Serotonin 1F receptor/5HT1F
Serotonin 5-HT1F receptor. Lasmiditan is a high-affinity, selective agonist of the 5-HT1F receptor. It exhibits a Ki of 2.21 nM for the human 5-HT1F receptor. It demonstrates a high degree of selectivity over other 5-HT receptor subtypes, particularly showing a >470-fold selectivity for 5-HT1F over 5-HT1B and 5-HT1D receptors. Lasmiditan's metabolites are practically inactive at the 5-HT1F receptor and all other evaluated 5-HT subtypes.

In an in vitro vascular contraction assay using rabbit saphenous vein rings, Lasmiditan did not cause contraction at concentrations up to 100 μM, unlike the 5-HT\(_{1B/1D}\) agonist sumatriptan [2]
Lasmiditan possesses a unique pyridinoyl-piperidine scaffold, a structural class not shared by any other antimigraine therapy. Its distinct chemical structure and pharmacological profile clearly set it apart from the triptan family of drugs. The high potency and selectivity of lasmiditan make it an ideal pharmacological tool to definitively investigate the role of the 5-HT1F receptor in the treatment of migraine headaches. [1]
Lasmiditan potently inhibits forskolin-stimulated cAMP formation in cells expressing the human 5-HT1F receptor, with an EC50 of 3.74 nM. Its functional selectivity for the 5-HT1F receptor versus the vasoconstrictive 5-HT1B receptor is >2600-fold. In contrast to triptans, lasmiditan does not cause contraction in an in vitro vascular assay using rabbit saphenous vein rings at concentrations up to 100 μM. Lasmiditan shows higher selectivity for the 5-HT1F receptor relative to other 5-HT(1) receptor subtypes than the first-generation agonist LY334370.

In an intravenous, placebo-controlled Phase II clinical trial, migraine patients receiving Lasmiditan doses ranging from 2.5 to 45 mg showed a linear dose-response relationship for headache relief at 2 hours. For the 20 mg dose, the headache relief rate was 64%, compared to 45% for placebo (therapeutic gain 19%) [2].
In an oral, placebo-controlled Phase II trial, Lasmiditan at doses of 50, 100, 200, and 400 mg was superior to placebo for headache relief at 2 hours. For the 400 mg dose, the headache relief rate was 64% versus 25% for placebo (therapeutic gain 38%). The pain-free rate at 2 hours for the 400 mg dose was 28% [2].
In preclinical rodent models relevant to migraine (dural plasma extravasation and c-Fos induction in the trigeminal nucleus caudalis following trigeminal ganglion stimulation), oral administration of Lasmiditan potently inhibited these markers [2]
In vivo, lasmiditan is orally active in two preclinical models of migraine involving electrical stimulation of the trigeminal ganglion. After oral administration, it potently decreases dural plasma protein extravasation and reduces the number of c-fos positive cells in the trigeminal nucleus caudalis at a dose of 3 mg/kg. In a Phase II clinical trial, an intravenous dose of 20 mg resulted in a headache relief rate of 64%, compared to 45% for placebo. In an oral Phase II trial, doses of 50, 100, 200, and 400 mg were all superior to placebo for headache relief at 2 hours.

In vitro binding assays demonstrated that lasmiditan exhibits high affinity for the 5-HT1F receptor, with a Ki value of 2.21 nM, while showing substantially lower affinity for the 5-HT1B and 5-HT1D receptor subtypes (Ki values of 1043 nM and 1357 nM, respectively), representing a selectivity ratio of over 470-fold. Compared to the first-generation 5-HT1F receptor agonist LY334370, lasmiditan displayed superior selectivity for the 5-HT1F receptor relative to other 5-HT1 receptor family members. Notably, unlike the 5-HT1B/1D receptor agonist sumatriptan, lasmiditan did not induce contraction of rabbit saphenous vein rings—a surrogate model for human coronary artery constriction—even at concentrations up to 100 μM. In two preclinical rodent models of migraine, oral administration of lasmiditan potently suppressed markers associated with trigeminal ganglion electrical stimulation, including dural plasma protein extravasation and the induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis. [1]
In vitro receptor-binding studies are performed using cloned human 5-HT1F receptors and other 5-HT receptor subtypes. Radioligand binding assays are used to determine the affinity (Ki) of lasmiditan for these receptors. These studies have shown that lasmiditan has a Ki of 2.2 nM and 1.8 nM for the human 5-HT1F receptor in separate assays. The compound's affinity for cloned mouse, rat, rabbit, and dog 5-HT1F receptors is also assessed, with measured IC50 values of 1.29 nM, 3.32 nM, 1.57 nM, 13.3 nM, and 4.87 nM for human, respectively.

In vitro cellular assays are conducted to evaluate the functional activity of lasmiditan. In cultured cells expressing the human 5-HT1F receptor, the compound's ability to inhibit forskolin-stimulated cAMP formation is measured, yielding an EC50 of 3.74 nM. Functional selectivity is further assessed by comparing its effects at the 5-HT1F receptor to those at the 5-HT1B receptor. Another functional assay measures the EC50 for 5-HT1F-mediated stimulation of [35S]GTPγS binding to membrane G-proteins, which was found to be 43 nM.

