Lasmiditan

Identification

Summary

Lasmiditan is an oral 5HT1F agonist used for the acute treatment of migraine headache with or without aura.

Brand Names

Reyvow

Generic Name

Lasmiditan

DrugBank Accession Number

DB11732

Background

Lasmiditan is an oral medication used in the termination of migraine headaches that was first approved for use in the United States in October 2019.^7,9 It was also approved by the European Commission on August 17, 2022.¹²

Traditionally, the triptan class of anti-migraine medications (e.g. sumatriptan) have seen preferential use in the acute treatment of migraines due to their relatively favourable efficacy and safety. Their use is not devoid of concerns, however, and their vasoconstrictive activity can lead to blood pressure lability and other cardiovascular side effects - for this reason, these medications are less suitable for use in patients with pre-existing cardiovascular disorders.⁴ Triptans abort migraines via action at several serotonin receptors, including 5-HT_1D and 5-HT_1B receptors, and activity at the 5-HT_1B receptor has been specifically implicated in their vasoconstrictive activity.^4,6

Lasmiditan, in contrast, is a highly selective agonist of 5-HT_1F receptors, carrying virtually no affinity for other receptors which appear to be largely responsible for the adverse effect profile of its predecessors - in other words, lasmiditan’s selectivity allows for the successful termination of migraines without causing vasoconstriction.^6,5 Selectivity for 5-HT_1F, a lack of vasoconstrictive activity, and the ability to terminate migraines through neuronal inhibition has resulted in the creation of a new class of anti-migraine medications in which lasmiditan is the first and only member: the neurally-acting anti-migraine medications (NAAMAs).^6,1

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Lasmiditan (DB11732)

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Weight

Average: 377.367
Monoisotopic: 377.135111321

Chemical Formula

C₁₉H₁₈F₃N₃O₂

Synonyms

• Lasmiditan

External IDs

• COL 144
• COL-144

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Pharmacology

Indication

Lasmiditan is indicated for the acute treatment of migraine with or without aura in adults.^7,11

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Symptomatic treatment of	Migraine with or without aura		••••••••••••	•••••		••••••

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Pharmacodynamics

Lasmiditan belongs to a new and novel class of acute anti-migraine medications that exert their effects via inhibition of neuronal firing rather than vasoconstriction of cerebral arteries.² Lasmiditan appears to have a relatively quick onset of action (an important characteristic in acute migraine treatment) with some patients reporting benefit within 20 minutes.⁶ Due to its ability to cause CNS depression (e.g. drowsiness, dizziness), lasmiditan may cause significant driving impairment and patients should be advised not to participate in activities requiring mental alertness for at least 8 hours after dosing.⁷ Lasmiditan may carry some potential for abuse and should be used with caution in patients who may be at risk of drug abuse - its controlled substance scheduling is currently under review in the United States by the Drug Enforcement Administration (DEA).⁷

The safety of lasmiditan in pregnancy is unknown and is currently being monitored with a pregnancy exposure registry created by Eli Lilly and Company.^7,10

Mechanism of action

The acute treatment of migraine headaches has, in the past, been achieved via constriction of cerebral blood vessels, as the acute dilation of these vessels observed during migraines was thought to be the cause of the associated pain.² The neurogenic hypothesis of migraine pathophysiology, an alternative to the vascular hypothesis, suggests that cerebral vasodilation is a secondary mechanism in migraine pathogenesis, and that the main contributor to migraine headache pain is the increased pathogenic firing of trigeminal nerve pathways.^2,6

While the precise mechanism of action of lasmiditan is unclear, it likely supports this neurogenic hypothesis by exerting its therapeutic effects through potent and selective agonism of the 5-HT_1F receptor.⁷ 5-HT_1F receptors are found in both the central and peripheral nervous system (on the central and peripheral ends of trigeminal neurons) and appear to contribute to hyperpolarization of nerve terminals and inhibition of trigeminal neuronal activity.^1,4 Lasmiditan's agonism at these receptors may, therefore, inhibit the firing of trigeminal nerves responsible for migraine headache pain.

