Lacosamide
Clinical data
Trade namesVimpat
Other names(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide
AHFS/Drugs.comMonograph
MedlinePlusa609028
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityHigh
Elimination half-life13 hours
ExcretionKidney
Identifiers
  • N2-acetyl-N-benzyl-D-homoserinamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.112.805
Chemical and physical data
FormulaC13H18N2O3
Molar mass250.298 g·mol−1
3D model (JSmol)
  • O=C(N[C@@H](C(=O)NCc1ccccc1)COC)C
  • InChI=1S/C13H18N2O3/c1-10(16)15-12(9-18-2)13(17)14-8-11-6-4-3-5-7-11/h3-7,12H,8-9H2,1-2H3,(H,14,17)(H,15,16)/t12-/m1/s1 checkY
  • Key:VPPJLAIAVCUEMN-GFCCVEGCSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Lacosamide, sold under the brand name Vimpat among others, is a medication used for the treatment of partial-onset seizures and primary generalized tonic-clonic seizures.[2] It is used by mouth or intravenously.[2]

It is available as a generic medication.[4][5]

Medical uses

Lacosamide is indicated for the treatment of partial-onset seizures and adjunctive therapy in the treatment of primary generalized tonic-clonic seizures.[2]

Off-label use

As with other anti-epileptic drugs (AEDs), lacosamide may have a variety of off-label uses, including for pain management and treatment of mental health disorders. Lacosamide and other AEDs have been used off-label in the management of bipolar disorder, cocaine addiction, dementia, depression, diabetic peripheral neuropathy, fibromyalgia, headache, hiccups, Huntington's disease, mania, migraine, obsessive-compulsive disorder, panic disorder, restless leg syndrome, and tinnitus. Combinations of AEDs are often employed for seizure reduction. Studies are underway for the use of lacosamide as a monotherapy for partial onset seizures, diabetic neuropathy, and fibromyalgia.[6]

Contraindications

The FDA has assigned lacosamide to pregnancy category C. Animal studies have reported incidences of fetal mortality and growth deficit. Lacosamide has not been tested during human pregnancy, and should be administered with caution. In addition, it has not been determined whether the excretion of lacosamide occurs in breast milk.[7]

Side effects

Lacosamide was generally well tolerated in adult patients with partial-onset seizures.[8] The side-effects most commonly leading to discontinuation were dizziness, ataxia, diplopia (double vision), nystagmus, nausea, vertigo and drowsiness. These adverse reactions were observed in at least 10% of patients.[2] Less common side-effects include tremors, blurred vision, vomiting and headache.[9]

Gastrointestinal

A generally well-tolerated drug, the most commonly reported gastrointestinal side effects of lacosamide are nausea, vomiting, and diarrhea.[10]

Central nervous system

Dizziness was the most common treatment-related adverse event. Other CNS effects are headache, drowsiness, blurred vision, involuntary movements, memory problems, diplopia (double vision), trembling or shaking of the hands, unsteadiness, ataxia.[11]

Psychiatric

Panic attacks; agitation or restlessness; irritability and aggression, anxiety, or depression; suicidality; insomnia and mania; altered mood; false and unusual sense of well-being. Lacosamide appears to have a low incidence of psychiatric side effects with psychosis reported in only 0.3% of patients.[6]

Cardiovascular

There is the risk of postural hypotension as well as arrhythmias. In addition, there is the possibility of atrioventricular block. There have also been post-marketing reports of lacosamide causing atrial fibrillation and atrial flutter in some populations, namely those with diabetic neuropathy.[12]

Allergies

There have been reports of rash[13] and pruritus.

Warnings

Suicidal behavior and ideation have been observed as early as one week after starting treatment with lacosamide, and is an adverse reaction to the use of most AEDs. In clinical trials with a medial treatment duration of 12 weeks, the incidence of suicidal ideation was 0.43% among 27,863 patients as opposed to 0.24% among 16,029 placebo-treated patients. Suicidal behavior was observed in 1 of every 530 patients treated.[6]

In pregnancy

In a study conducted to assess the teratogenic potential of AEDs in the zebrafish embryo, the teratogenicity index of lacosamide was found to be higher than that of lamotrigine, levetiracetam, and ethosuximide. Lacosamide administration resulted in different malformations in the neonatal zebrafish depending on dosage.[14]

Overdose

There is no known antidote in the event of an overdose.[15]

