Zavegepant

Identification

Summary

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

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

Investigational

Structure

3D

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Similar Structures

Structure for Zavegepant (DB15688)

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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

• Acute 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

Target	Actions	Organism
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 C_max 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.

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• Withdrawn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

Drug	Interaction
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Asunaprevir	The serum concentration of Zavegepant can be increased when it is combined with Asunaprevir.
Ataluren	The serum concentration of Zavegepant can be increased when it is combined with Ataluren.
Atazanavir	The serum concentration of Zavegepant can be increased when it is combined with Atazanavir.
Beclomethasone dipropionate	The serum concentration of Zavegepant can be increased when it is combined with Beclomethasone dipropionate.
Bempedoic acid	The serum concentration of Zavegepant can be increased when it is combined with Bempedoic acid.
Cabazitaxel	The serum concentration of Zavegepant can be increased when it is combined with Cabazitaxel.
Clarithromycin	The serum concentration of Zavegepant can be increased when it is combined with Clarithromycin.
Cobicistat	The serum concentration of Zavegepant can be increased when it is combined with Cobicistat.
Cobimetinib	The serum concentration of Zavegepant can be increased when it is combined with Cobimetinib.
Cyclosporine	The serum concentration of Zavegepant can be increased when it is combined with Cyclosporine.

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Food Interactions

No interactions found.

Products

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International/Other Brands

Zavzpret (Pfizer)

Categories

Drug Categories

• Antimigraine Preparations
• Calcitonin Gene-Related Peptide (CGRP) Antagonists
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Experimental Unapproved Treatments for COVID-19
• Heterocyclic Compounds, Fused-Ring
• MATE 1 Substrates
• MATE substrates
• Nasal Preparations
• OATP1B3 substrates
• P-glycoprotein substrates
• Pyrazoles
• Quinolines
• Receptors, Calcitonin Gene-Related Peptide, antagonists & inhibitors

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]

External Links

ChemSpider

30814207

BindingDB

50436107

ChEMBL

CHEMBL2397415

ZINC

ZINC000096271995

Wikipedia

Zavegepant

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2, 3	Completed	Treatment	Migraine	1
2, 3	Recruiting	Prevention	Migraine	1
2, 3	Terminated	Treatment	Coronavirus Disease 2019 (COVID‑19) / Covid 19 Infection	1
1	Completed	Treatment	Asthma	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Not Available

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Freely soluble	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.0696 mg/mL	ALOGPS
logP	2.85	ALOGPS
logP	2.14	Chemaxon
logS	-4	ALOGPS
pKa (Strongest Acidic)	12.38	Chemaxon
pKa (Strongest Basic)	8.81	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	116.91 Å2	Chemaxon
Rotatable Bond Count	6	Chemaxon
Refractivity	186.53 m3·mol-1	Chemaxon
Polarizability	71.32 Å3	Chemaxon
Number of Rings	7	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

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. 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]

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Drug created at May 21, 2020 14:18 / Updated at March 14, 2023 09:13