HOME

TheInfoList



OR:

Lacosamide, sold under the brand name Vimpat among others, is a
medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
used for the treatment of partial-onset seizures and primary generalized tonic-clonic seizures. It is used
by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...
or
intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
ly. It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
.


Medical uses

Lacosamide is
indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
for the treatment of partial-onset seizures and adjunctive therapy in the treatment of primary generalized tonic-clonic seizures.


Off-label use

As with other anti-epileptic drugs (AEDs), lacosamide may have a variety of off-label uses, including for
pain management Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute (medicine), acute and simple to chronic condition, chronic and challenging. Most physici ...
and treatment of
mental health disorders The ''Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition'' (DSM-5), is the 2013 update to the ''Diagnostic and Statistical Manual of Mental Disorders'', the taxonomic and diagnostic tool published by the American Psychiatri ...
. Lacosamide and other AEDs have been used off-label in the management of
bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...
, cocaine addiction,
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
, depression, diabetic peripheral neuropathy,
fibromyalgia Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...
,
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
,
hiccups A hiccup (scientific name singultus, from Latin for "sob, hiccup"; also spelled hiccough) is an involuntary contraction ( myoclonic jerk) of the diaphragm that may repeat several times per minute. The hiccup is an involuntary action involvi ...
,
Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...
,
mania Mania, also known as manic syndrome, is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome defined as a state of Abnormality (behavior), abnormally elevated arousal, affect (psychology), affect, and energy level. During a mani ...
,
migraine Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...
, obsessive-compulsive disorder,
panic disorder Panic disorder is a mental disorder, specifically an anxiety disorder, characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath ...
,
restless leg syndrome Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...
, and
tinnitus Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...
. 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.


Contraindications

The
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
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.


Side effects

Lacosamide was generally well tolerated in adult patients with partial-onset seizures. The side-effects most commonly leading to discontinuation were
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
,
ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
,
diplopia Diplopia is the simultaneous perception of two images of a single object that may be displaced in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often voluntary. However, when occ ...
(double vision),
nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) Eye movement (sensory), eye movement. People can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in visual impairment, re ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
,
vertigo Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...
and
drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
. These adverse reactions were observed in at least 10% of patients. Less common side-effects include
tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...
s,
blurred vision Blurred vision is an ocular symptom where vision becomes less precise and there is added difficulty to resolve fine details. Temporary blurred vision may involve dry eyes, eye infections, alcohol poisoning, hypoglycemia, or low blood pressur ...
,
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
and
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
.


Gastrointestinal

A generally well-tolerated drug, the most commonly reported gastrointestinal side effects of lacosamide are
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
,
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
, and
diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
.


Central nervous system

Dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
was the most common treatment-related adverse event. Other CNS effects are
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
,
drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
, blurred vision, involuntary movements, memory problems,
diplopia Diplopia is the simultaneous perception of two images of a single object that may be displaced in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often voluntary. However, when occ ...
(double vision), trembling or shaking of the hands, unsteadiness,
ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
.


Psychiatric

Panic attacks Panic attacks are sudden periods of intense fear and discomfort that may include palpitations, otherwise defined as a rapid, irregular heartbeat, sweating, chest pain or discomfort, shortness of breath, trembling, dizziness, numbness, con ...
; agitation or restlessness;
irritability Irritability is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimul ...
and
aggression Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...
,
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
, or depression; suicidality;
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
and
mania Mania, also known as manic syndrome, is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome defined as a state of Abnormality (behavior), abnormally elevated arousal, affect (psychology), affect, and energy level. During a mani ...
; 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.


Cardiovascular

There is the risk of postural hypotension as well as
arrhythmias Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beats ...
. In addition, there is the possibility of
atrioventricular block Atrioventricular block (AV block) is a type of heart block that occurs when the electrical signal traveling from the atria, or the upper chambers of the heart, to ventricles, or the lower chambers of the heart, is impaired. Normally, the sinoatr ...
. There have also been post-marketing reports of lacosamide causing
atrial fibrillation Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...
and
atrial flutter Atrial flutter (AFL) is a common abnormal heart rhythm that starts in the atrial chambers of the heart. When it first occurs, it is usually associated with a fast heart rate and is classified as a type of supraventricular tachycardia (SVT). ...
in some populations, namely those with
diabetic neuropathy Diabetic neuropathy includes various types of nerve damage associated with diabetes mellitus. The most common form, diabetic peripheral neuropathy, affects 30% of all diabetic patients. Studies suggests that cutaneous nerve branches, such as the s ...
.


