Identification

Name
Rufinamide
Accession Number
DB06201
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
Synonyms
  • Xilep
External IDs
CGP 33101 / E 2080 / E-2080 / E2080 / RUF 331
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BanzelSuspension40 mgOralEisai LimitedNot applicableNot applicableCanada
BanzelTablet100 mgOralEisai Limited2011-10-20Not applicableCanada
BanzelTablet, film coated200 mg/1OralEisai Limited2008-11-14Not applicableUs62856 0582 52 nlmimage10 483a2471
BanzelTablet400 mgOralEisai Limited2011-09-01Not applicableCanada
BanzelSuspension40 mg/1mLOralEisai Limited2011-03-03Not applicableUs
BanzelTablet200 mgOralEisai Limited2011-08-29Not applicableCanada
BanzelTablet, film coated400 mg/1OralEisai Limited2008-11-14Not applicableUs62856 0583 52 nlmimage10 ff39ff8f
InovelonTablet, film coated400 mgOralEisai Limited2007-01-16Not applicableEu
InovelonTablet, film coated200 mgOralEisai Limited2007-01-16Not applicableEu
InovelonTablet, film coated200 mgOralEisai Limited2007-01-16Not applicableEu
International/Other Brands
Banzel / Inovelon (Eisai Inc. )
Categories
UNII
WFW942PR79
CAS number
106308-44-5
Weight
Average: 238.1935
Monoisotopic: 238.066617308
Chemical Formula
C10H8F2N4O
InChI Key
POGQSBRIGCQNEG-UHFFFAOYSA-N
InChI
InChI=1S/C10H8F2N4O/c11-7-2-1-3-8(12)6(7)4-16-5-9(10(13)17)14-15-16/h1-3,5H,4H2,(H2,13,17)
IUPAC Name
1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide
SMILES
NC(=O)C1=CN(CC2=C(F)C=CC=C2F)N=N1

Pharmacology

Indication

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

Associated Conditions
Pharmacodynamics

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

Mechanism of action

Rufinamide is a triazole derivative antiepileptic that prolongs the inactive state of voltage gated sodium channels thus stabilizing membranes, ultimately blocking the spread of partial seizure activity.

TargetActionsOrganism
UMetabotropic glutamate receptor 5
inhibitor
Human
USodium channel protein type 9 subunit alpha
modulator
Human
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.

Volume of distribution

Rufinamide was evenly distributed between erythrocytes and plasma. The apparent volume of distribution is dependent upon dose and varies with body surface area. The apparent volume of distribution was about 50 L at 3200 mg/day. Volume of distribution is similar between adults and children and is non-linear.

Protein binding

26.3% - 34.8% with 90% binding to albumin (27%).

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.

Route of elimination

Renally (91%; 66% as CGP 47292, 2% as unchanged drug) and fecally (9%) eliminated.

Half life

Elimination half-life, healthy subjects and patients with epilepsy = 6-10 hours.

Clearance
Not Available
Toxicity

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

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AlbendazoleThe metabolism of Albendazole can be increased when combined with Rufinamide.
AlclometasoneThe metabolism of Alclometasone can be increased when combined with Rufinamide.
AlfuzosinThe metabolism of Alfuzosin can be increased when combined with Rufinamide.
AmcinonideThe metabolism of Amcinonide can be increased when combined with Rufinamide.
AmlodipineThe metabolism of Amlodipine can be increased when combined with Rufinamide.
AprepitantThe metabolism of Aprepitant can be increased when combined with Rufinamide.
AsunaprevirThe serum concentration of Asunaprevir can be decreased when it is combined with Rufinamide.
AzithromycinThe metabolism of Azithromycin can be increased when combined with Rufinamide.
BetamethasoneThe metabolism of Betamethasone can be increased when combined with Rufinamide.
BexaroteneThe metabolism of Bexarotene can be increased when combined with Rufinamide.
Food Interactions
  • Food increases plasma concentrations of rufinamide and slightly decreases half-life (by 3%)

References

Synthesis Reference

Emanuele ATTOLINO, Lino COLOMBO, Ilaria MORMINO, Pietro ALLEGRINI, "METHOD FOR THE PREPARATION OF RUFINAMIDE." U.S. Patent US20100234616, issued September 16, 2010.

