Revefenacin
Identification
- Summary
Revefenacin is an anticholinergic agent used to treat COPD.
- Generic Name
- Revefenacin
- DrugBank Accession Number
- DB11855
- Background
Revefenacin is a novel biphenyl carbamate tertiary amine agent that belongs to the family of the long-acting muscarinic antagonists (LAMA). 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 LAMA 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 LAMA 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
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 597.76
Monoisotopic: 597.331504885 - Chemical Formula
- C35H43N5O4
- Synonyms
- Revefenacin
- External IDs
- GSK-1160724
- GSK1160724
- TD-4208
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
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Chronic obstructive pulmonary disease, copd •••••••••••• •••••••• - Contraindications & Blackbox Warnings
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- 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 LAMAs 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
Target Actions Organism AMuscarinic acetylcholine receptor antagonistHumans - 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
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- 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.
- Adverse Effects
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- 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
- 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
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept The metabolism of Revefenacin can be increased when combined with Abatacept. Abemaciclib Abemaciclib may decrease the excretion rate of Revefenacin which could result in a higher serum level. Abiraterone The metabolism of Revefenacin can be decreased when combined with Abiraterone. Abrocitinib The serum concentration of Revefenacin can be increased when it is combined with Abrocitinib. Acebutolol The metabolism of Revefenacin can be decreased when combined with Acebutolol. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Yupelri Solution 175 ug/3mL Respiratory (inhalation) Mylan Specialty L.P. 2018-12-03 Not applicable US Yupelri Solution 175 ug/3mL Respiratory (inhalation) The Ritedose Corporation 2018-12-03 2019-07-31 US
Categories
- ATC Codes
- R03BB08 — Revefenacin
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Benzamide / Benzenoid / Benzoic acid or derivatives / Benzoyl / Benzylamine show 20 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- G2AE2VE07O
- CAS number
- 864750-70-9
- 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
References
- General References
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Melani AS: Long-acting muscarinic antagonists. Expert Rev Clin Pharmacol. 2015;8(4):479-501. doi: 10.1586/17512433.2015.1058154. [Article]
- Barnes PJ: Muscarinic receptor subtypes in airways. Life Sci. 1993;52(5-6):521-7. [Article]
- FDA approvals [Link]
- FDA news [Link]
- Respirology paper [Link]
- Theravance Biopharma Report Filing [Link]
- ATS Journals paper [Link]
- FDA Approved Drug Products: YUPELRI (revefenacin) inhalation solution, for oral inhalation use [Link]
- External Links
- PubChem Compound
- 11753673
- PubChem Substance
- 347828196
- ChemSpider
- 9928376
- 2102775
- ChEMBL
- CHEMBL3833319
- Wikipedia
- Revefenacin
- FDA label
- Download (1.44 MB)
- MSDS
- Download (56.5 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Chronic Obstructive Pulmonary Disease (COPD) 1 4 Recruiting Treatment Exacerbation of COPD 1 3 Completed Treatment Chronic Obstructive Pulmonary Disease (COPD) 5 3 Completed Treatment Chronic Obstructive Pulmonary Disease (COPD) / Low Peak Inspiratory Flow Rate (PIFR) 1 2 Completed Treatment Chronic Obstructive Pulmonary Disease (COPD) 4
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Solution Respiratory (inhalation) 175 ug/3mL Solution Respiratory (inhalation) 175 mcg/3ml - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7491736 No 2009-02-17 2025-03-10 US US8053448 No 2011-11-08 2025-03-10 US US7521041 No 2009-04-21 2025-03-10 US US10106503 No 2018-10-23 2025-03-10 US US7585879 No 2009-09-08 2025-03-10 US US7910608 No 2011-03-22 2025-03-10 US US8273894 No 2012-09-25 2025-03-10 US US8034946 No 2011-10-11 2025-03-10 US US7288657 No 2007-10-30 2025-12-23 US US7550595 No 2009-06-23 2025-03-10 US US9765028 No 2017-09-19 2030-07-14 US US8541451 No 2013-09-24 2031-08-25 US US10343995 No 2019-07-09 2025-03-10 US US10550081 No 2020-02-04 2030-07-14 US US11008289 No 2021-05-18 2030-07-14 US US11247969 No 2005-03-10 2025-03-10 US US11484531 No 2019-10-23 2039-10-23 US US11691948 No 2010-07-14 2030-07-14 US US11858898 No 2010-07-14 2030-07-14 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source boiling point (°C) 777.5 ºC at 760 mmHg 'MSDS' water solubility < 1 mg/ml 'MSDS' logP 3.22 'MSDS' - Predicted Properties
Property Value Source Water Solubility 0.00721 mg/mL ALOGPS logP 4.24 ALOGPS logP 3.81 Chemaxon logS -4.9 ALOGPS pKa (Strongest Acidic) 12.74 Chemaxon pKa (Strongest Basic) 8.65 Chemaxon Physiological Charge 2 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 108.21 Å2 Chemaxon Rotatable Bond Count 11 Chemaxon Refractivity 174.84 m3·mol-1 Chemaxon Polarizability 66.92 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 228.23396 predictedDeepCCS 1.0 (2019) [M+H]+ 230.54428 predictedDeepCCS 1.0 (2019) [M+Na]+ 236.4034 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- 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
- 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. [Article]
- Melani AS: Long-acting muscarinic antagonists. Expert Rev Clin Pharmacol. 2015;8(4):479-501. doi: 10.1586/17512433.2015.1058154. [Article]
- Barnes PJ: Muscarinic receptor subtypes in airways. Life Sci. 1993;52(5-6):521-7. [Article]
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
- 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. [Article]
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 at October 20, 2016 20:54 / Updated at June 01, 2022 17:06