Identification

Summary

Atogepant is an oral CGRP antagonist used for the preventative therapy of episodic migraine headaches.

Brand Names
Qulipta
Generic Name
Atogepant
DrugBank Accession Number
DB16098
Background

Atogepant is an oral antagonist of calcitonin gene-related peptide (CGRP) receptors indicated for the prevention of episodic migraine headaches. It was developed by AbbVie and received FDA approval under the brand name Qulipta in September 2021.7 While its approval was predated by two other members of the same drug family, namely ubrogepant and rimegepant, these agents are indicated only for abortive migraine therapy - atogepant is novel in that it is the first and only oral CGRP antagonist approved for preventative use in migraine.7

In patients requiring preventative migraine therapy, current practice guidelines recommend the use of certain anti-epileptic medications (e.g. valproic acid or topiramate) or beta-blockers (e.g. propranolol), all of which can be associated with significant adverse effects.5 The "gepants" family of drugs, including atogepant, are comparatively well-tolerated1,6 and may provide a desirable treatment option for patients struggling with adverse reactions to other preventative therapies.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 603.525
Monoisotopic: 603.170508599
Chemical Formula
C29H23F6N5O3
Synonyms
  • Atogepant
External IDs
  • AGN-241689
  • MK-8031

Pharmacology

Indication

Atogepant is indicated for the prevention of episodic migraine in adults.6

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Atogepant helps to prevent migraine headaches by antagonizing the activity of a pronociceptive molecule (CGRP) which has been implicated in migraine pathophysiology.6 Intended for preventative use, rather than abortive migraine therapy, atogepant is administered once daily.6

While no dose adjustments are required for patients with mild or moderate hepatic impairment, atogepant should be avoided in patients with severe hepatic impairment. Similarly, no dose adjustments are required for patients with mild or moderate renal impairment, but patients with severe renal impairment should be limited to a maximum daily dose of 10mg.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.1 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).1 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).1

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.2

Atogepant is an antagonist of the calcitonin gene-related peptide receptor6 - it competes with CGRP for occupancy at these receptors, preventing the actions of CGRP and its ability to induce and perpetuate migraine headache pain.

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

The time to peak plasma concentration following oral administration is approximately 2-3 hours.6 Atogepant displays dose-proportional pharmacokinetics up to approximately 3-fold its recommended maximum dosage, and its pharmacokinetics are not significantly influenced by co-administration with food.6

Volume of distribution

The mean apparent volume of distribution of atogepant is 292 L.6

Protein binding

Atogepant is extensively (~95.3%) protein-bound in plasma.6

Metabolism

The metabolism of atogepant is mediated primarily via CYP3A4.6 The most prevalent circulating compounds in plasma are atogepant itself and a glucuronide conjugate metabolite (M23),6 comprising approximately 75% and 15% of the administered dose, respectively,3 with at least 10 other metabolites detected in feces representing <10% of the administered dose.

Route of elimination

The elimination of atogepant occurs primarily via metabolism by CYP3A4.6 Following a single oral dose of radiolabeled atogepant to healthy male subjects, 42% of the administered dose was recovered as unchanged parent drug in the feces and 5% as unchanged parent drug in the urine.6 In total, approximately 81% of the radioactivity was recovered in the feces, with only 8% recovered in the urine.3

Half-life

The elimination half-life of atogepant following oral administration is approximately 11 hours.6

Clearance

The mean apparent oral clearance of atogepant is approximately 19 L/h.6

Adverse Effects
Adverseeffects
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Toxicity

There are no data regarding overdosage with atogepant. Symptoms of atogepant overdose are likely to be consistent with its adverse effect profile and may therefore include significant gastrointestinal effects, such as nausea and constipation, as well as fatigue and somnolence.6 A single oral dose of 300mg (5x the maximum recommended dose) did not result in any serious adverse events and did not appear to impact cardiac function.4

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 Atogepant can be increased when it is combined with Abametapir.
AbirateroneThe metabolism of Atogepant can be decreased when combined with Abiraterone.
AcetylcysteineThe serum concentration of Atogepant can be increased when it is combined with Acetylcysteine.
Aminohippuric acidThe serum concentration of Atogepant can be increased when it is combined with Aminohippuric acid.
AmiodaroneThe serum concentration of Atogepant can be increased when it is combined with Amiodarone.
AmprenavirThe serum concentration of Atogepant can be increased when it is combined with Amprenavir.
ApalutamideThe serum concentration of Atogepant can be decreased when it is combined with Apalutamide.
AprepitantThe metabolism of Atogepant can be decreased when combined with Aprepitant.
AsunaprevirThe serum concentration of Atogepant can be increased when it is combined with Asunaprevir.
AtalurenThe serum concentration of Atogepant can be increased when it is combined with Ataluren.
Interactions
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Food Interactions
  • Take with or without food. Co-administration with food does not affect the pharmacokinetics of atogepant to a clinically significant extent.

