Identification
- Summary
Gefapixant is a P2X3 receptor antagonist that reduces the cough reflex in patients with refractory or unexplained chronic cough.
- Generic Name
- Gefapixant
- DrugBank Accession Number
- DB15097
- Background
It has been estimated that 5-10% of adults globally suffer from chronic cough, which is defined as a cough lasting longer than eight weeks.4 A subset of these patients remain symptomatic despite thorough investigation and treatment, termed refractory chronic cough (RCC) if they have a cough that does not respond to conventional treatment or unexplained chronic cough (UCC) when no diagnosable cause for the cough can be determined.3 Existing treatments for chronic cough have been associated with considerable side effects, in particular opioids such as codeine or dextromethorphan.3
Gefapixant is a novel antagonist of the P2X3 receptor that works to reduce the cough reflex in patients with chronic cough. It received approval in both Japan and Switzerland in 2022 for the treatment of adult patients with RCC and UCC, and received subsequent approval in the EU in September 2023 for the same indications.3,2 It is the first therapy to be approved for the treatment of RCC or UCC in the EU.4
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Gefapixant (DB15097)
- Weight
- Average: 353.4
Monoisotopic: 353.115775286 - Chemical Formula
- C14H19N5O4S
- Synonyms
- Gefapixant
- External IDs
- AF-219
- R-1646
- RG-1646
- RO-4926219
- RO4926219
Pharmacology
- Indication
Gefapixant is indicated in adult patients for the treatment of refractory or unexplained chronic cough.2
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Refractory chronic cough •••••••••••• ••••• ••••••• •••• •••••• Treatment of Unexplained chronic cough •••••••••••• ••••• ••••••• •••• •••••• - Contraindications & Blackbox Warnings
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Gefapixant exerts its therapeutic effects via suppressing the cough reflex initiated by sensory C fibers of the vagus nerve.2 In clinical studies, patients experienced a significant reduction in 24-hour cough frequency compared to placebo - this reduction was apparent by Week 4 and persisted throughout the remainder of the primary efficacy period.2
As renal excretion is the primary route of elimination for gefapixant, patients with severe renal impairment (eGFR < 30 mL/min/1.73m2) may require dose adjustment to maintain appropriate systemic exposures.2
- Mechanism of action
Gefapixant is a selective antagonist of P2X3 receptors, with some activity against the P2X2/3 receptor subtype.2
P2X3 receptors are ATP-gated ion channels found on sensory C fibers of the vagus nerve in the airways. Under inflammatory conditions, ATP is released from airway mucosal cells where it can subsequently bind to P2X3 receptors on C fibers. The activation of vagal C fibers is perceived as an urge to cough and initiates a cough reflex.2 Gefapixant inhibits the binding of ATP to P2X3 receptors, thereby reducing excessive C fiber activation by extracellular ATP and dampening the subsequent cough reflex.2
Target Actions Organism AP2X purinoceptor 3 antagonistHumans UP2X purinoceptor 2 antagonistHumans - Absorption
The absolute bioavailability of gefapixant has not been evaluated but is estimated to be ≥78%.3 At the recommended dose of 45 mg twice daily, steady-state is achieved within 2 days and the steady-state mean plasma AUC and Cmax are 4,144 ng∙hr/mL and 531 ng/mL, respectively.2 The time to peak plasma concentration (Tmax) following oral administration ranges from one to four hours.2
The co-administration of gefapixant with a high-fat, high-calorie meal had no effect on its AUC or Cmax.2
- Volume of distribution
Based on population pharmacokinetic analyses, the estimated steady-state apparent volume of distribution is 133.8 L (Vc 101 L and Vp 32.8 L) following oral twice-daily administration of gefapixant 45 mg.3
- Protein binding
Gefapixant exhibits relatively low protein binding (55%) in vitro, and thus drug-drug interactions resulting from protein displacement are not expected.3
- Metabolism
Gefapixant is relatively minimally metabolized. Following oral administration, only 14% of the administered dose was recovered as metabolites in the urine and feces. Unchanged parent drug is the major (87%) drug-related component in plasma, with circulating metabolites accounting for <10% each.2
