Zavegepant

Identification

Summary

Zavegepant is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura.

Brand Names
Zavzpret
Generic Name
Zavegepant
DrugBank Accession Number
DB15688
Background

Zavegepant (BHV-3500) is a calcitonin gene-related peptide (CGRP) receptor antagonist.5 CGRP is released from sensory nerves and acts as a strong vasodilator, and thanks to these properties, it is involved in pain pathways. CGRP receptors are expressed in the central and peripheral nervous system; however, CGRP does not cross the blood-brain barrier, suggesting that it acts on peripheral nerves. In migraine, CGRP innervates pain-producing meningeal blood vessels and is released by trigeminal nerve stimulation. Since they inhibit these mechanisms and desensitize neuronal circuits, the use of CGRP receptor antagonists is beneficial in the treatment of migraine.2

Small molecule CGRP antagonists are also known as "gepants", and this category includes other drugs such as rimegepant and ubrogepant. Zavegepant is a third-generation CGRP receptor antagonist that is small in size and highly soluble. Due to its pharmacological properties, it can be administered intranasally.1,2 In March 2023, the FDA approved the use of zavegepant nasal spray for the acute treatment of migraine with or without aura in adults.5,6 A clinical trial (NCT04804033) is currently investigating the efficacy and safety of oral zavegepant in migraine prevention, and another one (NCT04987944) is evaluating the safety and efficacy of oral zavegepant (150 mg bid) in subjects with mild allergic asthma.3

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 638.817
Monoisotopic: 638.369287373
Chemical Formula
C36H46N8O3
Synonyms
  • 1-piperidinecarboxamide, 4-(1,2-dihydro-2-oxo-3-quinolinyl)-n-((1r)-1-((7-methyl-1h-indazol-5-yl)methyl)-2-(4-(1-methyl-4-piperidinyl)-1-piperazinyl)-2-oxoethyl)-
  • Vazegepant
  • Zavegepant
External IDs
  • BHV-3500
  • BMS-742413
  • BMS-742413-01

Pharmacology

Indication

Zavegepant in a nasal spray form is indicated for the acute treatment of migraine with or without aura in adults. It is not indicated for the preventive treatment of migraine.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAcute migraine••••••••••••••••••••• •• ••••••• •••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

The relationship between the pharmacodynamic activity of zavegepant and its mechanism of action is unclear. No clinically relevant differences were detected when comparing the resting blood pressure of healthy volunteers given sumatriptan and zavegepant concomitantly to those given sumatriptan alone. Using zavegepant leads to a clinically relevant QT interval prolongation at a dose up to 4 times the recommended daily dose.5 The use of zavegepant may cause hypersensitivity reactions, such as facial swelling and urticaria. If a hypersensitivity reaction occurs, the product label recommends discontinuing zavegepant and initiating appropriate therapy.5

Mechanism of action

Zavegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist used for the acute treatment of migraine.5 The pathophysiology of migraine has not been fully elucidated; however, specific vasoactive substances and neurotransmitters such as CGRP, neurokinin A, nitric oxide, and substance P may participate in the neurovascular and cortical spreading depression mechanisms.1 In acute migraine, the release of CGRP increases vasodilation and modulates neuronal excitability, which facilitates pain responses in structures for migraine pain transmission, such as the trigeminal system.4 Therefore, CGRP receptor antagonists such as zavegepant inhibit vasodilation mechanisms and desensitize neuronal circuits.2

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

After a single intranasal dose of zavegepant (10 mg), the peak plasma concentration was detected approximately 30 minutes later. The absolute bioavailability of zavegepant administered with a nasal spray is approximately 5%. Up to 40 mg (4 times the recommended dose of 10 mg), a single intranasal dose of zavegepant has slightly less than dose-proportional pharmacokinetics. There was no evidence of zavegepant accumulation with once-a-day zavegepant taken for 14 days.5

Compared to normal subjects, patients with moderate hepatic impairment (Child-Pugh B) have a Cmax and AUC 16% and 1.9-fold higher, respectively; however, these changes are not expected to be clinically significant based on clinical safety experience and minimal accumulation of drug exposures. In subjects with estimated creatinine clearance (CLcr) greater or equal to 30 mL/min, the differences in zavegepant pharmacokinetics are not expected to be clinically significant. In patients with a CLcr from 15 to 29 mL/min, zavegepant exposure may increase.5

