Identification

Name
Stiripentol
Accession Number
DB09118
Type
Small Molecule
Groups
Approved
Description

Stiripentol is an anticonvulsant drug used in the treatment of epilepsy as an adjunct therapy along with Clobazam and Valproic Acid. This drug is currently approved in the USA, Canada, and European countries as oral tablets marketed as Diacomit. FDA approval of this drug was granted on August 20, 2018 [6], [7]. Unrelated to other anticonvulsants, stiripentol belongs to the group of aromatic allylic alcohols and may potentiate the effect of other antiepileptic drugs (AEDs) due to pharmacokinetic interactions. It elevates the levels of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter that regulates electrical activity in the central nervous system.

Structure
Thumb
Synonyms
  • 1-(1,3-Benzodioxol-5-yl)-4,4-dimethyl-1-penten-3-ol
  • 4,4-Dimethyl-1-((3,4-methylenedioxy)phenyl)-1-penten-3-ol
  • Estiripentol
  • Stiripentol
  • Stiripentolum
External IDs
BCX 2600 / BCX-2600 / BRN 1313047
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DiacomitCapsule250 mgOralBiocodex Sa2013-05-01Not applicableCanada
DiacomitCapsule500 mgOralBiocodex2007-01-04Not applicableEu
DiacomitPowder, for suspension500 mgOralBiocodex2007-01-04Not applicableEu
DiacomitPowder, for suspension1 mg/1mgOralBIOCODEX INC.2018-08-21Not applicableUs
DiacomitPowder, for suspension250 mgOralBiocodex Sa2013-05-01Not applicableCanada
DiacomitCapsule500 mgOralBiocodex2007-01-04Not applicableEu
DiacomitPowder, for suspension500 mgOralBiocodex2007-01-04Not applicableEu
DiacomitCapsule250 mg/1OralBIOCODEX INC.2018-08-21Not applicableUs
DiacomitCapsule250 mgOralBiocodex2007-01-04Not applicableEu
DiacomitPowder, for suspension250 mgOralBiocodex2007-01-04Not applicableEu
Categories
UNII
R02XOT8V8I
CAS number
49763-96-4
Weight
Average: 234.295
Monoisotopic: 234.12559444
Chemical Formula
C14H18O3
InChI Key
IBLNKMRFIPWSOY-FNORWQNLSA-N
InChI
InChI=1S/C14H18O3/c1-14(2,3)13(15)7-5-10-4-6-11-12(8-10)17-9-16-11/h4-8,13,15H,9H2,1-3H3/b7-5+
IUPAC Name
(1E)-1-(2H-1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-ol
SMILES
CC(C)(C)C(O)\C=C\C1=CC2=C(OCO2)C=C1

Pharmacology

Indication

Indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy (SMEI, Dravet’s syndrome) whose seizures are not adequately controlled with clobazam and valproate.

Associated Conditions
Pharmacodynamics

Stiripentol is an orphan drug that effectively reduces seizure frequency in infantile epilepsy as an adjunct therapy and also exhibits a therapeutic advantage in improving the efficacy of other antiepileptic drugs. It potentiates GABA transmission by elevating the levels of the inhibitory neurotransmitters in the brain [2]. Stiripentol is a positive allosteric modulator of GABA-A receptors in the brain that enhances the opening duration of the channel by binding to a site different than the benzodiazepine binding site [1]. Reduced synaptosomal uptake of GABA and/or inhibition of GABA transaminase may also explain the role of stiripentol in reducing the events of seizure [5]. The anticonvulsant activity of stiripentol is age-dependent, with increased efficacy in younger patients [4].

Mechanism of action

Stiripentol enhances GABAergic inhibition and prolongs the open duration of GABA-A receptor chloride channels by a barbiturate-like mechanism [5]. It binds to GABA-A receptors containing any of the α, β, γ, or δ-subunits but displays strongest potency when bound to receptors containing α3 or δ subunits [4]. Stiripentol is an inhibitor of lactate dehydrogenase (LDH), which plays a physiological role in energy metabolism of neurons and regulation of neuronal excitation. It binds to the site separate from lactate and pyruvate binding sites of the enzyme and inhibits both pyruvate-to-lactate conversion and lactate-to-pyruvate conversion [3]. LDH inhibitors including stiripentol as antiepileptic treatments mimic ketogenic diet, where the energy source in the brain is switched from glucose to mainly ketone bodies. The ketone bodies directly regulate neuronal excitation and seizures via ATP-sensitive potassium channels and vesicular glutamate transporters [3]. As a potent inhibitor of hepatic cytochrome P450 enzymes, mainly CYP3A4 and CYP2C19, stiripentol co-administration with other antiepileptic drugs elevates the free unchanged active drugs (such as carbamazepine, sodium valproate, phenytoin, phenobarbital and many benzodiazepines) in the circulation to mediate their therapeutic actions.

