NAV

Gefapixant

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
3D
Similar Structures
Weight
Average: 353.4
Monoisotopic: 353.115775286
Chemical Formula
C14H19N5O4S
Synonyms
  • Gefapixant
External IDs
  • AF-219
  • R-1646
  • RG-1646
  • RO-4926219
  • RO4926219
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Pharmacology

Indication

Gefapixant is indicated in adult patients for the treatment of refractory or unexplained chronic cough.2

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofRefractory chronic cough•••••••••••••••••••••••• •••• ••••••
Treatment ofUnexplained chronic cough•••••••••••••••••••••••• •••• ••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

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

TargetActionsOrganism
AP2X purinoceptor 3
antagonist
Humans
UP2X purinoceptor 2
antagonist
Humans
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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Toxicity

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 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.
DrugInteraction
Integrate drug-drug
interactions in your software
AcarboseThe therapeutic efficacy of Acarbose can be increased when used in combination with Gefapixant.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be increased when used in combination with Gefapixant.
AlbiglutideThe therapeutic efficacy of Albiglutide can be increased when used in combination with Gefapixant.
AlogliptinThe therapeutic efficacy of Alogliptin can be increased when used in combination with Gefapixant.
BenzylpenicillinGefapixant 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.

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Product Ingredients
IngredientUNIICASInChI Key
Gefapixant citrateDFK0FC2VVV2310299-91-1AIJVJYUOMCRFOE-UHFFFAOYSA-N

Categories

ATC Codes
R05DB29 — GefapixantG01AE10 — Combinations of sulfonamides
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
  1. 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]
  2. EMA Summary of Product Characteristics: Lyfnua (gefapixant citrate) film-coated tablets for oral administration [Link]
  3. EMA CHMP Assessment Report: Lyfnua (gefapixant) [Link]
  4. Merck News Release: Merck Receives Positive European Union CHMP Opinion for Gefapixant [Link]
ChemSpider
58828660
BindingDB
50533006
ChEMBL
CHEMBL3716057
ZINC
ZINC000116342482
PDBe Ligand
AF9
Wikipedia
Gefapixant
PDB Entries
5yve

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3CompletedTreatmentChronic Cough (CC)6
2CompletedTreatmentAsthma1
2CompletedTreatmentChronic Cough (CC)2
2CompletedTreatmentCough / Idiopathic Pulmonary Fibrosis (IPF)1
2CompletedTreatmentEndometriosis related pain1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral45 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility140 mg/L at pH 5.23https://www.ema.europa.eu/en/documents/assessment-report/lyfnua-epar-public-assessment-report_en.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.503 mg/mLALOGPS
logP0.87ALOGPS
logP0.86Chemaxon
logS-2.8ALOGPS
pKa (Strongest Acidic)9.67Chemaxon
pKa (Strongest Basic)6.76Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area156.44 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity91.44 m3·mol-1Chemaxon
Polarizability34.62 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
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/MSsplash10-0udi-0009000000-6854909493e9dfe7b5f5
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0fb9-9004000000-6ff55c9549ad78c154c2
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f79-0139000000-76d849958e38a7b0ce55
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-01qc-4098000000-60d904b107b6b374cc1e
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00or-5792000000-a633dba59256cc8c492f
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-01rx-9242000000-b2eb3d05ea77b09e867d
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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insights and accelerate drug research.
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Details1. P2X purinoceptor 3
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
  1. EMA Summary of Product Characteristics: Lyfnua (gefapixant citrate) film-coated tablets for oral administration [Link]
Details2. P2X purinoceptor 2
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
  1. EMA Summary of Product Characteristics: Lyfnua (gefapixant citrate) film-coated tablets for oral administration [Link]

Transporters

Details1. P-glycoprotein 1
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
  1. EMA Summary of Product Characteristics: Lyfnua (gefapixant citrate) film-coated tablets for oral administration [Link]
  2. EMA CHMP Assessment Report: Lyfnua (gefapixant) [Link]
Details2. Multidrug and toxin extrusion protein 1
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
  1. EMA Summary of Product Characteristics: Lyfnua (gefapixant citrate) film-coated tablets for oral administration [Link]
  2. EMA CHMP Assessment Report: Lyfnua (gefapixant) [Link]
Details3. Multidrug and toxin extrusion protein 2
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
  1. EMA Summary of Product Characteristics: Lyfnua (gefapixant citrate) film-coated tablets for oral administration [Link]
  2. EMA CHMP Assessment Report: Lyfnua (gefapixant) [Link]
Details4. ATP-binding cassette sub-family G member 2
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
  1. EMA Summary of Product Characteristics: Lyfnua (gefapixant citrate) film-coated tablets for oral administration [Link]
  2. EMA CHMP Assessment Report: Lyfnua (gefapixant) [Link]

Drug created at May 20, 2019 14:49 / Updated at November 02, 2023 14:41