Rufinamide

Absorption

The oral suspension and tablet are bioequivalent on a mg per mg basis. Rufinamide is well absorbed but the rate is slow and the extent of absorption decreases as dose is increases. Based on urinary excretion, the extent of absorption was at least 85% following oral administration of a single dose of 600 mg rufinamide tablet under fed conditions. Bioavailability= 70%-85% (decreases with increasing doses); Tmax, fed and fasted states= 4-6 hours; Cmax, 10 mg/kg/day= 4.01 μL/mL; Cmax, 30mg/kg/day= 8.68 μL/mL; AUC (0h-12h), 10mg/kg/day= 37.8±47 μg·h/mL; AUC (0h-12h), 30mg/kg/day= 89.3±59 μg·h/mL.

Toxicity

The most commonly observed adverse reactions (≥10% and greater than placebo) were headache, dizziness, fatigue, somnolence, and nausea.

Description

Approximately 2.5 million people worldwide are afflicted with epilepsy, a devastating neurological disorder diagnosed by the tendency toward recurrent, unprovoked seizures, often of unknown etiology. Rufinamide has been launched primarily as adjunctive therapy of LGS. Its proposed mechanism of action involves the limitation of firing of sodium-dependent action potentials. The ultimate result is membrane stabilization. Since it does not exhibit measurable binding to monoamine, acetylcholine, histamine, glycine, AMPA/kainate, NMDA, or GABA receptors or systems, these receptor-mediated pathways are not anticipated to be involved in the exertion of rufinamide’s effects. Rufinamide displayed efficacy in several electrical and chemical animal seizure models.

Description

Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple seizure types. Rufinamide is an anticonvulsant. It inhibits the activation of voltage-gated sodium channel 1.1 (Na_v1.1) when used at a concentration of 100 μM. Rufinamide inhibits Na_v1.1, but not Na_v1.2, Na_v1.3, and Na_v1.6, opening and increases the action potential threshold in primary rat hippocampal neurons. It is an inhibitor of carbonic anhydrase VA (CAVA; K_i = 343.8 nM) that is selective for CAVA over CAI and CAII (K_is = >10,000 nM for both). Rufinamide (100 μM) prolongs the preictal phase and reduces seizure-like event frequency in an in vitro model of epileptiform activity in rat hippocampal slices. It inhibits seizures induced by pentylenetetrazole in a mouse model of epilepsy (ED₅₀ = 54 mg/kg, i.p.) and reduces kainic acid-induced neuronal cell death in the mouse hippocampal CA3 region when used at doses of 25, 50, and 100 mg/kg. Formulations containing rufinamide have been used in the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS).

Chemical properties

White Solid

Originator

Novartis (US)

The Uses of Rufinamide

Labelled Rufinamide (R701552). Antiepileptic triazole derivative which decreases firing by neurons at sodium channels. Anticonvulsant.

The Uses of Rufinamide

Rufinamide, a triazole derivative, is an anticonvulsant medication. It is used in combination with other medication and therapy to treat Lennox–Gastaut syndrome and various other seizure disorders. Rufinamide is presumed to involve stabilization of the so

The Uses of Rufinamide

Rufinamide has been used to test its analgesic effect on neuropathic pain in spared nerve injury (SNI) model.

Indications

Adjunct therapy for treatment of seizures associated with Lennox-Gastaut syndrome.

Background

Rufinamide is a triazole derivative and an anticonvulsant medication to treat seizure disorders like Lennox-Gastuat syndrome, a form of childhood epilepsy. Clinical trials suggest its efficacy in the treatment of partial seizures.

What are the applications of Application

Rufinamide is a sodium channel protein inhibitor

Definition

ChEBI: Rufinamide is a heteroarene and an aromatic amide.

brand name

Inovelon

General Description

An antiepileptic drug and anticonvulsant, Rufinamide is approved for the treatment of partial seizures associated with Lennox-Gastaut syndrome in adults and children 4 years and older. Rufinamide is marketed as Banzel® in the US and Inovelon® in the EU.

Biological Activity

Board spectrum anticonvulsant. Prolongs the inactivation of sodium channels and limits the frequency of action potential firing in cultured and acutely isolated neurons. Displays anticonvulsive activity in a range of animal seizure models.

Biochem/physiol Actions

Broad-spectrum anticonvulsant.

Pharmacokinetics

At high concentrations will inhibit action of mGluR5 subtype receptors thus preventing the production of glutamate.

Clinical Use

Adjunctive treatment of seizures in Lennox-Gastaut syndrome

Side Effects

Rufinamide was well tolerated with the most common adverse events including fatigue, somnolence, tremors, mild-to-moderate dizziness, nausea, headache, and diplopia. Since rufinamide is not metabolized by the CYP450 system, it is anticipated to have a low potential for interaction with drugs metabolized by the CYP isozymes. Rufinamide, however, does exhibit clinically relevant interactions with other antiepileptic drugs; concomitant treatment with valproate results in a reduction in rufinamide clearance while concomitant treatment with phenytoin, primidone, phenobarbital, carbamazepine, or vigabatrin causes an increase in rufinamide clearance. In these situations, rufinamide dosage adjustment may be required.

Synthesis

While rufinamide may be prepared by several related routes, the preferred starting material is 2,6-difluorobenzyl azide. Reaction with either 2-propynoic acid or 2-chloroacrylonitrile affords 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid or 1-(2,6-difluorobenzyl)- 1H-1,2,3-triazole-4-carbonitrile, respectively. For the carboxylic acid Shridhar Hegde and Michelle Schmidt intermediate, treatment with thionyl chloride followed by concentrated aqueous ammonium hydroxide or conversion to its methyl ester (methanol/sulfuric acid) with subsequent ammonolyis provides rufinamide.

Drug interactions

Potentially hazardous interactions with other drugs
Antidepressants: antagonism of anticonvulsant effect (convulsive threshold lowered); avoid with St John’s wort.
Antimalarials: mefloquine antagonises anticonvulsant effect.
Antipsychotics: antagonism of anticonvulsant effect (convulsive threshold lowered).
Oestrogens and progestogens: metabolism accelerated by rufinamide - reduced contraceptive effect.
Orlistat: possibly increased risk of convulsions with orlistat.
Ulipristal: possibly reduces contraceptive effect.

Metabolism

Rufinamide is extensively metabolized but has no active metabolites. Metabolism by carboxyesterases into inactive metabolite CGP 47292, a carboxylic acid derivative, via hydrolysis is the primary biotransformation pathway. A few minor additional metabolites were detected in urine, which appeared to be acyl-glucuronides of CGP 47292. The cytochrome P450 enzyme system or glutathiones are not involved with the metabolism of rufinamide. Rufinamide is a weak inhibitor of CYP 2E1. Rufinamide is a weak inducer of CYP 3A4 enzymes.

Metabolism

Almost exclusively eliminated by metabolism via hydrolysis of the carboxylamide group to the pharmacologically inactive acid derivative CGP 47292. Cytochrome P450-mediated metabolism is very minor. The formation of small amounts of glutathione conjugates cannot be completely excluded. 84.7% was excreted by the renal route.

storage

room temperature (desiccate)

References

1) Hakimian et al. (2007), Rufinamide: a new anti-epileptic medication; Expert Opin. Pharmacother. 8 1931 2) Gilchrist et al. (2014), Nav1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents; ACS Chem. Biol. 9 1204 3) Chen et al. (2018), Rufinamide, an antiepileptic drug, improves cognition and increases neurogenesis in the aged gerbil hippocampal dentate gyrus via increasing expressions of IGF-1, IGF-1R and p-CREB; Chem. Biol. Interact. 286 71