Lasmiditan has virtually no affinity for other 5-HT receptor subtypes or monoamine receptors (e.g. adrenergic, dopaminergic).^1,2,6

Target	Actions	Organism
A5-hydroxytryptamine receptor 1F	agonist	Humans

Absorption

Oral absorption of lasmiditan is quick, with a median t_max of 1.8 hours.⁷ An open-label study looking at absorption pharmacokinetics found the C_max and AUC_0-t of lasmiditan following oral administration to be 322.8 ± 122.0 ng/mL and 1892 ± 746.0 ng.h/mL, respectively.¹ The oral bioavailability of lasmiditan has been reported as approximately 40%.⁴

Co-administration of lasmiditan with a high-fat meal increased its C_max and AUC by 22% and 19%, respectively, and delayed T_max by approximately 1 hour - these differences in absorption are relatively minor and unlikely to be clinically significant.⁷ Similarly, severe renal impairment and mild-moderate hepatic impairment were found to increase both AUC and C_max, but not to a clinically significant extent.⁷

Volume of distribution

Lasmiditan has been shown to penetrate the blood-brain barrier.¹

Protein binding

Lasmiditan exhibits a concentration-independent plasma protein binding of approximately 55-60%.⁷

Metabolism

The hepatic and extra-hepatic metabolism of lasmiditan is catalyzed primarily by non-CYP enzymes, with ketone reduction appearing to be the primary pathway.⁷ While the specific enzymes involved in the metabolism of lasmiditan have not been elucidated, FDA labeling states that the following enzymes are not involved in its metabolism: monoamine oxidases, CYP450 reductase, xanthine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase, and aldo-keto reductases.⁷ The metabolites of lasmiditan have not been characterized in published research, but two of its metabolites (M7 and M18) are considered to be pharmacologically inactive.⁷

Route of elimination

Lasmiditan is eliminated primarily via metabolism,⁷ with renal excretion accounting for a small fraction of its total elimination. Of the small amount of drug found in the urine post-dose, approximately 66% is comprised of lasmiditan's S-M8 metabolite. Only 3% of an administered dose of lasmiditan was recovered unchanged in the urine,⁷ further implying a relatively extensive metabolism of this drug.

Half-life

The mean elimination half-life of lasmiditan is 5.7 hours.⁷

Clearance

Not Available

Adverse Effects

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Toxicity

Data regarding overdose of lasmiditan is currently unavailable. Non-clinical murine toxicology studies revealed no evidence of carcinogenesis, mutagenesis, or impairment of fertility⁷ at plasma concentrations well above those seen in humans.

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

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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1,2-Benzodiazepine	The risk or severity of adverse effects can be increased when Lasmiditan is combined with 1,2-Benzodiazepine.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Lasmiditan.
Abrocitinib	The serum concentration of Lasmiditan can be increased when it is combined with Abrocitinib.
Acebutolol	Lasmiditan may increase the bradycardic activities of Acebutolol.
Acetazolamide	The risk or severity of adverse effects can be increased when Lasmiditan is combined with Acetazolamide.

Food Interactions

• Avoid alcohol.
• Take with or without food. Co-administration with food slightly alters pharmacokinetics, but not to a clinically significant extent.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Lasmiditan succinate	W64YBJ346B	439239-92-6	MSOIHUHNGPOCTH-UHFFFAOYSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
1 Rayvow	Tablet, film coated	50 mg	Oral	Eli Lilly Nederland B.V.	2022-12-02	Not applicable
1 Rayvow	Tablet, film coated	100 mg	Oral	Eli Lilly Nederland B.V.	2022-12-02	Not applicable
1 Rayvow	Tablet, film coated	50 mg	Oral	Eli Lilly Nederland B.V.	2022-12-02	Not applicable
1 Rayvow	Tablet, film coated	100 mg	Oral	Eli Lilly Nederland B.V.	2022-12-02	Not applicable
1 Rayvow	Tablet, film coated	50 mg	Oral	Eli Lilly Nederland B.V.	2022-12-02	Not applicable

