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Name
Lasmiditan
Accession Number
DB11732
Type
Small Molecule
Groups
Approved, Investigational
Description

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

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-HT1D and 5-HT1B receptors, and activity at the 5-HT1B receptor has been specifically implicated in their vasoconstrictive activity.4,6

Lasmiditan, in contrast, is a highly selective agonist of 5-HT1F 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-HT1F, 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

Structure
Thumb
Synonyms
  • Lasmiditan
External IDs
COL 144 / COL-144
Product Ingredients
IngredientUNIICASInChI Key
Lasmiditan succinateW64YBJ346B439239-92-6MSOIHUHNGPOCTH-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ReyvowTablet100 mg/1OralEli Lilly and Company2019-10-11Not applicableUs
ReyvowTablet50 mg/1OralEli Lilly and Company2019-10-11Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
760I9WM792
CAS number
439239-90-4
Weight
Average: 377.367
Monoisotopic: 377.135111321
Chemical Formula
C19H18F3N3O2
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

Pharmacology

Indication

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

Associated Conditions
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

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-HT1F receptor.7 5-HT1F 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

TargetActionsOrganism
A5-hydroxytryptamine receptor 1F
agonist
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

Oral absorption of lasmiditan is quick, with a median tmax of 1.8 hours.7 An open-label study looking at absorption pharmacokinetics found the Cmax and AUC0-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 Cmax and AUC by 22% and 19%, respectively, and delayed Tmax 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 Cmax, 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
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.

Affected organisms
Not Available
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
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when Lasmiditan is combined with 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of serotonin syndrome can be increased when Lasmiditan is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of serotonin syndrome can be increased when Lasmiditan is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Lasmiditan is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of serotonin syndrome can be increased when Lasmiditan is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Lasmiditan is combined with 7-Nitroindazole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of serotonin syndrome can be increased when Lasmiditan is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Lasmiditan.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Lasmiditan.
AcepromazineThe risk or severity of adverse effects can be increased when Lasmiditan is combined with Acepromazine.
Additional Data Available
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  • Severity
    Severity

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  • Evidence Level
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Food Interactions
Not Available

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. [PubMed:28076702]
  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. [PubMed:20855361]
  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. [PubMed:30714429]
  4. Vila-Pueyo M: Targeted 5-HT1F Therapies for Migraine. Neurotherapeutics. 2018 Apr;15(2):291-303. doi: 10.1007/s13311-018-0615-6. [PubMed:29488143]
  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. [PubMed:31418454]
  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. [PubMed:25584073]
  7. FDA Approved Drugs: Reyvow [Link]
  8. AChemBlock: Lasmiditan hemisuccinate MSDS [Link]
  9. FDA News Release: Lasmiditan Approval [Link]
External Links
PubChem Compound
11610526
PubChem Substance
347828091
ChemSpider
9785281
ChEMBL
CHEMBL3039520
Wikipedia
Lasmiditan

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceAcute Treatment of Migraine / Migraine1
1CompletedBasic ScienceBioavailability Under Fed and Fasted Conditions / Healthy Volunteers1
1CompletedBasic ScienceHealthy Volunteers9
1CompletedBasic ScienceHealthy Volunteers / Pharmacokinetics1
1CompletedBasic ScienceMigraine2
1CompletedBasic ScienceMigraine Disorders1
1CompletedBasic SciencePrescription Drug Abuse (Not Dependent) / Recreational Drug Use1
1CompletedOtherMigraine1
1Not Yet RecruitingTreatmentHealthy Volunteers1
1RecruitingBasic ScienceHealthy Volunteers1
1RecruitingBasic ScienceMigraine1
2CompletedTreatmentMigraine1
2CompletedTreatmentMigraine Disorders1
2RecruitingTreatmentMigraine1
3CompletedTreatmentAcute Migraine1
3CompletedTreatmentAcute Migraine / Migraine With or Without Aura1
3CompletedTreatmentAcute Treatment of Migraine in Adults / Migraine Disorders1
3RecruitingTreatmentMigraine1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral100 mg/1
TabletOral50 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0175 mg/mLALOGPS
logP2.76ALOGPS
logP3.3ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)12.23ChemAxon
pKa (Strongest Basic)7.99ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area62.3 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity96.15 m3·mol-1ChemAxon
Polarizability35.61 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
show 10 more
Substituents
2-halobenzoic acid or derivatives / 4-halobenzoic acid or derivatives / Benzamide / Benzoyl / Aryl ketone / Aryl alkyl ketone / Fluorobenzene / Halobenzene / Aryl fluoride / Aryl halide
show 26 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

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. [PubMed:25584073]
  2. FDA Approved Drugs: Reyvow [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Lasmiditan was found to be an inhibitor of CYP2D6 in vitro, but subsequent in vivo interaction studies did not demonstrate a clinically significant inhibition of dextromethorphan metabolism, a recognized substrate of CYP2D6.
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 Drugs: Reyvow [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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 Drugs: Reyvow [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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 Drugs: Reyvow [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Lasmiditan appears to inhibit OCT1 transporters in vitro, but subsequent drug-drug interaction studies with sumatriptan, a substrate of OCT1, revealed no changes to sumatriptan pharmacokinetics.
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 Drugs: Reyvow [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Lasmiditan was found to inhibit MATE1 efflux transporters in vitro; the clinical significance of this inhibition in vivo is unclear.
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 Drugs: Reyvow [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Lasmiditan was found to inhibit MATE2 efflux transporters in vitro; the clinical significance of this inhibition in vivo is unclear.
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 Drugs: Reyvow [Link]

Drug created on October 20, 2016 14:43 / Updated on December 02, 2019 09:09