Identification

Name
Rimegepant
Accession Number
DB12457
Description

Rimegepant is an oral antagonist of the CGRP receptor developed by Biohaven Pharmaceuticals.5 It received FDA approval on February 27, 2020 for the acute treatment migraine headache.7 While several parenteral antagonists of CGRP and its receptor have been approved for migraine therapy (e.g. erenumab, fremanezumab, galcanezumab), rimegepant and ubrogepant are the only members of the "gepants" family of medications remaining in development, and the only CGRP antagonists that possess oral bioavailability.2

The current standard of migraine therapy involves abortive treatment with "triptans", such as sumatriptan, but these medications are contraindicated in patients with pre-existing cerebrovascular and cardiovascular disease due to their vasoconstrictive properties.2 Antagonism of the CGRP pathway has become an attractive target for migraine therapy as, unlike the triptans, oral CGRP antagonists have no observed vasoconstrictive properties and are therefore safer for use in patients with contraindications to standard therapy.1,2

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 534.568
Monoisotopic: 534.219095112
Chemical Formula
C28H28F2N6O3
Synonyms
  • Rimegepant
External IDs
  • BMS 927711
  • BMS-927711

Pharmacology

Indication

Rimegepant is indicated for the acute treatment of migraine with or without aura in adults.6

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Rimegepant helps to abort migraine headaches by preventing the activity of a pronociceptive molecule that has been implicated in migraine pathophysiology.6 It is intended for use as an abortive migraine therapy and therefore has a relatively rapid onset of effect, with most efficacy trials evaluating for effect at the 2 hour mark.6

Rimegepant does not require dose adjustment in patients with mild, moderate, or severe renal impairment,6 nor does it require dose adjustment in patients with mild or moderate hepatic impairment. In clinical trials, plasma concentrations of rimegepant were significantly higher in patients with severe (i.e. Child-Pugh C) hepatic impairment - it should therefore be avoided in this population.6 Hypersensitivity reactions have occurred during clinical studies and patients should be made aware of this possibility. Rimegepant should be discontinued immediately if hypersensitivity reaction occurs.6

Mechanism of action

The currently accepted theory of migraine pathophysiology considers dysfunction of the central nervous system, in particular the trigeminal ganglion, to be the root cause behind the condition.2 Activation of the trigeminal ganglion triggers the stimulation of trigeminal afferents that project to the spinal cord and synapse on various pain-sensing intra- and extracranial structures, such as the dura mater. Pain signals are then further transmitted via second-order ascending neurons to the brainstem, hypothalamus, and thalamic nuclei, and from there to several cortical regions (e.g. auditory, visual, motor cortices).2 The trigeminal ganglion appears to amplify and perpetuate the migraine headache pain through the activation of perivascular fibers and the release of molecules involved in pain generation, such as calcitonin gene-related peptide (CGRP).2

The α-isoform of CGRP, expressed in primary sensory neurons, is a potent vasodilator and has been implicated in migraine pathogenesis - CGRP levels are acutely elevated during migraine attacks, return to normal following treatment with triptan medications, and intravenous infusions of CGRP have been shown to trigger migraine-like headaches in migraine patients. In addition to its vasodilatory properties, CGRP appears to be a pronociceptive factor that modulates neuronal excitability to facilitate pain responses.3

Rimegepant is an antagonist of the calcitonin gene-related peptide receptor1 - it competes with CGRP for occupancy at these receptors, preventing the actions of CGRP and its ability to amplify and perpetuate migraine headache pain, ultimately terminating the headache.3

TargetActionsOrganism
ACalcitonin gene-related peptide type 1 receptor
antagonist
Humans
Absorption

The absolute oral bioavailability of rimegepant is approximately 64%.6 Following oral administration of the orally disintegrating tablet, maximum plasma concentrations were achieved at 1.5 hours (Tmax).6

When administered with a high-fat meal, Tmax is delayed by 1 hour, Cmax is decreased by 42-53%, and AUC is decreased by 32-38%.6 The clinical significance of this difference in pharmacokinetics is unknown.

Volume of distribution

At steady state, the volume of distribution is approximately 120 L.6

Protein binding

Rimegepant is approximately 96% plasma protein-bound.6 The specific proteins to which rimegepant binds have not been elucidated.