For clinical trials: In the intravenous study, hospitalized patients with moderate or severe migraine were treated with a range of intravenous Lasmiditan doses (2.5–45 mg) or placebo [2].
In the oral study, outpatients with moderate or severe migraine were randomized to receive a single oral dose of Lasmiditan (50, 100, 200, or 400 mg) or placebo [2]
In vivo animal models used to assess lasmiditan's efficacy include electrical stimulation of the trigeminal ganglion in rodents. Following oral administration, the compound's ability to decrease dural plasma protein extravasation and reduce c-fos positive cells in the trigeminal nucleus caudalis is measured. Other in vivo/ex vivo models include assessing KCI-stimulated CGRP release from dura mater and trigeminal ganglion, and evaluating the compound's effect on dural artery vasodilation.

Absorption, Distribution and Excretion
Oral absorption of lasmiditan is quick, with a median tmax of 1.8 hours. 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. The oral bioavailability of lasmiditan has been reported as approximately 40%. 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. Similarly, severe renal impairment and mild-moderate hepatic impairment were found to increase both AUC and Cmax, but not to a clinically significant extent.
Lasmiditan is eliminated primarily via metabolism, 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, further implying a relatively extensive metabolism of this drug.
Lasmiditan has been shown to penetrate the blood-brain barrier.

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Metabolism / Metabolites
The hepatic and extra-hepatic metabolism of lasmiditan is catalyzed primarily by non-CYP enzymes, with ketone reduction appearing to be the primary pathway. 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. 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.

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Biological Half-Life
The mean elimination half-life of lasmiditan is 5.7 hours.
Lasmiditan is a BCS Class I drug with high solubility and permeability. It is rapidly absorbed after oral administration, with a median Tmax of 2 hours and a geometric mean half-life (t1/2) of 4.1 hours. The compound is extensively metabolized, and 86.8% of total radioactivity is found in the urine. The PK profile is dose-proportional over a range of 25 to 400 mg. Cmax and AUC increase with dose from 100 to 200 mg, and repeat dosing does not result in accumulation.

Hepatotoxicity
In preregistration controlled trials of lasmiditan in several thousand patients, mild-to-moderate serum aminotransferase elevations arose in a small percentage of patients (1% or less) and overall rates were not different from those in placebo recipients. In the controlled trials and subsequently with general use, there have been no reports of liver injury with symptoms or jaundice attributed to lasmiditan.
Likelihood score: E (unlikely cause of clinically apparent acute liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
There is no published experience with lasmiditan during breastfeeding. If lasmiditan is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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

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In the intravenous Phase II trial, adverse events were generally mild, reported by 65% of patients on Lasmiditan and 43% on placebo [2]
In the oral Phase II trial, treatment-emergent adverse events were reported by 22% of placebo patients and by 65%, 73%, 87%, and 87% of patients receiving 50, 100, 200, and 400 mg of Lasmiditan, respectively. For the 100 mg and 400 mg doses, the majority of adverse events were moderate or severe in intensity. Common adverse events (incidence >5%) included dizziness, fatigue, vertigo, somnolence, paresthesia, heaviness, and nausea [2]
In preclinical toxicology studies, acute or repeated exposure to lasmiditan was associated with CNS-related clinical signs including hypoactivity, tremors, ataxia, and convulsions. The No-Observed-Adverse-Effect Level (NOAEL) in rats was determined to be 30 mg/kg/day. In dogs, a 39-week study identified the NOAEL as 30 mg/kg. The most common adverse effects in clinical trials are CNS-related, including dizziness (39.4%), somnolence (19.3%), fatigue, and paresthesia. These effects typically start within one hour post-dose. Lasmiditan is also classified as harmful if swallowed and very toxic to aquatic life.

[1]. Cephalalgia. 2010 Oct;30(10):1159-69.

[2]. J Headache Pain. 2012 Jun;13(4):271-5.

See also: Lamedittan (with active ingredient).

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Drug Indications
RAYVOW is indicated for the treatment of acute migraine attacks in adults, with or without aura.

Lasmiditan succinate (Reyvow) is the first and only member of a new class of anti-migraine medications known as neurally-acting anti-migraine medications (NAAMAs). Its mechanism of action involves agonism at the 5-HT1F receptor, which is believed to inhibit the release of calcitonin gene-related peptide (CGRP) and other neurotransmitters involved in migraine pathophysiology. The efficacy of lasmiditan for the acute treatment of migraine was established in two pivotal phase 3 randomized, double-blind, placebo-controlled trials, SAMURAI and SPARTAN. The American Headache Society recommends lasmiditan as an option for patients who have contraindications to triptans. Patients are advised to avoid activities requiring alertness, such as driving, for at least eight hours after taking the drug.

C42H42F6N6O8

872.82

872.297

439239-92-6

439239-90-4;613677-28-4 (HCl) 439239-92-6 (succinate) 2171471-98-8 (HCl dihydrate) 2171471-99 (HCl hydrate)

46927777

Typically exists as solid at room temperature

7.131

4

18

11

62

623

0

FC1C=C(C=C(C=1C(NC1=CC=CC(C(C2CCN(C)CC2)=O)=N1)=O)F)F.FC1C=C(C=C(C=1C(NC1=CC=CC(C(C2CCN(C)CC2)=O)=N1)=O)F)F.OC(CCC(=O)O)=O

MSOIHUHNGPOCTH-UHFFFAOYSA-N

InChI=1S/2C19H18F3N3O2.C4H6O4/c2*1-25-7-5-11(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;5-3(6)1-2-4(7)8/h2*2-4,9-11H,5-8H2,1H3,(H,23,24,27);1-2H2,(H,5,6)(H,7,8)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)