TargetActionsOrganism
AGABA-A receptor (anion channel)
agonist
positive allosteric modulator
Human
AL-lactate dehydrogenase A chain
inhibitor
Human
AL-lactate dehydrogenase B chain
inhibitor
Human
Absorption

Absorption of stiripentol is quick with the peak plasma concentration reached within 1.5 hours following oral administration. The systemic exposure increases in a dose-proportional relationship [5]. It is rapidly taken up into the brain and enters the cerebellum and medulla. It displays low bioavailability due to water insolubility and metabolism [2].

Volume of distribution

The average volume of distribution is 1.03 L/kg but does not display a dose-dependent relationship. It is expected to be distributed into the extravascular space and with a high degree of tissue binding [2].

Protein binding

Stiripentol binds extensively to circulating plasma proteins (about 99%) [5].

Metabolism

There are 13 metabolites from extensive metabolism stiripentol that are found in urine. The predominant metabolic pathways involve demethylenation and glucuronidation. Other metabolic pathways are oxidative cleavage of the methylenedioxy ring system, O-methylation of catechol metabolites, hydroxylation of the t-butyl group and conversion of the allylic alcohol side-chain to the isomeric 3-pentanone structure [2]. Based on in vitro studies, phase I metabolism of stiripentol involves enzymatic activity of CYP1A2, CYP2C19 and CYP3A4 [5].

Route of elimination

Renal elimination is mainly responsible for excretion of stiripentol. About 73% of total administered dose is found in urine as metabolites, while further 13-24% of the total dose is recovered in faeces as unchanged substance [5].

Half life

Elimination half life is approximately ranges from 4.5 to 13 hours, in a dose-dependent manner [5].

Clearance

Plasma clearance decreases markedly at high doses; it falls from approximately 40 L/kg/day at the dose of 600 mg/day to about 8 L/kg/day at the dose of 2,400 mg [5]. Decreased clearance is probably explained by inhibition of the cytochrome P450 isoenzymes that catalyzes stiripentol metabolism [5].

Toxicity

Most common adverse effects include anorexia, loss of appetite, nausea, vomiting, weight loss, reversible neutropenia, insomnia, drowsiness, ataxia, dystonia, hyperkinesia, hypotonia. Aggression, irritability, behaviour disorders, opposing behaviour, hyper excitability and sleep disorders may also be observed. Stiripentol does not demonstrate teratogenic, mutagenic, clastogenic, or carcinogenic potential [5]. Oral LD50 in rats is >3 g/kg [MSDS].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Stiripentol.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Stiripentol.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Stiripentol is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Stiripentol.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Stiripentol.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Stiripentol.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Stiripentol.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Stiripentol.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Stiripentol.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Stiripentol.
Food Interactions
Not Available