Volume of distribution

Intranasal zavegepant has a mean apparent volume of distribution of approximately 1774 L.5

Protein binding

Zavegepant has a plasma protein binding of approximately 90%.5

Metabolism

In vitro, zavegepant is mainly metabolized by CYP3A4, and by CYP2D6 to a lesser extent. After a single intravenous dose of [14C]-zavegepant (5 mg), approximately 90% of the circulating dose was unchanged zavegepant. None of the zavegepant metabolites detected in plasma were found at a proportion higher than 10% (no major metabolites).5

Route of elimination

Zavegepant is mainly excreted via the biliary/fecal route, while the renal route plays a minor role in its elimination. In healthy male subjects given a single dose of 5 mg [14C]-zavegepant intravenously, approximately 80% and 11% of the dose were recovered as unchanged zavegepant in feces and urine, respectively.5

Half-life

Following a 10 mg dose, intranasal zavegepant has an effective half-life of 6.55 hours.5

Clearance

Intranasal zavegepant has a mean apparent clearance of 266 L/h.5

Adverse Effects
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Toxicity

Toxicity information regarding zavegepant is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as serious hypersensitivity reaction occurs.5 Symptomatic and supportive measures are recommended. The intranasal administration of zavegepant to transgenic mice carrying c-Ha-ras oncogenes (Tg-rasH2) at a maximum concentration of 2.5 mg/day up to 26 weeks did not lead to the development of drug-related tumors. The same results were obtained when rats were given up to 18.8 mg/kg/day of intranasal zavegepant for up to 96 weeks, reaching a plasma exposure 140 times the one in humans receiving the maximum recommended human dose (MRHD). In in vitro and in vivo mutagenesis assays, zavegepant showed negative results. Male and female rats given up to 25 mg/kg/day of zavegepant subcutaneously before and during mating and up to gestation day 7 in females did not present adverse effects on fertility or reproductive performance. Plasma exposure was equivalent to 2800 times the one in humans given the MRHD.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
AsunaprevirThe serum concentration of Zavegepant can be increased when it is combined with Asunaprevir.
AtalurenThe serum concentration of Zavegepant can be increased when it is combined with Ataluren.
AtazanavirThe serum concentration of Zavegepant can be increased when it is combined with Atazanavir.
Beclomethasone dipropionateThe serum concentration of Zavegepant can be increased when it is combined with Beclomethasone dipropionate.
Bempedoic acidThe serum concentration of Zavegepant can be increased when it is combined with Bempedoic acid.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Zavegepant hydrochloride000QCM6HAL1414976-20-7VQDUWCSSPSOSNA-RYWNGCACSA-N
International/Other Brands
Zavzpret (Pfizer)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZavzpretSpray10 mg/0.1mLNasalPfizer Laboratories Div Pfizer Inc2023-06-01Not applicableUS flag
ZavzpretSpray10 mg/0.1mLNasalU.S. Pharmaceuticals2023-06-01Not applicableUS flag

Categories

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

Chemical Identifiers

UNII
ODU3ZAZ94J
CAS number
1337918-83-8
InChI Key
JJVAPHYEOZSKJZ-JGCGQSQUSA-N
InChI
InChI=1S/C36H46N8O3/c1-24-19-25(20-28-23-37-40-33(24)28)21-32(35(46)43-17-15-42(16-18-43)29-9-11-41(2)12-10-29)39-36(47)44-13-7-26(8-14-44)30-22-27-5-3-4-6-31(27)38-34(30)45/h3-6,19-20,22-23,26,29,32H,7-18,21H2,1-2H3,(H,37,40)(H,38,45)(H,39,47)/t32-/m1/s1
IUPAC Name
N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide
SMILES
CN1CCC(CC1)N1CCN(CC1)C(=O)[C@@H](CC1=CC2=C(NN=C2)C(C)=C1)NC(=O)N1CCC(CC1)C1=CC2=C(NC1=O)C=CC=C2

References

Synthesis Reference

Coric, V., et al. (2022). Intranasal pharmaceutical compositions of CGRP inhibitors (U.S. Patent No. 2022/0401439 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/52/df/a1/7382d960813673/US20220401439A1.pdf