Pharmacology

Pharmacodynamics

Lacosamide is a functionalized amino acid that produces activity in the maximal electroshock seizure (MES) test, that, like some other antiepileptic drugs (AEDs), are believed to act through voltage-gated sodium channels.[16] Lacosamide enhances the slow inactivation of voltage-gated sodium channels without affecting the fast inactivation of voltage-gated sodium channels. This inactivation prevents the channel from opening, helping end the action potential. Many antiepileptic drugs, like carbamazepine or lamotrigine, slow the recovery from inactivation and hence reduce the ability of neurons to fire action potentials. Inactivation only occurs in neurons firing action potentials; this means that drugs that modulate fast inactivation selectively reduce the firing in active cells. Slow inactivation is similar but does not produce complete blockade of voltage gated sodium channels, with both activation and inactivation occurring over hundreds of milliseconds or more. Lacosamide makes this inactivation happen at less depolarized membrane potentials. This means that lacosamide only affects neurons which are depolarized or active for long periods of time, typical of neurons at the focus of epilepsy.[17] Lacosamide administration results in the inhibition of repetitive neuronal firing, the stabilization of hyperexcitable neuronal membranes, and the reduction of long-term channel availability, but does not affect physiological function.[18] Lacosamide has a dual mechanism of action. It also modulates collapsin response mediator protein 2 (CRMP-2), preventing the formation of abnormal neuronal connections in the brain.[19]

Lacosamide does not affect AMPA, kainate, NMDA, GABAA, GABAB or a variety of dopaminergic, serotonergic, adrenergic, muscarinic or cannabinoid receptors and does not block potassium or calcium currents.[20] Lacosamide does not modulate the reuptake of neurotransmitters including norepinephrine, dopamine, and serotonin.[21] In addition, it does not inhibit GABA transaminase.[22]

Preclinical research

In preclinical trials, the effect of lacosamide administration on animal models of epilepsy was tested using the Frings audiogenic seizures (AGS)-susceptible mouse model of seizure activity with an effective dose (ED50) of 0.63 mg/kg, i.p..[23] The effect of lacosamide was also assessed using the MES test to detect inhibition of seizure spread.[24][25] Lacosamide administration was successful in preventing the spread of seizures induced by MES in mice (ED50 = 4.5 mg/kg, i.p.) and rats (ED50 = 3.9 mg/kg, p.o.).[23] In preclinical trials, administration of lacosamide in combination with other AEDs resulted in synergistic anticonvulsant effects. Lacosamide produced effects in animal models of essential tremor, tardive dyskinesia, schizophrenia, and anxiety.[26] Preclinical trials found the S-stereoisomer to be less potent than the R-stereoisomer in the treatment of seizures.[27]

Pharmacokinetics

When administered orally in healthy individuals, lacosamide is rapidly absorbed from the gastrointestinal tract. Little of the drug is lost via the first pass effect, and thus has an oral bioavailability of nearly 100%.[28] In adults, lacosamide demonstrates a low plasma protein binding of <15%, which reduces the potential for interaction with other drugs. Lacosamide is at its highest concentration in blood plasma approximately 1 to 4 hours after oral administration. Lacosamide has a half life of about 12–16 hours, which remains unchanged if the patients is also taking enzyme inducers. Consequently, the drug is administered twice per day at 12-hour intervals. Lacosamide is excreted renally, with 95% of the drug eliminated in the urine.[29] 40% of the compound remains unchanged from its original structure, while the rest of the elimination product consists of metabolites of lacosamide. Just 0.5% of the drug is eliminated in the feces.[30] The major metabolic pathway of lacosamide is CYP2C9, CY2C19, and CYP3A4-mediated demethylation.[31]

The dose-response curve for lacosamide is linear and proportional for oral doses of up to 800 mg and intravenous doses of up to 300 mg.[32] Lacosamide has low potential for drug-drug interactions, and no pharmacokinetic interactions have been found to occur with other (AEDs) that act on sodium channels.[33] A study on the binding of lacosamide to CRMP-2 in Xenopus oocytes showed both competitive and specific binding. Lacosamide has a Kd value just under 5 μM and a Bmax of about 200 pM/mg.[34] The volume of distribution (Vd) of lacosamide in plasma is 0.6 L/kg, which is close to the total volume of water. Lacosamide is ampiphilic and is thus hydrophilic while also lipophilic enough to cross the blood-brain barrier.[35]

Chemistry

Lacosamide is a powdery, white to light yellow crystalline compound. The chemical name of lacosamide is (R)-2-acetamido-N-benzyl-3-methoxypropionamide and the systemic name is N2-Acetyl-N-benzyl-O-methyl-D-serinamide.[21][36] Lacosamide is a functionalized amino acid molecule that has high solubility in water and DMSO, with a solubility of 20.1 mg/mL in phosphate-buffered saline (PBS, pH 7.5, 25 °C).[21][37] The molecule has six rotatable bonds and one aromatic ring. Lacosamide melts at 143-144 °C and boils at 536.447 °C at a pressure of 760 mmHg.[30][38]

Synthesis

The following three-step synthesis of lacosamide was proposed in 1996.

