Ubrogepant

Identification

Summary

Ubrogepant is an oral CGRP antagonist used in the acute treatment of migraine with or without aura.

Brand Names
Ubrelvy
Generic Name
Ubrogepant
DrugBank Accession Number
DB15328
Background

Ubrogepant is indicated for the acute treatment of migraine headaches with or without aura in adults.5 It was approved by the FDA on December 23, 2019, and is the first oral calcitonin gene-related peptide (CGRP) receptor antagonist approved for the acute treatment of migraine.6 Several oral small molecule CGRP receptor antagonists, belonging to a class of medications referred to as "gepants", have been investigated for migraines, but only ubrogepant and rimegepant remain in clinical development.3,4 Previous agents within this class were efficacious but limited by liver toxicity - this led to the development of ubrogepant, which was designed to be a hepatoxicity-free alternative to its predecessors.1 Several parenteral monoclonal antibodies acting against the CGRP pathway (e.g. erenumab, fremanezumab, galcanezumab) have also been approved in recent years.3

Compared to the current standard of therapy for migraine treatment, namely triptans such as sumatriptan and almotriptan, CGRP antagonists present several advantages.1 They appear to be better tolerated, do not contribute to medication overuse headaches, and carry no apparent cardiovascular risk, making them suitable for use in patients with cardiovascular disease.1 The development of oral gepants, including ubrogepant, may therefore constitute a significant advance in migraine headache treatment and may become the new standard of therapy in the treatment of this debilitating condition.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 549.554
Monoisotopic: 549.198774206
Chemical Formula
C29H26F3N5O3
Synonyms
  • Ubrogepant
  • Ubrogépant
  • Ubrogepantum
External IDs
  • MK-1602

Pharmacology

Indication

Ubrogepant is indicated for the acute treatment of migraine with or without aura in adults.5

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Ubrogepant acutely treats migraine headache pain by blocking the activity of a key transmitter involved in migraine pathogenesis.5 Exposure to ubrogepant can be significantly increased in patients with severe hepatic or renal insufficiency - dose adjustments are required for these patients in order to avoid excessive exposure, and ubrogepant is not recommended in patients with end-stage renal disease.5

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.3 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).3 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).3

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.4

Ubrogepant is a potent antagonist of the calcitonin gene-related peptide receptor5 - 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.4

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

Following oral administration, Tmax occurs between 0.7 and 1.5 h.4,5 When administered with a high-fat meal, Tmax is delayed by approximately 2 hours and Cmax was reduced by 22% with no significant changes to the AUC.5 Ubrogepant exhibits dose-proportional pharmacokinetics throughout the entirety of its recommended dosing range.5

Volume of distribution

The apparent central volume of distribution following oral administration is approximately 350 L.5

Protein binding

Ubrogepant is 87% protein-bound in vitro, although the specific proteins to which ubrogepant binds have not been elucidated.5

Metabolism

Ubrogepant is eliminated primarily via metabolism, the majority of which is mediated by CYP3A4.5 Two circulating glucuronide conjugates, along with unchanged parent drug, were found to be the most abundant circulating components in human plasma. The glucuronide metabolites reportedly carry 6000-fold less activity at CGRP receptors and are therefore considered to be pharmacologically inert.5

Route of elimination

The main route of elimination is fecal/biliary, while renal excretion is comparatively minor - following administration of a single oral dose to healthy subjects, approximately 42% of the dose was recovered unchanged in the feces and 6% was recovered unchanged in the urine.5

Half-life

Ubrogepant has an elimination half-life of 5-7 hours.5

Clearance

The apparent oral clearance of ubrogepant is approximately 87 L/h.5

Adverse Effects
Adverseeffects
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Toxicity

As clinical experience with ubrogepant is limited, detailed toxicity information is not readily available. Prescribing information for ubrogepant recommends a monitoring period of at least 24 hours following overdose based on its 5 to 7 hour half-life.5