The primary biotransformation pathways observed in gefapixant ADME studies included hydroxylation, O-demethylation, dehydrogenation, oxidation, and direct glucuronidation. Secondary biotransformation pathways included glucuronidation of O-demethylated metabolite as well as the formation of a metabolite that was O-demethylated and hydrogenated.3 The three most abundant circulating metabolites were: M1 (a glucuronide of O-demethylated gefapixant), M5 (a directly glucuronidated parent) and M13 (a hydroxylated metabolite.), which accounted for 1.0%, 6.3%, and 5.8%, respectively, of the total drug-related components in plasma.3
- Route of elimination
Gefapixant is primarily eliminated via renal excretion.2 Following a single oral radiolabeled dose in a healthy male subject, approximately 76.4% of the administered radioactivity was recovered in the urine and 22.6% was recovered in the feces.3,1 Unchanged parent drug accounted for 64% of the recovered dose in the feces and accounted for 20% of the recovered dose in the urine.3,1
- Half-life
The terminal half-life of gefapixant is 6-10 hours.2
- Clearance
Population pharmacokinetic analyses integrating data from Phase 1, 2, and 3 data showed a geometric mean apparent clearance (Cl/F) of 10.8 L/h.3 In clinical pharmacology studies, the observed clearance was 14.8 L/h and renal clearance was approximately 8.7 L/h.3
- Adverse Effects
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In a clinical study in which 8 healthy subjects were administered gefapixant 1800 mg twice daily (40 times greater than the recommended dose) for up to 14 days, participants were found to have crystallized gefapixant in the urine with no additional evidence of renal or urinary system injury.2
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAcarbose The therapeutic efficacy of Acarbose can be increased when used in combination with Gefapixant. Acetohexamide The therapeutic efficacy of Acetohexamide can be increased when used in combination with Gefapixant. Albiglutide The therapeutic efficacy of Albiglutide can be increased when used in combination with Gefapixant. Alogliptin The therapeutic efficacy of Alogliptin can be increased when used in combination with Gefapixant. Benzylpenicillin Gefapixant may decrease the excretion rate of Benzylpenicillin which could result in a higher serum level. - Food Interactions
- Take with or without food. The administration of gefapixant with food does not result in clinically significant differences in its pharmacokinetics.
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.- Product Ingredients
Ingredient UNII CAS InChI Key Gefapixant citrate DFK0FC2VVV 2310299-91-1 AIJVJYUOMCRFOE-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Lyfnua Tablet, film coated 45 mg Oral Merck Sharp & Dohme B.V. 2023-11-28 Not applicable EU 
Lyfnua Tablet, film coated 45 mg Oral Merck Sharp & Dohme B.V. 2023-11-28 Not applicable EU Lyfnua Tablet, film coated 45 mg Oral Merck Sharp & Dohme B.V. 2023-11-28 Not applicable EU Lyfnua Tablet, film coated 45 mg Oral Merck Sharp & Dohme B.V. 2023-11-28 Not applicable EU
Categories
- ATC Codes
- R05DB29 — Gefapixant
- R05DB — Other cough suppressants
- R05D — COUGH SUPPRESSANTS, EXCL. COMBINATIONS WITH EXPECTORANTS
- R05 — COUGH AND COLD PREPARATIONS
- R — RESPIRATORY SYSTEM
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- 6K6L7E3F1L
- CAS number
- 1015787-98-0
- InChI Key
- HLWURFKMDLAKOD-UHFFFAOYSA-N
- InChI
- InChI=1S/C14H19N5O4S/c1-7(2)8-4-10(22-3)12(24(17,20)21)5-9(8)23-11-6-18-14(16)19-13(11)15/h4-7H,1-3H3,(H2,17,20,21)(H4,15,16,18,19)
- IUPAC Name
- 5-[(2,4-diaminopyrimidin-5-yl)oxy]-2-methoxy-4-(propan-2-yl)benzene-1-sulfonamide
- SMILES
- COC1=C(C=C(OC2=CN=C(N)N=C2N)C(=C1)C(C)C)S(N)(=O)=O
References
- Synthesis Reference
Hong Ren, Kevin M. Maloney, Kallol Basu, Michael J. Di Maso, Guy R. Humphrey, Feng Peng, Richard Desmond, Douglas A. L. Otte, Embarek Alwedi, Wenjun Liu, Si-Wei Zhang, Siqing Song, Rebecca A. Arvary, Michael A. Zompa, Dan Lehnherr, Gary E. Martin, Hsieh Yao D. Chang, Anne E. Mohan, Francisco J. Guzman, Lisa Jellett, Alfred Y. Lee, Glenn Spencer, Elizabeth S. Fisher, John R. Naber, Hong Gao, Sachin Lohani, Rebecca T. Ruck, and Louis-Charles Campeau. Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 1: Introduction and Process Overview. Organic Process Research & Development 2020 24 (11), 2445-2452. DOI:10.1021/acs.oprd.0c00248