Metabolism

Rimegepant is metabolized by CYP3A4 and, to a lesser extent, CYP2C9.6 Specific metabolites of rimegepant have not been characterized and no major metabolites have been detected in plasma.6 Approximately 77% of an administered dose is eliminated unchanged,6 suggesting metabolism is likely to be a minor means of drug elimination.

Route of elimination

Following oral administration of radiolabeled rimegepant in healthy subjects, 78% of the administered radioactivity was recovered in feces and 24% in urine.6 Unchanged parent drug was the major component in each, comprising 42% and 51% of the recovered doses, respectively.

Half-life

The elimination half-life in healthy subjects is approximately 11 hours.6

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

There is no specific antidote for rimegepant overdosage and clinical experience is limited.6 Treatment should consist of general supportive and symptomatic measures including monitoring of vital signs and general observation. Hemodialysis is unlikely to be of benefit given rimegepant's high serum protein binding.6

Affected organisms
  • Humans and other mammals
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
AbametapirThe serum concentration of Rimegepant can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Rimegepant can be increased when it is combined with Abemaciclib.
AcetaminophenThe metabolism of Rimegepant can be increased when combined with Acetaminophen.
AfatinibThe serum concentration of Rimegepant can be increased when it is combined with Afatinib.
AlectinibThe serum concentration of Rimegepant can be increased when it is combined with Alectinib.
AlimemazineThe metabolism of Rimegepant can be increased when combined with Alimemazine.
AlpelisibThe metabolism of Rimegepant can be increased when combined with Alpelisib.
AmbrisentanThe serum concentration of Rimegepant can be increased when it is combined with Ambrisentan.
AminoglutethimideThe metabolism of Rimegepant can be increased when combined with Aminoglutethimide.
AmiodaroneThe serum concentration of Rimegepant can be increased when it is combined with Amiodarone.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take with or without food. Pharmacokinetics may be altered when administered with high-fat meals, but the clinical relevance of these effects is unknown.

Products

Product Ingredients
IngredientUNIICASInChI Key
Rimegepant sulfate1383NM3Q0H1374024-48-2SOGUOEZRYKUOHR-CQZKMDJHSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Nurtec ODTTablet, orally disintegrating75 mg/75mgOralBiohaven Pharmaceuticals, Inc2020-03-05Not applicableUS flag
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

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as imidazopyridines. These are organic polycyclic compounds containing an imidazole ring fused to a pyridine ring. Imidazole is 5-membered ring consisting of three carbon atoms, and two nitrogen centers at the 1- and 3-positions. Pyridine is a 6-membered ring consisting of five carbon atoms and one nitrogen center.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Imidazopyridines
Sub Class
Not Available
Direct Parent
Imidazopyridines
Alternative Parents
Piperidinecarboxylic acids / Fluorobenzenes / Aralkylamines / Pyridines and derivatives / N-substituted imidazoles / Aryl fluorides / Heteroaromatic compounds / Carbamate esters / Ureas / Azacyclic compounds
show 5 more
Substituents
Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Carbamic acid ester / Carbonyl group
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
997WVV895X
CAS number
1289023-67-1
InChI Key
KRNAOFGYEFKHPB-ANJVHQHFSA-N
InChI
InChI=1S/C28H28F2N6O3/c29-20-6-1-4-17(23(20)30)18-8-9-22(25-19(24(18)31)5-2-12-32-25)39-28(38)35-14-10-16(11-15-35)36-21-7-3-13-33-26(21)34-27(36)37/h1-7,12-13,16,18,22,24H,8-11,14-15,31H2,(H,33,34,37)/t18-,22+,24-/m0/s1
IUPAC Name
(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-5H,6H,7H,8H,9H-cyclohepta[b]pyridin-9-yl 4-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-1-yl}piperidine-1-carboxylate
SMILES
N[[email protected]]1[[email protected]@H](CC[[email protected]@H](OC(=O)N2CCC(CC2)N2C(=O)NC3=NC=CC=C23)C2=C1C=CC=N2)C1=C(F)C(F)=CC=C1

References

Synthesis Reference

Luo G, Chen L, Conway CM, Kostich W, Macor JE, Dubowchik GM: Asymmetric Synthesis of Heterocyclic Analogues of a CGRP Receptor Antagonist for Treating Migraine. Org Lett. 2015 Dec 18;17(24):5982-5.