References

General References
  1. Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H: Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels. Epilepsia. 2006 Apr;47(4):704-16. [PubMed:16650136]
  2. Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ: Stiripentol. A novel antiepileptic drug. Pharmacol Rep. 2005 Mar-Apr;57(2):154-60. [PubMed:15886413]
  3. Sada N, Lee S, Katsu T, Otsuki T, Inoue T: Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science. 2015 Mar 20;347(6228):1362-7. doi: 10.1126/science.aaa1299. [PubMed:25792327]
  4. Grosenbaugh DK, Mott DD: Stiripentol in refractory status epilepticus. Epilepsia. 2013 Sep;54 Suppl 6:103-5. doi: 10.1111/epi.12291. [PubMed:24001087]
  5. European Medicines Agency (EMA): DIACOMIT Summary of Product Characteristics [Link]
  6. FDA approved Drugs [Link]
  7. FDA label, Diacomit [File]
External Links
PubChem Compound
5311454
PubChem Substance
310265035
ChemSpider
4470940
ChEMBL
CHEMBL1983350
Wikipedia
Stiripentol
ATC Codes
N03AX17 — Stiripentol
AHFS Codes
  • 28:12.92 — Miscellaneous Anticonvulsants
MSDS
Download (56.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4No Longer AvailableNot AvailableDravet Syndrome1
4RecruitingTreatmentEpilepsies1
Not AvailableAvailableNot AvailableDravet Syndrome2
Not AvailableAvailableNot AvailableDravet Syndrome / Epileptic Encephalopathies Associated With SCN1A Mutations1
Not AvailableRecruitingNot AvailableEpilepsies1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral250 mg
CapsuleOral250 mg/1
CapsuleOral500 mg/1
CapsuleOral500 mg
Powder, for suspensionOral1 mg/1mg
Powder, for suspensionOral250 mg
Powder, for suspensionOral500 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)64MSDS
boiling point (°C)365.4MSDS
water solubilityInsoluble Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ, 2005.
logP3.53MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.405 mg/mLALOGPS
logP3.01ALOGPS
logP3.12ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)14.34ChemAxon
pKa (Strongest Basic)-3.1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area38.69 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity66.77 m3·mol-1ChemAxon
Polarizability26.21 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

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

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzodioxoles. These are organic compounds containing a benzene ring fused to either isomers of dioxole. Dioxole is a five-membered unsaturated ring of two oxygen atoms and three carbon atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodioxoles
Sub Class
Not Available
Direct Parent
Benzodioxoles
Alternative Parents
Styrenes / Secondary alcohols / Oxacyclic compounds / Acetals / Hydrocarbon derivatives
Substituents
Benzodioxole / Styrene / Benzenoid / Secondary alcohol / Oxacycle / Acetal / Organic oxygen compound / Hydrocarbon derivative / Organooxygen compound / Alcohol
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Agonist
Positive allosteric modulator
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:
References
  1. Fisher JL: The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator. Neuropharmacology. 2009 Jan;56(1):190-7. doi: 10.1016/j.neuropharm.2008.06.004. Epub 2008 Jun 10. [PubMed:18585399]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Nad binding
Specific Function
Not Available
Gene Name
LDHA
Uniprot ID
P00338
Uniprot Name
L-lactate dehydrogenase A chain
Molecular Weight
36688.465 Da
References
  1. Sada N, Lee S, Katsu T, Otsuki T, Inoue T: Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science. 2015 Mar 20;347(6228):1362-7. doi: 10.1126/science.aaa1299. [PubMed:25792327]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Nad binding
Specific Function
Not Available
Gene Name
LDHB
Uniprot ID
P07195
Uniprot Name
L-lactate dehydrogenase B chain
Molecular Weight
36638.225 Da
References
  1. Sada N, Lee S, Katsu T, Otsuki T, Inoue T: Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science. 2015 Mar 20;347(6228):1362-7. doi: 10.1126/science.aaa1299. [PubMed:25792327]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. European Medicines Agency (EMA): DIACOMIT Summary of Product Characteristics [Link]
  2. EMA label, stiripentol [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. European Medicines Agency (EMA): DIACOMIT Summary of Product Characteristics [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
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
References
  1. European Medicines Agency (EMA): DIACOMIT Summary of Product Characteristics [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Tran A, Rey E, Pons G, Rousseau M, d'Athis P, Olive G, Mather GG, Bishop FE, Wurden CJ, Labroo R, Trager WF, Kunze KL, Thummel KE, Vincent JC, Gillardin JM, Lepage F, Levy RH: Influence of stiripentol on cytochrome P450-mediated metabolic pathways in humans: in vitro and in vivo comparison and calculation of in vivo inhibition constants. Clin Pharmacol Ther. 1997 Nov;62(5):490-504. doi: 10.1016/S0009-9236(97)90044-8. [PubMed:9390105]
  2. Chiron C: Stiripentol. Expert Opin Investig Drugs. 2005 Jul;14(7):905-11. doi: 10.1517/13543784.14.7.905 . [PubMed:16022579]
  3. EMA label, stiripentol [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ: Stiripentol. A novel antiepileptic drug. Pharmacol Rep. 2005 Mar-Apr;57(2):154-60. [PubMed:15886413]

Drug created on September 22, 2015 13:59 / Updated on December 18, 2018 05:46