500pm

(R)-2-amino-3-hydroxypropanoic acid is treated with acetic anhydride and acetic acid. The product is treated first with N-methylmorpholine, isobutyl chloroformate, and benzylamine, next with methyl iodide and silver oxide, forming lacosamide.[39]

More efficient routes to synthesis have been proposed in recent years, including the following.[40]

Lacosamide synthesis[41]

History

Lacosamide was discovered at the University of Houston in 1996.[39][42] They hypothesized that modified amino acids may be therapeutically useful in the treatment of epilepsy. A few hundred such molecules were synthesized over several years and these were tested phenotypically in an epilepsy disease model performed in rats. N-benzyl-2-acetamido-3-methoxypropionamide was found to be highly efficacious in this model, with the biological activity traced specifically to its R enantiomer.[39]

This compound was to become lacosamide after being licensed by Schwarz Pharma, which completed its pre-clinical and early clinical development. After its purchase of Schwarz Pharma in 2006, UCB completed the clinical development program and obtained marketing approval for lacosamide. Its precise mechanism of action was unknown at the time of approval, and the exact amino acid targets involved remain uncertain to this day.[16]

The U.S. Food and Drug Administration (FDA) accepted UCB's New Drug Application for lacosamide as of November 29, 2007, beginning the approval process for the drug.[43][44] UCB also filed for marketing approval in the European Union (EU); the European Medicines Agency accepted the marketing application for review in May 2007.[43][45]

The drug was approved in the EU on September 3, 2008.[46] It was approved in the US on October 29, 2008.[47] The release of lacosamide was delayed owing to an objection about its placement into schedule V of the Controlled Substances Act. The FDA issued their final rule of placement into Schedule V on June 22, 2009.[48]

Lacosamide's US patent expired on March 17, 2022.[49]

Partial-onset seizures

Lacosamide was tested in three placebo-controlled, double-blind, randomized trials of at least 1300 patients.[50] In a multi center, multinational, placebo-controlled, double-blind, randomized clinical trial conducted to determine the efficacy and safety of different doses of lacosamide on individuals with poorly controlled partial-onset seizures, lacosamide was found significantly to reduce seizure frequency when given in addition to other antiepileptics, at doses of 400 and 600 milligrams a day.[51]

Peripheral neuropathy

In a smaller trial of patients with diabetic neuropathy, lacosamide also provided significantly better pain relief when compared to placebo.[52] Lacosamide administration in combination with 1-3 other AEDs was well tolerated in patients. Lacosamide administered at 400 mg/day was found to significantly reduce pain in patients with diabetic neuropathy in a multi center, double-blind, placebo-controlled Phase III trial with a treatment duration of 18 weeks.[53]

A small (n=24) study for small fiber peripheral neuropathy also showed positive results.[54]

Society and culture

Names

Lacosamide is the international nonproprietary name (INN). It was formerly known as erlosamide, harkoseride, SPM-927, and ADD 234037.[21]

Lacosamide is sold under the brand name Vimpat by UCB, and under the brand name Motpoly XR by Acute Pharmaceuticals.[55][56] In Pakistan, it is marketed by G.D. Searle as Lacolit.[57]

Research

Clinical trials are underway for the use of lacosamide as monotherapy for partial-onset seizures.[50] There is no evidence that lacosamide provides additional value over current antiepileptic drugs (AEDs) for the treatment of partial-onset seizures, but it may offer a safety advantage.[33] Newer AEDs, including lacosamide, vigabatrin, felbamate, gabapentin, tiagabine, and rufinamide have been found to be more tolerable and safer than older drugs such as carbamazepine, phenytoin, and valproate.[58]