Categories

ATC Codes

N02CC08 — Lasmiditan

• N02CC — Selective serotonin (5HT1) agonists
• N02C — ANTIMIGRAINE PREPARATIONS
• N02 — ANALGESICS
• N — NERVOUS SYSTEM

Drug Categories

• Amides
• Analgesics
• Antidepressive Agents
• Antimigraine Preparations
• BCRP/ABCG2 Inhibitors
• Central Nervous System Depressants
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
• Cytochrome P-450 Enzyme Inhibitors
• MATE 1 Inhibitors
• MATE 2 Inhibitors
• MATE inhibitors
• Nervous System
• Neurotransmitter Agents
• OCT1 inhibitors
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
• Serotonin (5-HT) 1F Receptor Agonists
• Serotonin Agents

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as 4-halobenzoic acids and derivatives. These are benzoic acids or derivatives carrying a halogen atom at the 4-position of the benzene ring.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Benzoic acids and derivatives

Direct Parent

4-halobenzoic acids and derivatives

Alternative Parents

2-halobenzoic acids and derivatives / Benzamides / Aryl alkyl ketones / Benzoyl derivatives / Fluorobenzenes / Aryl fluorides / Pyridines and derivatives / Piperidines / Gamma-amino ketones / Imidolactams / Heteroaromatic compounds / Vinylogous halides / Trialkylamines / Amino acids and derivatives / Secondary carboxylic acid amides / Azacyclic compounds / Hydrocarbon derivatives / Organic oxides / Organofluorides / Organopnictogen compounds

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Substituents

2-halobenzoic acid or derivatives / 4-halobenzoic acid or derivatives / Amine / Amino acid or derivatives / Aromatic heteromonocyclic compound / Aryl alkyl ketone / Aryl fluoride / Aryl halide / Aryl ketone / Azacycle / Benzamide / Benzoyl / Carboxamide group / Carboxylic acid derivative / Fluorobenzene / Gamma-aminoketone / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Imidolactam / Ketone / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Piperidine / Pyridine / Secondary carboxylic acid amide / Tertiary aliphatic amine / Tertiary amine / Vinylogous halide

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Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

760I9WM792

CAS number

439239-90-4

InChI Key

XEDHVZKDSYZQBF-UHFFFAOYSA-N

InChI

InChI=1S/C19H18F3N3O2/c1-25-7-5-11(6-8-25)18(26)15-3-2-4-16(23-15)24-19(27)17-13(21)9-12(20)10-14(17)22/h2-4,9-11H,5-8H2,1H3,(H,23,24,27)

