Stiripentol, known by its brand name Diacomit®, is a prescription anticonvulsant medication used as an adjunctive therapy to control seizures. It is not used as a standalone treatment but rather in combination with other anti-seizure medications. Its primary and approved indication is for the treatment of seizures associated with Dravet syndrome. This severe and rare form of genetic epilepsy begins in infancy and is notoriously difficult to control with conventional medications. The specific patient population for whom stiripentol is approved are individuals with Dravet syndrome, aged 6 months and older, who are also taking the medication clobazam.
The Primary Indication: Dravet Syndrome
Dravet syndrome is a catastrophic form of epilepsy, characterized by prolonged and frequent seizures that begin in the first year of life. These seizures often lead to developmental delays and other neurological complications. The majority of cases are caused by a mutation in the SCN1A gene, which codes for a voltage-gated sodium channel. Standard antiepileptic drugs often fail to control seizures in these patients, making management particularly challenging.
Stiripentol has demonstrated significant effectiveness in reducing the frequency of convulsive seizures and improving overall seizure control in patients with Dravet syndrome when added to a regimen including clobazam and sometimes valproate. Long-term observational studies have confirmed that stiripentol can reduce the frequency of status epilepticus, a dangerous condition involving continuous or rapidly recurring seizures, in a significant percentage of patients. Its use, especially when initiated early, is associated with lower seizure frequency and less severe neurological impairment in adulthood.
The Multifaceted Mechanism of Action
Stiripentol is an unusual antiepileptic drug because its therapeutic effects result from a combination of several distinct mechanisms, which likely explains its efficacy in such a drug-resistant condition.
Enhancing GABAergic Inhibition
Gamma-aminobutyric acid (GABA) is the brain's main inhibitory neurotransmitter, and seizures are often caused by a breakdown in this inhibitory signaling. Stiripentol enhances GABAergic neurotransmission in several ways:
- Positive allosteric modulation of GABA$_{A}$ receptors: It binds to GABA$_{A}$ receptors at a site different from benzodiazepines (like clobazam), which increases the time the receptor is open and boosts inhibitory signaling. This synergistic effect with clobazam is a key aspect of its therapy.
- Inhibition of GABA transaminase: Stiripentol can inhibit the enzyme responsible for breaking down GABA, leading to higher concentrations of the neurotransmitter in the brain.
Inhibiting Cytochrome P450 Enzymes
Stiripentol is a potent inhibitor of several hepatic cytochrome P450 (CYP) enzymes, particularly CYP2C19 and CYP3A4. This metabolic inhibition is a crucial part of its therapeutic profile, as it:
- Increases the plasma concentration of clobazam and its active metabolite, N-desmethylclobazam, boosting their antiepileptic effect.
- Affects the levels of other co-administered medications, necessitating careful dosage adjustments.
Modulating Ion Channels
Beyond its GABAergic and metabolic effects, stiripentol also demonstrates activity on neuronal ion channels. It has been shown to block voltage-gated sodium and T-type calcium channels, which are involved in the generation of seizures. This channel-blocking property further contributes to its broad-spectrum anticonvulsant activity.
Impact on Glucose Metabolism
Studies suggest that stiripentol regulates glucose energy metabolism and inhibits lactate dehydrogenase (LDH), a mechanism that could help terminate seizure activity. This unique property is also being explored for its therapeutic potential in other diseases, such as glioblastoma.
Dosage, Administration, and Important Considerations
Stiripentol is available as capsules and as a powder for oral suspension. It is important to follow the prescribed dosage and administration instructions carefully. Stiripentol is typically administered in divided doses with meals. It is crucial that the capsules not be opened or broken and that the oral powder is mixed with water and consumed immediately during a meal. Taking it with food helps reduce stomach upset and ensures proper absorption.
- Gradual Withdrawal: Abruptly stopping stiripentol can lead to increased seizure frequency, including status epilepticus. Any discontinuation or dosage reduction must be done gradually under a doctor's supervision.
- Monitoring: Due to its potential impact on blood counts and weight, patients require regular hematologic testing and growth monitoring, especially children.