References

  1. ↑ Anvisa (March 31, 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published April 4, 2023). Archived from the original on August 3, 2023. Retrieved August 16, 2023.
  2. 1 2 3 4 5 "Vimpat- lacosamide tablet, film coated VIMPAT- lacosamide kit VIMPAT- lacosamide injection VIMPAT- lacosamide solution". DailyMed. December 13, 2021. Archived from the original on March 25, 2022. Retrieved March 24, 2022.
  3. ↑ "Lacosamide Adroiq". Union Register of medicinal products. June 1, 2023. Retrieved June 6, 2023.
  4. ↑ "Drugs@FDA: Lacosamide". U.S. Food and Drug Administration (FDA). Archived from the original on March 25, 2022. Retrieved March 24, 2022.
  5. ↑ "2022 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). March 3, 2023. Archived from the original on June 30, 2023. Retrieved June 30, 2023.
  6. 1 2 3 Halford JJ, Lapointe M (2009). "Clinical perspectives on lacosamide". Epilepsy Currents. 9 (1): 1–9. doi:10.1111/j.1535-7511.2008.01273.x. PMC 2668106. PMID 19396339.
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  42. ↑ "Anticonvulsant enantiomeric amino acid derivatives". google.com. Archived from the original on October 31, 2021. Retrieved September 10, 2018.
  43. 1 2 "UCB Announces FDA Filing for lacosamide in the Treatment of Diabetic Neuropathic Pain" (Press release). UCB. November 29, 2007. Archived from the original on September 25, 2008. Retrieved November 29, 2007.
  44. ↑ "UCB Announces FDA Filing for lacosamide in the Treatment of Partial Onset Seizures in Adults with Epilepsy" (Press release). UCB. November 29, 2007. Archived from the original on September 25, 2008. Retrieved November 29, 2007.
  45. ↑ Wan Y (August 17, 2007). "Marketing application for lacosamide (Vimpat) filed in EU for treatment of diabetic neuropathic pain". PharmaTimes through the UK National electronic Library for Medicines. Archived from the original on February 9, 2012. Retrieved November 30, 2007.
  46. ↑ "Vimpat Approved in Europe" (Press release). UCB. September 3, 2008. Archived from the original on September 19, 2008. Retrieved September 17, 2008.
  47. ↑ "UCB's Vimpat approved by U.S. FDA as adjunctive therapy for partial onset seizures in adults" (Press release). UCB. October 29, 2008. Archived from the original on November 14, 2008. Retrieved November 25, 2008.
  48. ↑ "FDA places lacosamide in Schedule V" (Press release). U.S. Food and Drug Administration (FDA). June 22, 2009. Retrieved June 28, 2009.
  49. ↑ "Generic Vimpat Availability". Drugs.com. Archived from the original on January 13, 2022. Retrieved January 13, 2022.
  50. 1 2 Doty P, Hebert D, Mathy FX, Byrnes W, Zackheim J, Simontacchi K (July 2013). "Development of lacosamide for the treatment of partial-onset seizures". Annals of the New York Academy of Sciences. 1291 (1): 56–68. Bibcode:2013NYASA1291...56D. doi:10.1111/nyas.12213. PMC 3759704. PMID 23859801.
  51. ↑ Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD (July 2007). "Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures". Epilepsia. 48 (7): 1308–1317. doi:10.1111/j.1528-1167.2007.01188.x. PMID 17635557. S2CID 25986031.
  52. ↑ Rauck RL, Shaibani A, Biton V, Simpson J, Koch B (February 2007). "Lacosamide in painful diabetic peripheral neuropathy: a phase 2 double-blind placebo-controlled study". The Clinical Journal of Pain. 23 (2): 150–158. doi:10.1097/01.ajp.0000210957.39621.b2. PMID 17237664. S2CID 6651958.
  53. ↑ "SCHWARZ PHARMA Highlights the Results of 13 Lacosamide Data Presentations at North American Regional Epilepsy Congress in San Diego". Schwarz Pharma. Archived from the original on June 25, 2016. Retrieved April 2, 2014.
  54. ↑ de Greef BT, Hoeijmakers JG, Geerts M, Oakes M, Church TJ, Waxman SG, et al. (February 2019). "Lacosamide in patients with Nav1.7 mutations-related small fibre neuropathy: a randomized controlled trial". Brain. 142 (2): 263–275. doi:10.1093/brain/awy329. PMID 30649227.
  55. ↑ "Lacosamide". Epilepsy Foundation. February 22, 2023. Retrieved July 5, 2023.
  56. ↑ "Motpoly XR (lacosamide) – New drug approval". professionals.optumrx.com. Retrieved July 5, 2023.
  57. ↑ "Alternate brands of LACOLIT". www.druginfosys.com. Retrieved July 5, 2023.
  58. ↑ "Antiepileptic drugs". Archived from the original on March 6, 2015. Retrieved April 2, 2014.

Further reading

  • "Lacosamide". Drug Information Portal. U.S. National Library of Medicine.
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