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 Ubrogepant can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Ubrogepant can be increased when it is combined with Abemaciclib.
AbirateroneThe serum concentration of Ubrogepant can be increased when it is combined with Abiraterone.
AcalabrutinibThe serum concentration of Ubrogepant can be increased when it is combined with Acalabrutinib.
AcetaminophenThe serum concentration of Ubrogepant can be increased when it is combined with Acetaminophen.
AfatinibThe serum concentration of Ubrogepant can be increased when it is combined with Afatinib.
AlectinibThe serum concentration of Ubrogepant can be increased when it is combined with Alectinib.
AlpelisibThe serum concentration of Ubrogepant can be increased when it is combined with Alpelisib.
AmbrisentanThe serum concentration of Ubrogepant can be increased when it is combined with Ambrisentan.
AmiodaroneThe serum concentration of Ubrogepant can be increased when it is combined with Amiodarone.
Interactions
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Food Interactions
  • Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of ubrogepant.
  • Take with or without food. Co-administration with food slightly alters pharmacokinetics, but not to a clinically significant extent.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
UbrelvyTablet50 mg/1OralAllergan, Inc.2019-12-23Not applicableUS flag
UbrelvyTablet100 mg/1OralAllergan, Inc.2019-12-23Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
AD0O8X2QJR
CAS number
1374248-77-7
InChI Key
DDOOFTLHJSMHLN-ZQHRPCGSSA-N
InChI
InChI=1S/C29H26F3N5O3/c1-16-20(17-6-3-2-4-7-17)11-22(26(39)37(16)15-29(30,31)32)35-25(38)19-10-18-12-28(13-23(18)34-14-19)21-8-5-9-33-24(21)36-27(28)40/h2-10,14,16,20,22H,11-13,15H2,1H3,(H,35,38)(H,33,36,40)/t16-,20-,22+,28+/m1/s1
IUPAC Name
(6S)-N-[(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide
SMILES
C[C@@H]1[C@@H](C[C@H](NC(=O)C2=CN=C3C[C@]4(CC3=C2)C(=O)NC2=NC=CC=C42)C(=O)N1CC(F)(F)F)C1=CC=CC=C1

References

Synthesis Reference

Leonardo R. Allain, et. al., "Formulations for CGRP receptor antagonists." Australian Patent AU2014318741B2, published December 06, 2018.

General References
  1. Moreno-Ajona D, Chan C, Villar-Martinez MD, Goadsby PJ: Targeting CGRP and 5-HT1F Receptors for the Acute Therapy of Migraine: A Literature Review. Headache. 2019 Jul;59 Suppl 2:3-19. doi: 10.1111/head.13582. [Article]
  2. Rubio-Beltran E, Chan KY, Danser AJ, MaassenVanDenBrink A, Edvinsson L: Characterisation of the calcitonin gene-related peptide receptor antagonists ubrogepant and atogepant in human isolated coronary, cerebral and middle meningeal arteries. Cephalalgia. 2019 Nov 1:333102419884943. doi: 10.1177/0333102419884943. [Article]
  3. 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]
  4. 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]
  5. FDA Approved Drug Products: Ubrelvy (ubrogepant) oral tablets [Link]
  6. FDA News Release: Ubrogepant approval [Link]
ChemSpider
28536135
RxNav
2268216
ChEMBL
CHEMBL2364638
ZINC
ZINC000095598454
Wikipedia
Ubrogepant

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentMigraine Headache, With or Without Aura3
3RecruitingTreatmentMigraine1
2CompletedTreatmentMigraine2
1CompletedBasic ScienceMigraine1
1CompletedTreatmentMigraine1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral100 mg/1
TabletOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8912210No2014-12-162031-11-10US flag
US10117836No2018-11-062035-01-30US flag
US9499545No2016-11-222031-11-10US flag
US9833448No2017-12-052031-11-10US flag
US8754096No2014-06-172032-07-19US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP3.07ChemAxon
pKa (Strongest Acidic)11.74ChemAxon
pKa (Strongest Basic)3.83ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area104.29 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity140.97 m3·mol-1ChemAxon
Polarizability53.78 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
Not Available

Targets

Drugtargets2
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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. Blumenfeld AM, Goadsby PJ, Dodick DW, Hutchinson S, Liu C, Finnegan M, Trugman JM, Szegedi A: Efficacy of ubrogepant based on prior exposure and response to triptans: A post hoc analysis. Headache. 2021 Mar;61(3):422-429. doi: 10.1111/head.14089. Epub 2021 Mar 22. [Article]
  2. FDA Approved Drug Products: Ubrelvy (ubrogepant) oral tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: Ubrelvy (ubrogepant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: Ubrelvy (ubrogepant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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: Ubrelvy (ubrogepant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: Ubrelvy (ubrogepant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Serotonin binding
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOA
Uniprot ID
P21397
Uniprot Name
Amine oxidase [flavin-containing] A
Molecular Weight
59681.27 Da
References
  1. FDA Approved Drug Products: Ubrelvy (ubrogepant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. FDA Approved Drug Products: Ubrelvy (ubrogepant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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
  1. FDA Approved Drug Products: Ubrelvy (ubrogepant) oral 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: Ubrelvy (ubrogepant) oral 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: Ubrelvy (ubrogepant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: Ubrelvy (ubrogepant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: Ubrelvy (ubrogepant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. FDA Approved Drug Products: Ubrelvy (ubrogepant) oral 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: Ubrelvy (ubrogepant) oral tablets [Link]

Drug created on May 20, 2019 15:15 / Updated on October 04, 2021 20:51