Stiripentol
Identification
- Summary
Stiripentol is an anticonvulsant agent used with clobazam and valproate as an adjunct to treat refractory generalized tonic-clonic seizures in Dravet syndrome.
- Brand Names
- Diacomit
- Generic Name
- Stiripentol
- DrugBank Accession Number
- DB09118
- Background
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
Structure for Stiripentol (DB09118)
- 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.
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- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- 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 agonistpositive allosteric modulatorHumans AL-lactate dehydrogenase A chain inhibitorHumans AL-lactate dehydrogenase B chain inhibitorHumans - 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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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.
- 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.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The metabolism of 1,2-Benzodiazepine can be decreased when combined with Stiripentol. 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. 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. 
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- 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
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Diacomit Powder, for suspension 250 mg Oral Biocodex 2016-09-07 Not applicable EU 
Diacomit Capsule 250 mg/1 Oral BIOCODEX, INC. 2018-08-21 Not applicable US 
Diacomit Powder, for suspension 500 mg / sachet Oral Biocodex Sa 2013-05-01 Not applicable Canada 
Diacomit Capsule 500 mg Oral Biocodex 2016-09-07 Not applicable EU Diacomit Capsule 250 mg Oral Biocodex 2016-09-07 Not applicable EU Diacomit Powder, for suspension 250 mg/1 Oral BIOCODEX, INC. 2018-08-21 Not applicable US Diacomit Capsule 250 mg Oral Biocodex Sa 2013-05-01 Not applicable Canada Diacomit Powder, for suspension 500 mg Oral Biocodex 2016-09-07 Not applicable EU Diacomit Powder, for suspension 250 mg Oral Biocodex 2016-09-07 Not applicable EU Diacomit Capsule 500 mg Oral Biocodex 2016-09-07 Not applicable EU
Categories
- ATC Codes
- N03AX17 — Stiripentol
- 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
- Affected organisms
- 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
- 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. [Article]
- Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ: Stiripentol. A novel antiepileptic drug. Pharmacol Rep. 2005 Mar-Apr;57(2):154-60. [Article]
- 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. [Article]
- Grosenbaugh DK, Mott DD: Stiripentol in refractory status epilepticus. Epilepsia. 2013 Sep;54 Suppl 6:103-5. doi: 10.1111/epi.12291. [Article]
- European Medicines Agency (EMA): DIACOMIT Summary of Product Characteristics [Link]
- FDA approved Drugs [Link]
- FDA label, Diacomit [File]
- External Links
- PubChem Compound
- 5311454
- PubChem Substance
- 310265035
- ChemSpider
- 4470940
- 2054968
- ChEMBL
- CHEMBL1983350
- Wikipedia
- Stiripentol
- MSDS
- Download (56.5 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Unknown Status Treatment Epilepsies 1 2 Completed Treatment Primary Hyperoxaluria 1 1 Completed Basic Science Healthy Subjects (HS) 1 Not Available Approved for Marketing Not Available Dravet Syndrome (DS) 1 Not Available No Longer Available Not Available Dravet Syndrome (DS) 2 Not Available No Longer Available Not Available Dravet Syndrome (DS) / 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 250 MG Capsule Oral 250 mg/1 Capsule Oral 500 mg/1 Capsule Oral 500 MG Powder, for suspension Oral 250 mg/1 Powder, for suspension Oral 250 MG Powder, for suspension Oral 250 mg / sachet Powder, for suspension Oral 500 mg/1 Powder, for suspension Oral 500 MG Powder, for suspension Oral 500 mg / sachet - 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
Targets
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- AgonistPositive 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
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- 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
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- 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
- 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. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- Kind
- Protein
- Organism
- Humans
- 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
- European Medicines Agency (EMA): DIACOMIT Summary of Product Characteristics [Link]
- Kind
- Protein
- Organism
- Humans
- 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
- European Medicines Agency (EMA): DIACOMIT Summary of Product Characteristics [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- 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. [Article]
- Chiron C: Stiripentol. Expert Opin Investig Drugs. 2005 Jul;14(7):905-11. doi: 10.1517/13543784.14.7.905 . [Article]
- EMA label, stiripentol [File]
- Kind
- Protein
- Organism
- Humans
- 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
- Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ: Stiripentol. A novel antiepileptic drug. Pharmacol Rep. 2005 Mar-Apr;57(2):154-60. [Article]
Drug created on September 22, 2015 19:59 / Updated on September 19, 2021 19:53