Allergies

There have been reports of
rash A rash is a change of the skin that affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracke ...
and
pruritus An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...
.


Warnings

Suicidal behavior and ideation have been observed as early as one week after starting treatment with lacosamide, and is an
adverse reaction An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complic ...
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.


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 Lamotrigine ( ), sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastau ...
,
levetiracetam Levetiracetam, sold under the brand name Keppra among others, is a novel antiepileptic drug. (medication) used to treat epilepsy. It is used for Focal seizure, partial-onset, Myoclonic epilepsy, myoclonic, or tonic–clonic seizures, and is ta ...
, and
ethosuximide Ethosuximide, sold under the brand name Zarontin among others, is a medication used to treat absence seizures. It may be used by itself or with other antiseizure medications such as valproic acid. Ethosuximide is taken by mouth. Ethosuximide ...
. Lacosamide administration resulted in different malformations in the neonatal zebrafish depending on dosage.


Overdose

There is no known
antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon antidoton)'', "(medicine) given as a remedy". An older term in English which is ...
in the event of an overdose.


Pharmacology


Pharmacodynamics

Lacosamide is a functionalized amino acid that produces activity in the maximal electroshock seizure (MES) test, that, like some other
antiepileptic drugs Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatment ...
(AEDs), are believed to act through
voltage-gated sodium channels Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels. Classification They are classified into 2 types: Function In exc ...
. Lacosamide enhances the slow inactivation of voltage-gated sodium channels without affecting the fast inactivation of
voltage-gated sodium channels Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels. Classification They are classified into 2 types: Function In exc ...
. This inactivation prevents the channel from opening, helping end the action potential. Many antiepileptic drugs, like
carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...
or
lamotrigine Lamotrigine ( ), sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastau ...
, slow the recovery from inactivation and hence reduce the ability of neurons to fire
action potentials An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific cell rapidly rises and falls. ...
. 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 potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. It equals the interior potential minus the exterior potential. This is th ...
s. 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 Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
. 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. 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. Lacosamide does not affect
AMPA α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate Glutamic acid (symbol Glu or E; kn ...
, kainate,
NMDA ''N''-methyl--aspartic acid, or ''N''-methyl--aspartate (NMDA), is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unl ...
, GABAA, GABAB or a variety of
dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...
, serotonergic,
adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...
, muscarinic or
cannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
receptors and does not block potassium or calcium currents. Lacosamide does not modulate the
reuptake Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmi ...
of
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
s including
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
,
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
, and
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
. In addition, it does not inhibit
GABA transaminase In enzymology, 4-aminobutyrate transaminase (), also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that catalysis, catalyzes the chemical reaction: :4-aminobutanoate + 2-oxoglutarate \rightleftharpoons suc ...
.


Preclinical research

In preclinical trials, the effect of lacosamide administration on animal models of
epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
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.. The effect of lacosamide was also assessed using the MES test to detect inhibition of seizure spread. 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.). 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 Essential tremor (ET), also called benign tremor, familial tremor, and idiopathic tremor, is a medical condition characterized by involuntary rhythmic contractions and relaxations ( oscillations or twitching movements) of certain muscle groups i ...
,
tardive dyskinesia Tardive dyskinesia (TD) is an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...
,
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
, and
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
. Preclinical trials found the S-stereoisomer to be less potent than the R-stereoisomer in the treatment of seizures.


Pharmacokinetics

When administered orally in healthy individuals, lacosamide is rapidly absorbed from the
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
. Little of the drug is lost via the
first pass effect The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...
, and thus has an oral
bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
of nearly 100%. 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. 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. The major metabolic pathway of lacosamide is CYP2C9, CY2C19, and CYP3A4-mediated
demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen at ...
. 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. 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. A study on the binding of lacosamide to CRMP-2 in ''
Xenopus ''Xenopus'' () (Gk., ξενος, ''xenos'' = strange, πους, ''pous'' = foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described with ...
'' oocytes showed both competitive and specific binding. Lacosamide has a Kd value just under 5 μM and a Bmax of about 200 pM/mg. The
volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...
(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 A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...
while also
lipophilic Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...
enough to cross the blood-brain barrier.


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. 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). The molecule has six rotatable bonds and one
aromatic In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated system, conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugati ...
ring. Lacosamide melts at 143-144 °C and boils at 536.447 °C at a pressure of 760 mmHg.


