Eslicarbazepine acetate (ESL), sold under the brand names Aptiom and Zebinix among others, is an anticonvulsant medication approved for use in Europe and the United States as monotherapy or as additional therapy for partial-onset seizures

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

. Similarly to

oxcarbazepine Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalized seizures. It has been used both alone and as add-on therapy in people with ...

, ESL behaves as a prodrug to (''S'')-(+)- licarbazepine. As such, their

mechanisms of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...

are identical.

Contraindications

Eslicarbazepine acetate is contraindicated in people with second- or third-degree

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 ...

, a type of heart block, and in people who are hypersensitive to eslicarbazepine,

or carbazepine.

Adverse effects

Adverse effects are similar to oxcarbazepine. The most common ones (more than 10% of patients) are tiredness and dizziness. Other fairly common side effects (1 to 10%) include impaired coordination,

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

disorders such as

diarrhoea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

, nausea and vomiting,

rash A rash is a change of the human skin which 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, c ...

(1.1%), and

hyponatremia Hyponatremia or hyponatraemia is a low concentration of sodium in the blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symptoms can be a ...

(low

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...

blood levels, 1.2%). There may also be an increased risk of suicidal thoughts.

Overdose

Symptoms of overdosing are similar to adverse effects of standard doses - severe hyponatraemia,

somnolence 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 ...

, uncoordinated/unsteady gait,

hemiparesis Hemiparesis, or unilateral paresis, is weakness of one entire side of the body ('' hemi-'' means "half"). Hemiplegia is, in its most severe form, complete paralysis of half of the body. Hemiparesis and hemiplegia can be caused by different medi ...

(weakness of one side of the body), along with visual and gastrointestinal disturbances. No specific

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". Antidotes for anticoagulants are s ...

is available. Eslicarbazepine and metabolites can be dialyzed.

Interactions

Like oxcarbazepine, eslicarbazepine can reduce plasma levels of drugs that are metabolized by the liver enzymes CYP3A4 (verified in studies for

simvastatin Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of hear ...

and the oral contraceptive levonorgestrel/

ethinylestradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disord ...

) and

UDP-glucuronosyltransferase Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...

, and increase plasma levels of drugs metabolized by

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...

. Interaction studies have been conducted with a number of common anticonvulsants.

Carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...

reduces

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...

concentrations of eslicarbazepine, probably because it induces

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...

. This drug combination also increased the risk for

diplopia Diplopia is the simultaneous perception of two images of a single object that may be displaced horizontally or vertically in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often v ...

, impaired coordination and dizziness in a clinical study.

Phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an 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 seizures. The in ...

also reduces eslicarbazepine plasma concentrations, which may be due to increased glucuronidation of eslicarbazepine; and concomitant administration results in an increase in phenytoin serum concentrations, which is probably due to inhibition of CYP2C19. Combinations with lamotrigine,

topiramate Topiramate, sold under the brand name Topamax among others, is a carbonic anhydrase inhibitor medication used to treat epilepsy and prevent migraines. It has also been used in alcohol dependence. For epilepsy this includes treatment for gener ...

valproic acid Valproate (VPA) and its valproic acid, 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 ...

levetiracetam Levetiracetam, sold under the brand name Keppra among others, is a medication used to treat epilepsy. It is used for partial-onset, myoclonic, or tonic–clonic seizures and is taken either by mouth as an immediate or extended release formu ...

showed no significant interactions in studies, although eslicarbazepine has been shown to cause a minor reduction in lamotrigine levels.

Pharmacology

Mechanism of action

The active component, eslicarbazepine, has the same mechanism of action as oxcarbazepine (which is a prodrug for licarbazepine, the

racemate In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

of eslicarbazepine) and most likely the closely related carbamazepine. It stabilises the inactive state of

voltage-gated sodium channel 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 and can be classified according to the trigger that opens the channel ...

s, allowing for less sodium to enter neural cells, which leaves them less excitable. According to some sources, it has not been shown conclusively that this is the actual mechanism.