- General References
- Nussbaum JC, Hussain A, Ma B, Min KC, Chen Q, Tomek C, Iwamoto M, Stoch SA: Characterization of the absorption, metabolism, excretion, and mass balance of gefapixant in humans. Pharmacol Res Perspect. 2022 Feb;10(1):e00924. doi: 10.1002/prp2.924. [Article]
- EMA Summary of Product Characteristics: Lyfnua (gefapixant citrate) film-coated tablets for oral administration [Link]
- EMA CHMP Assessment Report: Lyfnua (gefapixant) [Link]
- Merck News Release: Merck Receives Positive European Union CHMP Opinion for Gefapixant [Link]
- External Links
- ChemSpider
- 58828660
- BindingDB
- 50533006
- ChEMBL
- CHEMBL3716057
- ZINC
- ZINC000116342482
- PDBe Ligand
- AF9
- Wikipedia
- Gefapixant
- PDB Entries
- 5yve
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Chronic Cough (CC) 6 2 Completed Treatment Asthma 1 2 Completed Treatment Chronic Cough (CC) 2 2 Completed Treatment Cough / Idiopathic Pulmonary Fibrosis (IPF) 1 2 Completed Treatment Endometriosis related pain 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 45 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility 140 mg/L at pH 5.23 https://www.ema.europa.eu/en/documents/assessment-report/lyfnua-epar-public-assessment-report_en.pdf - Predicted Properties
Property Value Source Water Solubility 0.503 mg/mL ALOGPS logP 0.87 ALOGPS logP 0.86 Chemaxon logS -2.8 ALOGPS pKa (Strongest Acidic) 9.67 Chemaxon pKa (Strongest Basic) 6.76 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 156.44 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 91.44 m3·mol-1 Chemaxon Polarizability 34.62 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0udi-0009000000-6854909493e9dfe7b5f5 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0fb9-9004000000-6ff55c9549ad78c154c2 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0f79-0139000000-76d849958e38a7b0ce55 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-01qc-4098000000-60d904b107b6b374cc1e Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00or-5792000000-a633dba59256cc8c492f Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-01rx-9242000000-b2eb3d05ea77b09e867d Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Receptor for ATP that acts as a ligand-gated cation channel (PubMed:27626375). Plays a role in sensory perception. Required for normal perception of pain. Required for normal taste perception (By similarity).
- Specific Function
- Atp binding
- Gene Name
- P2RX3
- Uniprot ID
- P56373
- Uniprot Name
- P2X purinoceptor 3
- Molecular Weight
- 44288.65 Da
References
- EMA Summary of Product Characteristics: Lyfnua (gefapixant citrate) film-coated tablets for oral administration [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- General Function
- Ion channel gated by extracellular ATP involved in a variety of cellular responses, such as excitatory postsynaptic responses in sensory neurons, neuromuscular junctions (NMJ) formation, hearing, perception of taste and peristalsis. In the inner ear, regulates sound transduction and auditory neurotransmission, outer hair cell electromotility, inner ear gap junctions, and K(+) recycling. Mediates synaptic transmission between neurons and from neurons to smooth muscle.
- Specific Function
- Atp binding
- Gene Name
- P2RX2
- Uniprot ID
- Q9UBL9
- Uniprot Name
- P2X purinoceptor 2
- Molecular Weight
- 51753.75 Da
References
- EMA Summary of Product Characteristics: Lyfnua (gefapixant citrate) film-coated tablets for oral administration [Link]
Transporters
- 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
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Monovalent cation:proton antiporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
- Gene Name
- SLC47A1
- Uniprot ID
- Q96FL8
- Uniprot Name
- Multidrug and toxin extrusion protein 1
- Molecular Weight
- 61921.585 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Drug transmembrane transporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
- Gene Name
- SLC47A2
- Uniprot ID
- Q86VL8
- Uniprot Name
- Multidrug and toxin extrusion protein 2
- Molecular Weight
- 65083.915 Da
References
- 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
References
Drug created at May 20, 2019 14:49 / Updated at November 02, 2023 14:41