Voltage-gated sodium channel (VGSC)

Cenobamate (YKP-3089) is proposed to exert antiseizure effects by selectively blocking the inactivated state of the sodium channel and by preferentially blocking persistent sodium current. It is also proposed to facilitate increased presynaptic GABA release to potentiate inhibitory synaptic transmission.[1]

Cenobamate (YKP-3089) is a tetrazole derivative with antiseizure properties reported in multiple animal models of epilepsy. YKP3089 has demonstrated anticonvulsant activity in several animal seizure models including 6 Hz, hippocampus kindling, electroshock, PTZ, picrotoxin, and pilocarpine-induced seizure models.[1]

A recent report analyzed the seizure-free rates in two double-blind placebo-controlled studies of patients with refractory partial-onset seizures treated with YKP3089. The first was a phase II randomized, double-blind, placebo-controlled 12-week study of YKP3089 assessing the efficacy and tolerability of 200 mg/day YKP3089 as adjunctive therapy in patients with partial-onset seizures (NCT01397968). The study enrolled approximately 222 patients and the primary outcome measure was percent change in seizure frequency as compared to baseline over the course of a 12-week treatment period. Seizure-free rates were 28% for YKP3089 compared to 9% for placebo. The other phase II, double-blind, placebo-controlled dose–response study was conducted in 437 patients who were randomized to placebo or 100, 200, and 400 mg/day YKP3089 (NCT01866111). YKP3089 100, 200, and 400 mg/day produced seizure-free rates of 3%, 11%, and 20% respectively as compared to 1% with placebo. Adverse effects were dose related and included somnolence, dizziness, diplopia, and gait disturbances. Currently, an open-label, multicenter, safety, and pharmacokinetic study of YKP3089 as adjunctive therapy in patients with partial-onset seizures is recruiting participants with a planned enrollment of 1200 patients (NCT02535091). Results are expected in 2018.

Absorption, Distribution and Excretion
Cenobamate is 88% orally bioavailable with a Tmax of 1-4 hours. A high fat meal does not significantly impact the pharmacokinetics of cenobamate.
Cenobamate is 87.8% eliminated in the urine and 5.2% in the feces.
The apparent volume of distribution of cenobamate is 40-50L.
The apparent oral clearance of cenobamate is 0.45-0.63L/h for a 100-400mg/day dose.

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Metabolism / Metabolites
Data regarding the metabolism of cenobamate is lacking, however it is mostly glucuronidated by UGT2B7 and UGT2B4 or oxidized by a number of cytochromes.

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Biological Half-Life
The terminal half life of cenobamate is 50-60h.

Hepatotoxicity
In controlled clinical trials, addition of cenobamate to standard anticonvulsant therapy was associated with transient, mild-to-moderate serum aminotransferase elevations in 1% to 4% of patients. In the preregistration trials of cenobamate, there were no cases of clinically apparent liver injury with jaundice. However, among 953 patients with exposure to cenobamate in these trials, there were three cases of DRESS syndrome accompanied by serum aminotransferase elevations, which arose during the first 3 to 6 weeks of treatment in subjects who had a relative rapid initial titration (4 to 6 weeks). In large open label studies using a more prolonged titration period (12 weeks), no instances of DRESS syndrome were reported among more than 1000 participants. Felbamate, a structurally related carbamate anticonvulsant, is a well-known cause of drug induced liver injury and has a boxed warning and restricted availability because of severe hypersensitivity reactions including acute liver failure and aplastic anemia. Thus, clinically significant liver injury from cenobamate may occur and can be severe, but is rare.
Likelihood score: D (possible rare cause of clinically apparent liver injury in the context of generalized hypersensitivity syndrome).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of cenobamate during breastfeeding. If cenobamate is required by a nursing mother, 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. Monitor the infant for excessive drowsiness.
◉ 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
Cenobamate is 60% protein bound in plasma, mainly serum albumin.

[1]. Expert Review of Clinical Pharmacology. 11 (1): 27–45. doi:10.1080/17512433.2018.1386553
[2]. Emerging drugs for focal epilepsy. Expert Opin Emerg Drugs. 2013Mar;18(1):87-95. doi: 10.1517/14728214.2013.750294;

Cenobamate is a DEA Schedule V controlled substance. Substances in the DEA Schedule V have a low potential for abuse relative to substances listed in Schedule IV and consist primarily of preparations containing limited quantities of certain narcotics. It is a Depressants substance.
Cenobamate, or YKP-3089, is an antiepileptic drug developed by SK Pharmaceuticals and used to treat partial onset seizures. The exact mechanism of action has not been described in the literature, though it positively modulates GABAA and inhibits voltage gated sodium channels. Cenobamate was granted FDA approval on 21 November 2019.
The mechanism of action of cenobamate is as a Sodium Channel Antagonist, and GABA A Receptor Positive Modulator, and Cytochrome P450 2B6 Inhibitor, and Cytochrome P450 2C19 Inhibitor, and Cytochrome P450 3A Inhibitor, and Cytochrome P450 2B6 Inducer, and Cytochrome P450 2C8 Inducer, and Cytochrome P450 3A4 Inducer.
Cenobamate is a tetrazole carbamate anticonvulsant used as therapy of partial onset seizures in adults. Cenobamate is associated with a low-to-moderate rate of serum aminotransferase elevations during therapy and has been linked to cases of clinically apparent liver injury usually in the context of a multiorgan hypersensitivity syndrome such as drug reaction with eosinophilia and systemic symptoms (DRESS).

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Drug Indication
Cenobamate is indicated for the treatment of partial onset seizures in adults.
Adjunctive treatment of focal-onset seizures with or without secondary generalisation in adult patients with epilepsy who have not been adequately controlled despite a history of treatment with at least 2 anti-epileptic medicinal products.
Treatment of epilepsy

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Mechanism of Action
Cenobamate inhibits voltage gated sodium channels and is a positive GABA_A modulator. However, the exact mechanism of action remains unknown. Inhibition of voltage gated sodium channels increases the threshold for generating action potentials and decreases the number of action potentials.

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Pharmacodynamics
The mechanism of cenobamate is unknown, however it modulates GABA_A and inhibit voltage gated sodium channels. Cenobamate is given once daily and so it has a long duration of action. The therapeutic window is wide as doses of 750mg can be well tolerated. Patients should be counselled regarding the risk of DRESS syndrome, QT interval shortening, suicidal behavior, and neurological adverse effects.

C10H10CLN5O2

267.671700000763

267.052

913088-80-9

913088-80-9 913087-59-9

11962412

Typically exists as solid at room temperature

1.5

1

5

5

18

293

1

C1=CC=C(C(=C1)[C@H](CN2N=CN=N2)OC(=O)N)Cl

GFHAXPJGXSQLPT-VIFPVBQESA-N

InChI=1S/C10H10ClN5O2/c11-8-4-2-1-3-7(8)9(18-10(12)17)5-16-14-6-13-15-16/h1-4,6,9H,5H2,(H2,12,17)/t9-/m0/s1

(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate

YKP-3089; YKP3089; YKP3089; Cenobamate; Xcopri; 913088-80-9; Cenobamate [INN]; UNII-P85X70RZWS; P85X70RZWS; trade name: Xcopr;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.)