Synthesis

The following three-step synthesis of lacosamide was proposed in 1996. (''R'')-2-amino-3-hydroxypropanoic acid is treated with
acetic anhydride Acetic anhydride, or ethanoic anhydride, is the chemical compound with the chemical formula, formula . Commonly abbreviated , it is one the simplest organic acid anhydride, anhydrides of a carboxylic acid and is widely used in the production of c ...
and
acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main compone ...
. The product is treated first with ''N''-methylmorpholine, isobutyl chloroformate, and
benzylamine Benzylamine, also known as phenylmethylamine, is an Organic chemistry, organic chemical compound with the Structural formula#Condensed formulas, condensed structural formula C6H5CH2NH2 (sometimes abbreviated as Phenyl group#Nomenclature, PhCH2NH2 ...
, next with
methyl iodide Iodomethane, also called methyl iodide, and commonly abbreviated "MeI", is the chemical compound with the formula CH3I. It is a dense, colorless, volatile liquid. In terms of chemical structure, it is related to methane by replacement of one h ...
and
silver oxide Silver oxide is the chemical compound with the formula Ag2 O. It is a fine black or dark brown powder that is used to prepare other silver compounds. Preparation Silver oxide can be prepared by combining aqueous solutions of silver nitrate and ...
, forming lacosamide. More efficient routes to synthesis have been proposed in recent years, including the following.


History

Lacosamide was discovered at the University of Houston in 1996. 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. 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. The U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) accepted UCB's
New Drug Application The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...
for lacosamide as of November 29, 2007, beginning the approval process for the drug. UCB also filed for marketing approval in the
European Union The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are Geography of the European Union, located primarily in Europe. The u ...
(EU); the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
accepted the marketing application for review in May 2007. The drug was approved in the EU on September 3, 2008. It was approved in the US on October 29, 2008. The release of lacosamide was delayed owing to an objection about its placement into schedule V of the
Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...
. The FDA issued their final rule of placement into Schedule V on June 22, 2009. Lacosamide's US
patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...
expired on March 17, 2022.


Partial-onset seizures

Lacosamide was tested in three placebo-controlled,
double-blind In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...
, randomized trials of at least 1300 patients. In a multi center, multinational, placebo-controlled, double-blind, randomized clinical trial conducted to determine the
efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...
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.


Peripheral neuropathy

In a smaller trial of patients with
diabetic neuropathy Diabetic neuropathy includes various types of nerve damage associated with diabetes mellitus. The most common form, diabetic peripheral neuropathy, affects 30% of all diabetic patients. Studies suggests that cutaneous nerve branches, such as the s ...
, lacosamide also provided significantly better
pain relief Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...
when compared to
placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...
. 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. A small (n=24) study for
small fiber peripheral neuropathy Small fiber peripheral neuropathy is a type of peripheral neuropathy that occurs from damage to the small unmyelinated and myelinated peripheral nerve fibers. These fibers, categorized as C fibers and small Aδ fibers, are present in skin, perip ...
also showed positive results.


Society and culture


Names

Lacosamide is the international nonproprietary name (INN). It was formerly known as erlosamide, harkoseride, SPM-927, and ADD 234037. Lacosamide is sold under the brand name Vimpat by UCB, and under the brand name Motpoly XR by Acute Pharmaceuticals. In
Pakistan Pakistan, officially the Islamic Republic of Pakistan, is a country in South Asia. It is the List of countries and dependencies by population, fifth-most populous country, with a population of over 241.5 million, having the Islam by country# ...
, it is marketed by G.D. Searle as Lacolit.


Research

Clinical trials are underway for the use of lacosamide as monotherapy for partial-onset seizures. 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. Newer AEDs, including lacosamide,
vigabatrin Vigabatrin, sold under the brand name Vigafyde among others, is a medication used in the management and treatment of Epileptic spasms, infantile spasms and refractory complex partial seizures. It works by inhibiting the catabolism, breakdown o ...
,
felbamate Felbamate (marketed under the brand name Felbatol by MedPointe) is an anticonvulsant used in the treatment of epilepsy. It is used to treat partial seizures (with and without generalization) in adults and partial and generalized seizures associ ...
,
gabapentin Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat neuropathic pain and also for partial seizures of epilepsy. It is a commonly used medication for the treatment of neuropath ...
,
tiagabine Tiagabine, sold under the brand name Gabitril, is an anticonvulsant medication produced by Cephalon that is used in the treatment of epilepsy. The drug is also used off-label in the treatment of anxiety disorders including panic disorder. Medi ...
, and rufinamide have been found to be more tolerable and safer than older drugs such as
carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...
,
phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence se ...
, and
valproate Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with ...
.


References


Further reading

* {{Authority control Acetamides Anticonvulsants Belgian inventions Benzyl compounds Ethers Sodium channel blockers