IUPAC Name

2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide

SMILES

CN1CCC(CC1)C(=O)C1=CC=CC(NC(=O)C2=C(F)C=C(F)C=C2F)=N1

References

General References

1. Capi M, de Andres F, Lionetto L, Gentile G, Cipolla F, Negro A, Borro M, Martelletti P, Curto M: Lasmiditan for the treatment of migraine. Expert Opin Investig Drugs. 2017 Feb;26(2):227-234. doi: 10.1080/13543784.2017.1280457. [Article]
2. Nelson DL, Phebus LA, Johnson KW, Wainscott DB, Cohen ML, Calligaro DO, Xu YC: Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia. 2010 Oct;30(10):1159-69. doi: 10.1177/0333102410370873. Epub 2010 Jun 15. [Article]
3. Lupi C, Benemei S, Guerzoni S, Pellesi L, Negro A: Pharmacokinetics and pharmacodynamics of new acute treatments for migraine. Expert Opin Drug Metab Toxicol. 2019 Mar;15(3):189-198. doi: 10.1080/17425255.2019.1578749. Epub 2019 Feb 12. [Article]
4. Vila-Pueyo M: Targeted 5-HT1F Therapies for Migraine. Neurotherapeutics. 2018 Apr;15(2):291-303. doi: 10.1007/s13311-018-0615-6. [Article]
5. Rubio-Beltran E, Labastida-Ramirez A, Haanes KA, van den Bogaerdt A, Bogers AJJC, Zanelli E, Meeus L, Danser AHJ, Gralinski MR, Senese PB, Johnson KW, Kovalchin J, Villalon CM, MaassenVanDenBrink A: Characterization of binding, functional activity and contractile responses of the selective 5-HT1F receptor agonist lasmiditan. Br J Pharmacol. 2019 Aug 16. doi: 10.1111/bph.14832. [Article]
6. Reuter U, Israel H, Neeb L: The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine. Ther Adv Neurol Disord. 2015 Jan;8(1):46-54. doi: 10.1177/1756285614562419. [Article]
7. FDA Approved Drugs: Reyvow (lasmiditan) tablets for oral use [Link]
8. AChemBlock: Lasmiditan hemisuccinate MSDS [Link]
9. FDA News Release: Lasmiditan Approval [Link]
10. Migraine Pregnancy Registry [Link]
11. EMA Approved Drug Products: Rayvow (lasmiditan) Oral Tablets [Link]
12. EMA Medicines Overview: Rayvow (lasmiditan) [Link]

External Links

Human Metabolome Database

HMDB0304879

PubChem Compound

11610526

PubChem Substance

347828091

ChemSpider

9785281

RxNav

2256930

ChEMBL

CHEMBL3039520

ZINC

ZINC000003818355

PDBe Ligand

05X

Wikipedia

Lasmiditan

PDB Entries

7exd

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
3	Completed	Treatment	Acute Migraine	2
3	Completed	Treatment	Migraine	2
3	Completed	Treatment	Migraine Headache, With or Without Aura	1
3	Recruiting	Treatment	Migraine	2
2	Completed	Treatment	Migraine	3

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	100 mg
Tablet, film coated	Oral	200 mg
Tablet, film coated	Oral	50 mg
Tablet	Oral	100 mg/1
Tablet	Oral	200 mg/1
Tablet	Oral	50 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8748459	No	2014-06-10	2023-03-27
US7423050	No	2008-09-09	2025-04-06
US11053214	No	2021-07-06	2037-12-05

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0175 mg/mL	ALOGPS
logP	2.76	ALOGPS
logP	3.3	Chemaxon
logS	-4.3	ALOGPS
pKa (Strongest Acidic)	12.23	Chemaxon
pKa (Strongest Basic)	7.99	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	62.3 Å2	Chemaxon
Rotatable Bond Count	4	Chemaxon
Refractivity	96.15 m3·mol-1	Chemaxon
Polarizability	35.61 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	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	splash10-004i-0009000000-11d02cfc6ea7cda141d0
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-1039000000-6121f83b5344bff1cee3
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-03di-0009000000-d7606286a6d12dfd55db
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0690-0279000000-39749172230ce9c7e084
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-03di-2839000000-32ff415a0119ee4fad3a
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0005-2911000000-3c058329d33fbc26b2a6
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	189.14946	predicted	DeepCCS 1.0 (2019)
[M+H]+	191.56987	predicted	DeepCCS 1.0 (2019)
[M+Na]+	198.73103	predicted	DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.

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Details1. 5-hydroxytryptamine receptor 1F

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

General Function

Serotonin receptor activity

Specific Function

G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various alkaloids and psychoactive substances. Ligand binding causes a conformation change that trig...

Gene Name

HTR1F

Uniprot ID

P30939

Uniprot Name

5-hydroxytryptamine receptor 1F

Molecular Weight

41708.505 Da

References

1. Reuter U, Israel H, Neeb L: The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine. Ther Adv Neurol Disord. 2015 Jan;8(1):46-54. doi: 10.1177/1756285614562419. [Article]
2. FDA Approved Drugs: Reyvow (lasmiditan) tablets for oral use [Link]

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Drug created at October 20, 2016 20:43 / Updated at December 01, 2022 11:26