Rimegepant

Identification

Summary

Rimegepant is an oral CGRP receptor antagonist used for the acute treatment of migraines with or without aura in adults.

Brand Names

Nurtec

Generic Name

Rimegepant

DrugBank Accession Number

DB12457

Background

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 and was subsequently approved by the European Commission in April 2022 for both the treatment and prevention of migraines.¹⁰ While several parenteral antagonists of CGRP and its receptor have been approved for migraine therapy (e.g. erenumab, fremanezumab, galcanezumab), rimegepant and ubrogepant were the only CGRP antagonists that possessed oral bioavailability² until the approval of atogepant in 2021.⁹

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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Rimegepant (DB12457)

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Weight

Average: 534.568
Monoisotopic: 534.219095112

Chemical Formula

C₂₈H₂₈F₂N₆O₃

Synonyms

• Rimegepant

External IDs

• BMS 927711
• BMS-927711

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Pharmacology

Indication

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

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Prevention of	Episodic migraine		••••••••••••	•••••		••••••• •••••• ••••••••••••••
Treatment of	Migraine with aura		••••••••••••	•••••		••••••• •••••• ••••••••••••••
Treatment of	Migraine without aura		••••••••••••	•••••		••••••• •••••• ••••••••••••••

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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

Target	Actions	Organism
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 (T_max).⁶

When administered with a high-fat meal, T_max is delayed by 1 hour, C_max 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

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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

Pathways

Not Available

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Not Available

Interactions

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Rimegepant can be increased when it is combined with Abametapir.
Abemaciclib	The serum concentration of Rimegepant can be increased when it is combined with Abemaciclib.
Abrocitinib	The serum concentration of Rimegepant can be increased when it is combined with Abrocitinib.
Acetaminophen	The metabolism of Rimegepant can be increased when combined with Acetaminophen.
Adagrasib	The serum concentration of Rimegepant can be increased when it is combined with Adagrasib.

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.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Rimegepant sulfate	1383NM3Q0H	1374024-48-2	SOGUOEZRYKUOHR-CQZKMDJHSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Nurtec ODT	Tablet, orally disintegrating	75 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2020-03-05	Not applicable
Nurtec ODT	Tablet, orally disintegrating	75 mg	Oral	Pfizer Canada Ulc	Not applicable	Not applicable
Nurtec ODT	Tablet, orally disintegrating	75 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2020-03-05	Not applicable
Vydura	Tablet	75 mg	Oral	Pfizer Europe Ma Eeig	2022-05-17	Not applicable
Vydura	Tablet	75 mg	Oral	Pfizer Europe Ma Eeig	2022-06-07	Not applicable

Categories

ATC Codes

N02CD06 — Rimegepant

• N02CD — Calcitonin gene-related peptide (CGRP) antagonists
• N02C — ANTIMIGRAINE PREPARATIONS
• N02 — ANALGESICS
• N — NERVOUS SYSTEM

Drug Categories

• Analgesics
• Antimigraine Preparations
• BCRP/ABCG2 Substrates
• Calcitonin Gene-Related Peptide (CGRP) Antagonists
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (weak)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• MATE 1 Inhibitors
• MATE inhibitors
• Migraine Disorders
• Nervous System
• OAT3/SLC22A8 Inhibitors
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B3 inhibitors
• OCT2 Inhibitors
• P-glycoprotein substrates

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 / Organofluorides / Organic oxides / Monoalkylamines / Hydrocarbon derivatives / Carbonyl compounds

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Substituents

Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Carbamic acid ester / Carbonyl group / Fluorobenzene / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Imidazopyridine / Monocyclic benzene moiety / N-substituted imidazole / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Piperidine / Piperidinecarboxylic acid / Primary aliphatic amine / Primary amine / Pyridine / Urea

show 21 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

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[C@H]1[C@@H](CC[C@@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. [Article]
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. [Article]
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. [Article]
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. [Article]
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]
9. PR Newswire: FDA Approves QULIPTA™ (atogepant), the First and Only Oral CGRP Receptor Antagonist Specifically Developed for the Preventive Treatment of Migraine [Link]
10. Pfizer: Pfizer and Biohaven’s VYDURA® (Rimegepant) Granted First Ever Marketing Authorization by European Commission for Both Acute Treatment of Migraine and Prophylaxis of Episodic Migraine [Link]

External Links

PubChem Compound

51049968

PubChem Substance

347828697

ChemSpider

27289072

BindingDB

50400098

RxNav

2282307

ChEMBL

CHEMBL2178422

ZINC

ZINC000068267814

Wikipedia

Rimegepant

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	Active Not Recruiting	Treatment	Episodic Migraine / Migraine / Phonophobia / Photophobia	1
4	Completed	Treatment	Episodic Migraine / Migraine	1
4	Completed	Treatment	Pain	1
4	Not Yet Recruiting	Treatment	Irritable Bowel Syndrome (IBS)	1
4	Recruiting	Prevention	Migraine	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, orally disintegrating	Oral	75 mg
Tablet, orally disintegrating	Oral	75 mg/1
Tablet	Oral	75 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8314117	No	2012-11-20	2031-02-22
US8759372	No	2014-06-24	2033-02-25
US11083724	No	2021-08-10	2039-03-25

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Slightly soluble	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.0755 mg/mL	ALOGPS
logP	2.68	ALOGPS
logP	2.95	Chemaxon
logS	-3.8	ALOGPS
pKa (Strongest Acidic)	10.7	Chemaxon
pKa (Strongest Basic)	8.95	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	113.68 Å2	Chemaxon
Rotatable Bond Count	4	Chemaxon
Refractivity	139.58 m3·mol-1	Chemaxon
Polarizability	54.23 Å3	Chemaxon
Number of Rings	6	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	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	splash10-000i-0020090000-680604351c331e059f38
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00kf-0170940000-a54d6c55c376590a7a08
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-000i-0010090000-ef1daf0a19034c17db05
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-000i-1010930000-fbac8c164f116686e655
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01p9-0940130000-3219feb48f0dc8de0de4
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a59-0970010000-d36654675bc679229c62

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	221.11198	predicted	DeepCCS 1.0 (2019)
[M+H]+	223.2506	predicted	DeepCCS 1.0 (2019)
[M+Na]+	229.1376	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Calcitonin gene-related peptide type 1 receptor

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. [Article]
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. [Article]
3. FDA Approved Drug Products: Nurtec ODT (rimegepant) orally disintegrating tablets [Link]

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Drug created at October 20, 2016 22:28 / Updated at April 30, 2022 04:55