-10Us
US8273894No2012-09-252025-03-10Us
US8034946No2011-10-112025-03-10Us
US7288657No2007-10-302025-12-23Us
US7550595No2009-06-232025-03-10Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)777.5 ºC at 760 mmHg'MSDS'
water solubility< 1 mg/ml'MSDS'
logP3.22'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.00721 mg/mLALOGPS
logP4.24ALOGPS
logP3.81ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)12.74ChemAxon
pKa (Strongest Basic)8.65ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area108.21 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity174.84 m3·mol-1ChemAxon
Polarizability66.92 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as n-benzylpiperidines. These are heterocyclic Compounds containing a piperidine ring conjugated to a benzyl group through one nitrogen ring atom.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Benzylpiperidines
Direct Parent
N-benzylpiperidines
Alternative Parents
Biphenyls and derivatives / Phenylcarbamic acid esters / Benzamides / Piperidinecarboxamides / Benzoyl derivatives / Benzylamines / Phenylmethylamines / Aralkylamines / Carbamate esters / Tertiary carboxylic acid amides
show 6 more
Substituents
N-benzylpiperidine / Biphenyl / Phenylcarbamic acid ester / Benzamide / Benzoic acid or derivatives / Piperidinecarboxamide / Benzoyl / Benzylamine / Phenylmethylamine / Aralkylamine
show 20 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein group
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...

Components:
References
  1. Hegde SS, Pulido-Rios MT, Luttmann MA, Foley JJ, Hunsberger GE, Steinfeld T, Lee T, Ji Y, Mammen MM, Jasper JR: Pharmacological properties of revefenacin (TD-4208), a novel, nebulized long-acting, and lung selective muscarinic antagonist, at human recombinant muscarinic receptors and in rat, guinea pig, and human isolated airway tissues. Pharmacol Res Perspect. 2018 Apr 30;6(3):e00400. doi: 10.1002/prp2.400. eCollection 2018 Jun. [PubMed:29736245]
  2. Melani AS: Long-acting muscarinic antagonists. Expert Rev Clin Pharmacol. 2015;8(4):479-501. doi: 10.1586/17512433.2015.1058154. [PubMed:26109098]
  3. Barnes PJ: Muscarinic receptor subtypes in airways. Life Sci. 1993;52(5-6):521-7. [PubMed:8441331]

Enzymes

Kind
Protein
Organism
Humans
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. Pudi KK, Barnes CN, Moran EJ, Haumann B, Kerwin E: A 28-day, randomized, double-blind, placebo-controlled, parallel group study of nebulized revefenacin in patients with chronic obstructive pulmonary disease. Respir Res. 2017 Nov 2;18(1):182. doi: 10.1186/s12931-017-0647-1. [PubMed:29096627]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
Kind
Protein
Organism
Humans
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
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da

Drug created on October 20, 2016 14:54 / Updated on June 04, 2019 07:28