- Phenylketonuria (PKU): The powder for oral suspension contains phenylalanine and should be used with caution in patients with PKU.
Common and Serious Side Effects
As with all medications, stiripentol can cause side effects. The most common adverse reactions reported in clinical trials include:
- Somnolence (drowsiness)
- Decreased appetite and weight loss
- Agitation or irritability
- Ataxia (problems with balance or coordination)
- Hypotonia (decreased muscle tone)
- Nausea and vomiting
- Insomnia
Serious side effects requiring immediate medical attention are less common but include:
- Blood dyscrasias: Neutropenia (low white blood cell count) and thrombocytopenia (low platelet count).
- Suicidal ideation and behavior: A small number of patients taking anticonvulsants, including stiripentol, may experience suicidal thoughts or actions.
Significant Drug-Drug Interactions
The CYP enzyme inhibition caused by stiripentol leads to clinically significant interactions with other drugs. Clinicians must be aware of and manage these effects to prevent toxicity.
- Clobazam: The most critical interaction is with clobazam, as stiripentol dramatically increases its concentration. The dosage of clobazam should be reduced when starting stiripentol to avoid excessive sedation and side effects.
- Valproic Acid: Stiripentol can also increase valproate levels, and dosage adjustments may be necessary if adverse effects like loss of appetite occur.
- Fenfluramine: For patients also receiving fenfluramine, lower doses of fenfluramine are required when co-administered with stiripentol.
- Other CNS Depressants: The sedative effects of stiripentol are additive with other CNS depressants, including alcohol, antihistamines, and opioids.
- CYP Inducers: Concomitant use of strong CYP enzyme inducers like rifampin or phenytoin should be avoided or carefully monitored, as they can reduce stiripentol's effectiveness.
Stiripentol vs. Other Dravet Syndrome Treatments
Recent comparative studies provide insight into how stiripentol measures up against other modern add-on therapies for Dravet syndrome, such as fenfluramine (Fintepla) and cannabidiol (Epidiolex).
| Feature | Stiripentol (Diacomit) | Fenfluramine (Fintepla) | Cannabidiol (Epidiolex) |
|---|---|---|---|
| Mechanism | Enhances GABA, inhibits CYP enzymes, modulates ion channels | Modulates serotonin signaling | Modulates GPR55 and other receptors, mechanism not fully understood |
| Efficacy (Convulsive Seizures) | High efficacy, similar to fenfluramine; highest seizure-free rate in some trials | High efficacy, similar to stiripentol | Lower efficacy compared to stiripentol and fenfluramine |
| Side Effects (Common) | Somnolence, decreased appetite, weight loss, ataxia | Decreased appetite, weight loss, lethargy, fatigue | Somnolence, sedation, decreased appetite, abnormal liver function |
| Serious Adverse Events | Neutropenia, thrombocytopenia, suicidality | Heart valve issues (with high doses), pulmonary hypertension | Liver injury, suicidality |
| Required Concomitant Drug | Approved for use with clobazam | Often used with other ASMs | Often used with clobazam and/or valproate |
Off-Label Uses and Future Research
While stiripentol is only officially approved for Dravet syndrome, its unique pharmacological profile has led to research into other applications. Studies have explored its effectiveness in other drug-resistant pediatric epilepsies, with some promising results, particularly in treating specific seizure types or status epilepticus. Furthermore, its metabolic effects on lactate dehydrogenase have prompted research into non-epileptic conditions like glioblastoma and primary hyperoxaluria, although these are still in the early stages.
Conclusion: A Cornerstone in Dravet Syndrome Management
In summary, the drug stiripentol is used for the adjunctive treatment of seizures associated with Dravet syndrome in children and adults. Its efficacy in this drug-resistant condition is driven by a multimodal mechanism that includes enhancing GABAergic inhibition and inhibiting CYP enzymes, which increases the effectiveness of co-administered medications like clobazam. While effective, its use requires careful management of drug interactions and monitoring for common side effects and serious adverse events. Ongoing research continues to uncover potential benefits beyond its approved indication, highlighting its complex and important role in treating severe epilepsy.