General References
  1. Rissardo JP, Caprara ALF: Gepants for Acute and Preventive Migraine Treatment: A Narrative Review. Brain Sci. 2022 Nov 24;12(12):1612. doi: 10.3390/brainsci12121612. [Article]
  2. Noor N, Angelette A, Lawson A, Patel A, Urits I, Viswanath O, Yazdi C, Kaye AD: A Comprehensive Review of Zavegepant as Abortive Treatment for Migraine. Health Psychol Res. 2022 Jun 28;10(3):35506. doi: 10.52965/001c.35506. eCollection 2022. [Article]
  3. Altamura C, Brunelli N, Marcosano M, Fofi L, Vernieri F: Gepants - a long way to cure: a narrative review. Neurol Sci. 2022 Sep;43(9):5697-5708. doi: 10.1007/s10072-022-06184-8. Epub 2022 Jun 2. [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: ZAVZPRET (zavegepant) nasal spray (March 2023) [Link]
  6. BioSpace: Pfizer’s Biohaven Bet Pays Off Again as Migraine Nasal Spray Wins Approval [Link]
ChemSpider
30814207
BindingDB
50436107
RxNav
2637955
ChEMBL
CHEMBL2397415
ZINC
ZINC000096271995
Wikipedia
Zavegepant

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentMigraine1
3Not Yet RecruitingTreatmentMigraine1
3RecruitingTreatmentMigraine1
2, 3CompletedTreatmentAcute Migraine1
2, 3CompletedTreatmentMigraine1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SprayNasal10 mg/0.1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7220862No2007-05-222024-01-21US flag
US7314883No2008-01-012023-12-05US flag
US8481546No2013-07-092031-10-07US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityFreely solubleFDA label
Predicted Properties
PropertyValueSource
Water Solubility0.0696 mg/mLALOGPS
logP2.85ALOGPS
logP2.14Chemaxon
logS-4ALOGPS
pKa (Strongest Acidic)12.38Chemaxon
pKa (Strongest Basic)8.81Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area116.91 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity186.53 m3·mol-1Chemaxon
Polarizability71.32 Å3Chemaxon
Number of Rings7Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
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/MSsplash10-000i-0000009000-c933641a930ac3b50cd2
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-0000009000-b1344f06cd2ebc7975fc
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-3103009000-94305e8c9976a73e6fba
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-05q0-0098608000-8da204d0c247fa7bc775
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-052k-3982016000-81d96c15d67288188a60
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-03dr-0944434000-a3eebef6b98e9984f8f7
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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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. Mercer SE, Chaturvedula PV, Conway CM, Cook DA, Davis CD, Pin SS, Macci R, Schartman R, Signor LJ, Widmann KA, Whiterock VJ, Chen P, Xu C, Herbst JJ, Kostich WA, Thalody G, Macor JE, Dubowchik GM: Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists. Bioorg Med Chem Lett. 2021 Jan 1;31:127624. doi: 10.1016/j.bmcl.2020.127624. Epub 2020 Oct 21. [Article]
  2. Noor N, Angelette A, Lawson A, Patel A, Urits I, Viswanath O, Yazdi C, Kaye AD: A Comprehensive Review of Zavegepant as Abortive Treatment for Migraine. Health Psychol Res. 2022 Jun 28;10(3):35506. doi: 10.52965/001c.35506. eCollection 2022. [Article]
  3. Practical Neurology: Vazegepant, Investigational Drug Being Studied for Migraine, to Enter Phase 2 Trial for COVID-19 Treatment [Link]
  4. FDA Approved Drug Products: ZAVZPRET (zavegepant) nasal spray (March 2023) [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: ZAVZPRET (zavegepant) nasal spray (March 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: ZAVZPRET (zavegepant) nasal spray (March 2023) [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: ZAVZPRET (zavegepant) nasal spray (March 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Virus receptor activity
Specific Function
The hepatic sodium/bile acid uptake system exhibits broad substrate specificity and transports various non-bile acid organic compounds as well. It is strictly dependent on the extracellular presenc...
Gene Name
SLC10A1
Uniprot ID
Q14973
Uniprot Name
Sodium/bile acid cotransporter
Molecular Weight
38118.64 Da
References
  1. FDA Approved Drug Products: ZAVZPRET (zavegepant) nasal spray (March 2023) [Link]
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: ZAVZPRET (zavegepant) nasal spray (March 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. FDA Approved Drug Products: ZAVZPRET (zavegepant) nasal spray (March 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. FDA Approved Drug Products: ZAVZPRET (zavegepant) nasal spray (March 2023) [Link]

Drug created at May 21, 2020 14:18 / Updated at November 01, 2023 05:14