General References
  1. Lipton RB, Croop R, Stock EG, Stock DA, Morris BA, Frost M, Dubowchik GM, Conway CM, Coric V, Goadsby PJ: Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. N Engl J Med. 2019 Jul 11;381(2):142-149. doi: 10.1056/NEJMoa1811090. [PubMed:31291516]
  2. Negro A, Martelletti P: Gepants for the treatment of migraine. Expert Opin Investig Drugs. 2019 Jun;28(6):555-567. doi: 10.1080/13543784.2019.1618830. Epub 2019 May 17. [PubMed:31081399]
  3. Martelletti P, Giamberardino MA: Advances in orally administered pharmacotherapy for the treatment of migraine. Expert Opin Pharmacother. 2019 Feb;20(2):209-218. doi: 10.1080/14656566.2018.1549223. Epub 2018 Nov 26. [PubMed:30475090]
  4. Luo G, Chen L, Conway CM, Kostich W, Macor JE, Dubowchik GM: Asymmetric Synthesis of Heterocyclic Analogues of a CGRP Receptor Antagonist for Treating Migraine. Org Lett. 2015 Dec 18;17(24):5982-5. doi: 10.1021/acs.orglett.5b02921. Epub 2015 Dec 9. [PubMed:26650258]
  5. BiopharmaDive: 5 FDA Approval Decisions to Watch in the 1st Quarter [Link]
  6. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]
  7. Biohaven Pharmaceuticals Press Release: Nurtec ODT FDA Approval [Link]
  8. CaymanChem: Rimegepant MSDS [Link]
PubChem Compound
51049968
PubChem Substance
347828697
ChemSpider
27289072
BindingDB
50400098
RxNav
2282307
ChEMBL
CHEMBL2178422
ZINC
ZINC000068267814
Wikipedia
Rimegepant

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAcute Migraine / Migraine Disorders / Phonophobia / Photophobia1
3CompletedTreatmentMigraine Headache, With or Without Aura1
3Not Yet RecruitingTreatmentAcute Migraine1
2CompletedTreatmentAcute Treatment of Migraine / Migraine1
2RecruitingTreatmentTrigeminal Neuralgia (TN)1
2, 3Active Not RecruitingPreventionMigraine1
2, 3CompletedTreatmentMigraine Headache, With or Without Aura1
1CompletedTreatmentMigraine1
Not AvailableNo Longer AvailableNot AvailableMigraine1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, orally disintegratingOral75 mg/75mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8314117No2012-11-202031-02-22US flag
US8759372No2014-06-242033-02-25US flag
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
water solubilitySlightly solubleFDA label
Predicted Properties
PropertyValueSource
Water Solubility0.0755 mg/mLALOGPS
logP2.68ALOGPS
logP2.95ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)10.7ChemAxon
pKa (Strongest Basic)8.95ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area113.68 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity139.58 m3·mol-1ChemAxon
Polarizability54.23 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
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/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

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Specific Function
Adrenomedullin receptor activity
Gene Name
CALCRL
Uniprot ID
Q16602
Uniprot Name
Calcitonin gene-related peptide type 1 receptor
Molecular Weight
52928.98 Da
References
  1. Lipton RB, Croop R, Stock EG, Stock DA, Morris BA, Frost M, Dubowchik GM, Conway CM, Coric V, Goadsby PJ: Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. N Engl J Med. 2019 Jul 11;381(2):142-149. doi: 10.1056/NEJMoa1811090. [PubMed:31291516]
  2. Negro A, Martelletti P: Gepants for the treatment of migraine. Expert Opin Investig Drugs. 2019 Jun;28(6):555-567. doi: 10.1080/13543784.2019.1618830. Epub 2019 May 17. [PubMed:31081399]
  3. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Rimegepant is a weak inhibitor of CYP3A4 that exhibits time-dependent inhibition.
General Function
Vitamin d3 25-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 performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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
References
  1. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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
References
  1. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Quaternary ammonium group transmembrane transporter activity
Specific Function
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
Gene Name
SLC22A2
Uniprot ID
O15244
Uniprot Name
Solute carrier family 22 member 2
Molecular Weight
62579.99 Da
References
  1. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]

Drug created on October 20, 2016 16:28 / Updated on June 12, 2020 10:53

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