Products

Products2
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International/Other Brands
Qulipta (AbbVie)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
QuliptaTablet30 mg/1OralAbbVie Inc.2021-09-30Not applicableUS flag
QuliptaTablet10 mg/1OralAbbVie Inc.2021-09-30Not applicableUS flag
QuliptaTablet60 mg/1OralAbbVie Inc.2021-09-30Not applicableUS flag

Categories

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

Chemical Identifiers

UNII
7CRV8RR151
CAS number
1374248-81-3
InChI Key
QIVUCLWGARAQIO-OLIXTKCUSA-N
InChI
InChI=1S/C29H23F6N5O3/c1-13-16(22-18(30)4-5-19(31)23(22)32)8-20(26(42)40(13)12-29(33,34)35)38-25(41)15-7-14-9-28(10-21(14)37-11-15)17-3-2-6-36-24(17)39-27(28)43/h2-7,11,13,16,20H,8-10,12H2,1H3,(H,38,41)(H,36,39,43)/t13-,16-,20+,28+/m1/s1
IUPAC Name
(6S)-N-[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)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=C4C=CC=N2)C(=O)N1CC(F)(F)F)C1=C(F)C(F)=CC=C1F

References

General References
  1. 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]
  2. 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]
  3. Rowe J, Chan H, Chandrasekar P, Rojo J, Boinpally R: Mass Balance and Metabolism of Carbon-14 Atogepant in Healthy Male Participants. Neurology. 2021 April 13;96(15):Supplement 1425. [Article]
  4. Boinpally R, McNamee B, Yao L, Butler M, McGeeney D, Borbridge L, Periclou A: A Single Supratherapeutic Dose of Atogepant Does Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized, Single-Dose, Phase 1 Crossover Trial. Clin Pharmacol Drug Dev. 2021 Sep;10(9):1099-1107. doi: 10.1002/cpdd.940. Epub 2021 May 4. [Article]
  5. Ha H, Gonzalez A: Migraine Headache Prophylaxis. Am Fam Physician. 2019 Jan 1;99(1):17-24. [Article]
  6. FDA Approved Drug Products: Qulipta (atogepant) tablets for oral use [Link]
  7. PR Newswire: FDA Approves QULIPTA™ (atogepant), the First and Only Oral CGRP Receptor Antagonist Specifically Developed for the Preventive Treatment of Migraine [Link]
ChemSpider
59718640
RxNav
2571813
ChEMBL
CHEMBL3991065
Wikipedia
Atogepant

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentChronic Migraine / Coronavirus Disease 2019 (COVID‑19)1
3CompletedPreventionEpisodic Migraine1
3CompletedTreatmentChronic Migraine1
3CompletedTreatmentEpisodic Migraine2
3Enrolling by InvitationPreventionChronic Migraine1
3Enrolling by InvitationTreatmentChronic Migraine / Episodic Migraine1
3RecruitingTreatmentChronic Migraine / Episodic Migraine1
3RecruitingTreatmentEpisodic Migraine1
2, 3CompletedPreventionMigraine Headache, With or Without Aura1
1CompletedTreatmentMigraine1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral10 mg/1
TabletOral30 mg/1
TabletOral60 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityPractically insoluble in waterhttps://www.rxabbvie.com/pdf/qulipta_pi.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.0263 mg/mLALOGPS
logP3.62ALOGPS
logP3.5ChemAxon
logS-4.4ALOGPS
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
Refractivity141.62 m3·mol-1ChemAxon
Polarizability53.45 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. FDA Approved Drug Products: Qulipta (atogepant) tablets for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
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: Qulipta (atogepant) tablets for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
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: Qulipta (atogepant) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
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: Qulipta (atogepant) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
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: Qulipta (atogepant) tablets for oral use [Link]
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. FDA Approved Drug Products: Qulipta (atogepant) tablets for oral use [Link]
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. FDA Approved Drug Products: Qulipta (atogepant) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. FDA Approved Drug Products: Qulipta (atogepant) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
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: Qulipta (atogepant) tablets for oral use [Link]

Drug created at December 15, 2020 18:05 / Updated at October 23, 2021 07:17