Eslicarbazepine acetate

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Eslicarbazepine acetate
Eslicarbazepine acetate structure.svg
Systematic (IUPAC) name
(S)-10-Acetoxy- 10,11-dihydro- 5H-dibenz[b,f]azepine- 5-carboxamide
Clinical data
Trade names Aptiom, Zebinix
AHFS/Drugs.com entry
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Protein binding ~30%[1]
Metabolism UGT(?)
Metabolites Eslicarbazepine (active), glucuronides (inactive), etc.
Biological half-life 10–20 hrs
Excretion ~90% renal
Identifiers
CAS Number 236395-14-5
ATC code N03AF04 (WHO)
PubChem CID: 179344
DrugBank DB09119
ChemSpider 156110
UNII BEA68ZVB2K
KEGG D09612
ChEBI CHEBI:87016
ChEMBL CHEMBL87992 YesY
Chemical data
Formula C17H16N2O3
Molecular mass 296.320 g/mol
  • CC(=O)OC2Cc1ccccc1N(C(N)=O)c3c2cccc3
  • InChI=1S/C17H16N2O3/c1-11(20)22-16-10-12-6-2-4-8-14(12)19(17(18)21)15-9-5-3-7-13(15)16/h2-9,16H,10H2,1H3,(H2,18,21)/t16-/m0/s1
  • Key:QIALRBLEEWJACW-INIZCTEOSA-N

Eslicarbazepine acetate (trade names Aptiom in the US and Zebinix in Europe), abbreviated as ESL, is an anticonvulsant medication approved for use in Europe and the United States as monotherapy or adjunctive therapy (additional therapy) for partial-onset seizures epilepsy.[2][3][4]

Similarly to oxcarbazepine, ESL behaves as a prodrug to (es)licarbazepine.[5] As such, their mechanisms of action are identical.[6]

Contraindications

Eslicarbazepine acetate is contraindicated in people with second- or third-degree atrioventricular block, a type of heart block.[7]

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 disorders such as diarrhoea, nausea and vomiting, rash (1.1%), and hyponatraemia (low sodium blood levels, 1.2%).[4][7]

Overdose

Symptoms of overdosing are similar to adverse effects of standard doses. They include (severe) hyponatraemia, somnolence, walking difficulties, hemiparesis (weakness of one side of the body), diplopia, and gastrointestinal disorders. No specific antidote is available. Eslicarbazepine and metabolites can be dialyzed.[4][7]

Interactions

Like oxcarbazepine, eslicarbazepine can reduce plasma levels of drugs that are metabolized by the liver enzymes CYP3A4 (verified in studies for simvastatin and the oral contraceptive levonorgestrel/ethinyl estradiol) and UDP-glucuronosyltransferase, and increase plasma levels of drugs metabolized by CYP2C19.[4][7]

Interaction studies have been conducted with a number of common anticonvulsants. Carbamazepine reduces blood plasma concentrations of eslicarbazepine, probably because it induces glucuronidation. This drug combination also increased the risk for diplopia, impaired coordination and dizziness in a clinical study. Phenytoin also reduces ESL plasma concentrations, probably due to inhibition of CYP2C19. Combinations with lamotrigine, topiramate, valproic acid or levetiracetam showed no relevant interactions in studies.[7]

Pharmacology

Mechanism of action

The active component, eslicarbazepine, has the same mechanism of action as oxcarbazepine (which is a prodrug for licarbazepine, the racemate of eslicarbazepine) and most likely the closely related carbamazepine. It stabilises the inactive state of voltage-gated sodium channels, allowing for less sodium to enter neural cells, which leaves them less excitable.[8] According to some sources, it has not been shown conclusively that this is the actual mechanism.[4][7]

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 is somewhat less than 40%. Biological half-life is 10 to 20 hours, and steady-state concentrations are reached after four to five days after start of the treatment.[4][7] 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.[9]

Other metabolites of ESL are the less active (R)-licarbazepine (5%; the stereoisomer of eslicarbazepine), the pharmacologically active oxcarbazepine (1%), and inactive glucuronides 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 accout for a few percent of the excreted drug.[4][7]

Pharmacogenomics

Persons with certain genetic variations in human leukocyte antigens (HLAs) are under increased risk of developing skin reactions such as acute generalized exanthematous pustulosis (AGEP), but also severe ones such as Stevens–Johnson and DRESS syndrome, under treatment with carbamazepine and drugs with related chemical structures. This is true for the HLA-A*3101 allele, which occurs in 2 to 5% of Europeans and 10% of Japanese people, and the HLA-B*1502 allele, which is mainly found in people of Asian descent. Theoretically, this may also apply to ESL.[7]

Physical and chemical properties

As the name suggests, eslicarbazepine acetate is an ester of eslicarbazepine, the active metabolite, and acetic acid. Eslicarbazepine itself is the pharmacologically more active of the two stereoisomers of licarbazepine.[4] More specifically, it is (S)-(+)-licarbazepine.

Related drugs and active metabolites for comparison

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.[10] 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.[11][12] In the US it is marketed by Sunovion (formerly Sepracor) and was approved in November 2013.[2]

Research

Studies for the use of ESL as an anticonvulsant for children are under way as of 2016.[13]

Like oxcarbazepine, ESL has potential uses for the treatment of trigeminal neuralgia[citation needed] and bipolar disorder. A 2015 assessment showed no statistical difference to placebo for the latter disorder.[14]

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 FDA Professional Drug Information about Aptiom.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Clinical trial number NCT00988156 for "Eslicarbazepine Acetate (BIA 2 093) as Therapy for Refractory Partial Seizures in Children" at ClinicalTrials.gov
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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