Pharmacokinetics

Eslicarbazepine acetate is absorbed to at least 90% from the gut, independently of food intake. It is quickly metabolised to eslicarbazepine, so that the original substance cannot be detected in the bloodstream. Peak plasma levels of eslicarbazepine are reached after 2–3 (1–4) hours, and

plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse t ...

is somewhat less than 40%.

Biological half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

is 10 to 20 hours, and steady-state concentrations are reached after four to five days after start of the treatment. Oxcarbazepine, for comparison, is also nearly completely absorbed from the gut, and peak plasma concentrations of licarbazepine are reached after 4.5 hours on average after oxcarbazepine intake. Plasma protein binding and half-life are of course the same. Other metabolites of ESL are the less active (''R'')-(−)-licarbazepine (5%; the

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

of eslicarbazepine), the pharmacologically active oxcarbazepine (1%), and inactive

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

s of all of these substances. The drug is excreted mainly via the urine, of which two thirds are in the form of eslicarbazepine and one third in the form of eslicarbazepine glucuronide. The other metabolites only account for a few percent of the excreted drug.

Pharmacogenomics

Persons with certain genetic variations in

human leukocyte antigen The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of th ...

s (HLAs) are under increased risk of developing skin reactions such as

acute generalized exanthematous pustulosis Acute generalized exanthematous pustulosis (AGEP) (also known as pustular drug eruption and toxic pustuloderma) is a rare skin reaction that in 90% of cases is related to medication administration. AGEP is characterized by sudden skin eruptions th ...

(AGEP), but also severe ones such as Stevens–Johnson and

DRESS syndrome Drug reaction with eosinophilia and systemic symptoms (DRESS), also termed drug-induced hypersensitivity syndrome (DIHS), is a rare reaction to certain medications. It involves primarily a widespread skin rash, fever, swollen lymph nodes, and c ...

, under treatment with carbamazepine and drugs with related chemical structures. This is true for the

HLA-A HLA-A is a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of ...

*3101 allele, which occurs in 2 to 5% of Europeans and 10% of Japanese people, and the

HLA-B HLA-B (major histocompatibility complex, class I, B) is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen (HLA) compl ...

*1502 allele, which is mainly found in people of Asian descent. Theoretically, this may also apply to ESL.

Chemistry

As the name suggests, eslicarbazepine acetate is the acetate

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides a ...

prodrug of eslicarbazepine. Eslicarbazepine itself is the pharmacologically more active of the two stereoisomers of licarbazepine. More specifically, it is (''S'')-(+)-licarbazepine. ;Related drugs and active metabolites for comparison: File:Eslicarbazepine structure.svg, Eslicarbazepine, the active metabolite of ESL File:Oxcarbazepine.svg,

Oxcarbazepine Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalized seizures. It has been used both alone and as add-on therapy in people with ...

File:Licarbazepine structure.svg, Licarbazepine, the active metabolite of oxcarbazepine File:Carbamazepine.svg,

History

Eslicarbazepine acetate was developed by the Portuguese pharmaceutical company Bial. In early 2009, Bial sold the marketing rights in Europe to the Japanese company

Eisai was a Japanese Buddhist priest, credited with founding the Rinzai school, the Japanese line of the Linji school of Zen Buddhism. In 1191, he introduced this Zen approach to Japan, following his trip to China from 1187 to 1191, during which he w ...

. The drug was approved in the European Union in April 2009 under the trade names ''Zebinix'' and ''Exalief'', but was marketed only under the first name. In the US it is marketed by Sunovion (formerly Sepracor) and was approved in November 2013.

Research

Studies for the use of ESL as an anticonvulsant for children are under way . Like oxcarbazepine, ESL has potential uses for the treatment of

trigeminal neuralgia Trigeminal neuralgia (TN or TGN), also called Fothergill disease, tic douloureux, or trifacial neuralgia is a long-term pain disorder that affects the trigeminal nerve, the nerve responsible for sensation in the face and motor functions such as ...

and

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

. A 2015 assessment showed no statistical difference to placebo for the latter disorder.

References

External links

* {{DEFAULTSORT:Eslicarbazepine Acetate Acetate esters Anticonvulsants CYP3A4 inducers Dibenzazepines Enantiopure drugs Portuguese inventions Ureas