Stiripentol

Identification

Name

Stiripentol

Accession Number

DB09118

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.

Type

Small Molecule

Groups

Approved

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Stiripentol (DB09118)

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Weight

Average: 234.295
Monoisotopic: 234.12559444

Chemical Formula

C₁₄H₁₈O₃

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

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

• Dravet Syndrome

Contraindications & Blackbox Warnings

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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.

Target	Actions	Organism
AGABA(A) Receptor	agonist positive allosteric modulator	Humans
AL-lactate dehydrogenase A chain	inhibitor	Humans
AL-lactate dehydrogenase B chain	inhibitor	Humans

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.

Adverse Effects

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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

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Stiripentol which could result in a higher serum level.
Abametapir	The serum concentration of Stiripentol can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Stiripentol can be increased when combined with Abatacept.
Abemaciclib	The metabolism of Abemaciclib can be decreased when combined with Stiripentol.
Abiraterone	The serum concentration of Stiripentol can be increased when it is combined with Abiraterone.
Acalabrutinib	The metabolism of Acalabrutinib can be decreased when combined with Stiripentol.
Acarbose	Acarbose may decrease the excretion rate of Stiripentol which could result in a higher serum level.
Acebutolol	The metabolism of Acebutolol can be decreased when combined with Stiripentol.
Aceclofenac	Aceclofenac may decrease the excretion rate of Stiripentol which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Stiripentol which could result in a higher serum level.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

• Avoid alcohol. Ingesting alcohol may increase the dizziness and drowsiness that can be caused by stiripentol.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of stiripentol and may reduce its serum concentration.
• Take with a full glass of water.
• Take with food.

Products

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Unlock Additional Data
Diacomit	Capsule	250 mg	Oral	Biocodex	2007-01-04	Not applicable
Diacomit	Powder, for suspension	250 mg	Oral	Biocodex	2007-01-04	Not applicable
Diacomit	Capsule	250 mg/1	Oral	BIOCODEX, INC.	2018-08-21	Not applicable
Diacomit	Capsule		Oral	Biocodex Sa	2013-05-01	Not applicable
Diacomit	Capsule	500 mg	Oral	Biocodex	2007-01-04	Not applicable
Diacomit	Powder, for suspension	500 mg	Oral	Biocodex	2007-01-04	Not applicable
Diacomit	Powder, for suspension	250 mg/1	Oral	BIOCODEX, INC.	2018-08-21	Not applicable
Diacomit	Powder, for suspension		Oral	Biocodex Sa	2013-05-01	Not applicable
Diacomit	Capsule	250 mg	Oral	Biocodex	2007-01-04	Not applicable
Diacomit	Powder, for suspension	250 mg	Oral	Biocodex	2007-01-04	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Categories

ATC Codes

N03AX17 — Stiripentol

• N03AX — Other antiepileptics
• N03A — ANTIEPILEPTICS
• N03 — ANTIEPILEPTICS
• N — NERVOUS SYSTEM

Drug Categories

• Anticonvulsants
• Central Nervous System Agents
• Central Nervous System Depressants
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 Inhibitors (strong)
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strong)
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Dioxoles
• Drugs causing inadvertant photosensitivity
• Drugs that are Mainly Renally Excreted
• Miscellaneous Anticonvulsants
• Nervous System
• Photosensitizing Agents

Chemical TaxonomyProvided by Classyfire

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

Acetal / Alcohol / Aromatic heteropolycyclic compound / Benzenoid / Benzodioxole / Hydrocarbon derivative / Organic oxygen compound / Organooxygen compound / Oxacycle / Secondary alcohol

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Chemical Identifiers

UNII

R02XOT8V8I

CAS number

49763-96-4

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

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

RxNav

2054968

ChEMBL

CHEMBL1983350

Wikipedia

Stiripentol

AHFS Codes

• 28:12.92 — Miscellaneous Anticonvulsants

MSDS

Download (56.5 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Unknown Status	Treatment	Epilepsies	1
2	Active Not Recruiting	Treatment	Primary Hyperoxaluria	1
1	Completed	Basic Science	Healthy Volunteers	1
Not Available	Approved for Marketing	Not Available	Dravet Syndrome	1
Not Available	No Longer Available	Not Available	Dravet Syndrome	2
Not Available	No Longer Available	Not Available	Dravet Syndrome / Epileptic Encephalopathies Associated With SCN1A Mutations	1
Not Available	Recruiting	Not Available	Epilepsies	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral
Capsule	Oral	250 mg
Capsule	Oral	250 mg/1
Capsule	Oral	500 mg
Capsule	Oral	500 mg/1
Powder, for suspension	Oral
Powder, for suspension	Oral	250 mg
Powder, for suspension	Oral	250 mg/1
Powder, for suspension	Oral	500 mg
Powder, for suspension	Oral	500 mg/1

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	64	MSDS
boiling point (°C)	365.4	MSDS
water solubility	Insoluble	Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ, 2005.
logP	3.53	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	0.405 mg/mL	ALOGPS
logP	3.01	ALOGPS
logP	3.12	ChemAxon
logS	-2.8	ALOGPS
pKa (Strongest Acidic)	14.34	ChemAxon
pKa (Strongest Basic)	-3.1	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	38.69 Å2	ChemAxon
Rotatable Bond Count	3	ChemAxon
Refractivity	66.77 m3·mol-1	ChemAxon
Polarizability	26.21 Å3	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

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Drug created on September 22, 2015 13:59 / Updated on October 27, 2020 11:13