US20100234616
General References
  1. Arroyo S: Rufinamide. Neurotherapeutics. 2007 Jan;4(1):155-62. [PubMed:17199032]
  2. Hakimian S, Cheng-Hakimian A, Anderson GD, Miller JW: Rufinamide: a new anti-epileptic medication. Expert Opin Pharmacother. 2007 Aug;8(12):1931-40. [PubMed:17696794]
  3. Authors unspecified: Rufinamide: CGP 33101, E 2080, RUF 331, Xilep. Drugs R D. 2005;6(4):249-52. [PubMed:15991887]
  4. Wier HA, Cerna A, So TY: Rufinamide for pediatric patients with Lennox-Gastaut syndrome: a comprehensive overview. Paediatr Drugs. 2011 Apr 1;13(2):97-106. doi: 10.2165/11586920-000000000-00000. [PubMed:21351809]
External Links
KEGG Drug
D05775
PubChem Compound
129228
PubChem Substance
175427055
ChemSpider
114471
ChEBI
134966
ChEMBL
CHEMBL1201754
PharmGKB
PA166131606
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Rufinamide
ATC Codes
N03AF03 — Rufinamide
AHFS Codes
  • 28:12.92 — Miscellaneous Anticonvulsants
FDA label
Download (562 KB)
MSDS
Download (76.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceSeizures1
2CompletedTreatmentGeneralized Anxiety Disorder (GAD)1
2WithdrawnTreatmentPain / Peripheral Nerve Injury (PNI)1
3CompletedTreatmentEpilepsies1
3CompletedTreatmentLennox-Gastaut Syndrome (LGS)3
3CompletedTreatmentRefractory Partial Onset Seizures1
4RecruitingTreatmentEpilepsies1
Not AvailableRecruitingNot AvailableLennox-Gastaut Syndrome (LGS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SuspensionOral40 mg
SuspensionOral40 mg/1mL
TabletOral100 mg
TabletOral200 mg
TabletOral400 mg
Tablet, film coatedOral200 mg/1
Tablet, film coatedOral400 mg/1
SuspensionOral40 mg/ml
Tablet, film coatedOral100 mg
Tablet, film coatedOral200 mg
Tablet, film coatedOral400 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7750028Yes1999-04-192019-04-19Us
US8076362Yes1998-12-082018-12-08Us
US6740669Yes2003-05-142023-05-14Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsoluble FDA label
logP0.835MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.642 mg/mLALOGPS
logP0.95ALOGPS
logP1.27ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)12.69ChemAxon
pKa (Strongest Basic)-1.1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area73.8 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity67.07 m3·mol-1ChemAxon
Polarizability20.42 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9777
Caco-2 permeable-0.5301
P-glycoprotein substrateNon-substrate0.7407
P-glycoprotein inhibitor INon-inhibitor0.9422
P-glycoprotein inhibitor IINon-inhibitor0.9633
Renal organic cation transporterNon-inhibitor0.6685
CYP450 2C9 substrateNon-substrate0.8452
CYP450 2D6 substrateNon-substrate0.8723
CYP450 3A4 substrateNon-substrate0.5567
CYP450 1A2 substrateNon-inhibitor0.5
CYP450 2C9 inhibitorNon-inhibitor0.8201
CYP450 2D6 inhibitorNon-inhibitor0.8454
CYP450 2C19 inhibitorNon-inhibitor0.5561
CYP450 3A4 inhibitorNon-inhibitor0.7995
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5438
Ames testAMES toxic0.6126
CarcinogenicityNon-carcinogens0.8415
BiodegradationNot ready biodegradable0.9945
Rat acute toxicity2.5067 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9484
hERG inhibition (predictor II)Non-inhibitor0.7869
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-004i-0910000000-a314da5a33a86592abf7
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-004i-0900000000-781e2b7783abce7a674e
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-004i-0900000000-bca7363efb0d671e2fb1
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-004i-0900000000-669fadc72a03a956a9eb
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-004i-0900000000-f083b635f8c982b0967a
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-004i-0900000000-2e6c721563aec618517e
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-2920000000-3337dbd96c7fe51848b9
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-3900000000-ba447bc09eda637e577b

Taxonomy

Description
This compound belongs to the class of organic compounds known as 2-heteroaryl carboxamides. These are compounds containing a heteroaromatic ring that carries a carboxamide group.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Carboxylic acid derivatives
Direct Parent
2-heteroaryl carboxamides
Alternative Parents
Fluorobenzenes / Aryl fluorides / Vinylogous amides / Triazoles / Heteroaromatic compounds / Primary carboxylic acid amides / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds
show 3 more
Substituents
2-heteroaryl carboxamide / Fluorobenzene / Halobenzene / Aryl fluoride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Azole / 1,2,3-triazole / Heteroaromatic compound
show 14 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Glutamate receptor activity
Specific Function
G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down...
Gene Name
GRM5
Uniprot ID
P41594
Uniprot Name
Metabotropic glutamate receptor 5
Molecular Weight
132467.635 Da
References
  1. Wier HA, Cerna A, So TY: Rufinamide for pediatric patients with Lennox-Gastaut syndrome: a comprehensive overview. Paediatr Drugs. 2011 Apr 1;13(2):97-106. doi: 10.2165/11586920-000000000-00000. [PubMed:21351809]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Modulator
General Function
Voltage-gated sodium channel activity
Specific Function
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a...
Gene Name
SCN9A
Uniprot ID
Q15858
Uniprot Name
Sodium channel protein type 9 subunit alpha
Molecular Weight
226370.175 Da
References
  1. Suter MR, Kirschmann G, Laedermann CJ, Abriel H, Decosterd I: Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state. Anesthesiology. 2013 Jan;118(1):160-72. doi: 10.1097/ALN.0b013e318278cade. [PubMed:23221868]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Triglyceride lipase activity
Specific Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acy...
Gene Name
CES1
Uniprot ID
P23141
Uniprot Name
Liver carboxylesterase 1
Molecular Weight
62520.62 Da
References
  1. Williams ET, Carlson JE, Lai WG, Wong YN, Yoshimura T, Critchley DJ, Narurkar M: Investigation of the metabolism of rufinamide and its interaction with valproate. Drug Metab Lett. 2011 Dec;5(4):280-9. [PubMed:22022867]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Drug created on March 19, 2008 10:17 / Updated on October 16, 2018 08:38