Stiripentol

Drug Information: Stiripentol

Stiripentol is an anticonvulsant medication primarily used in the treatment of Dravet syndrome, a severe form of epilepsy that begins in infancy. It’s often used in conjunction with other anticonvulsant medications like valproate and clobazam to control seizures. Stiripentol is thought to enhance GABAergic neurotransmission in the brain, which helps to reduce neuronal excitability and suppress seizure activity. It is available as capsules or powder for oral suspension. Because of its interactions with other anti-epileptic drugs and potential for serious adverse effects, its use requires careful monitoring by a qualified physician.

Category

Neurological Drugs – Anticonvulsant

Mechanism of Action

Stiripentol’s mechanism of action is multifaceted and not fully understood, but it is believed to primarily act as a GABA enhancer. GABA (gamma-aminobutyric acid) is the primary inhibitory neurotransmitter in the brain, and enhancing its function can reduce neuronal excitability and suppress seizures. Specifically, Stiripentol’s GABA-enhancing effects are thought to occur through several mechanisms:

1. Increasing GABA levels: Stiripentol inhibits enzymes responsible for GABA metabolism, leading to higher concentrations of GABA in the synaptic cleft. This allows GABA to bind more effectively to its receptors.

2. Positive Allosteric Modulation of GABA_A Receptors: Stiripentol binds to a site on the GABA_A receptor distinct from the GABA binding site. This allosteric modulation enhances the receptor’s response to GABA, increasing chloride ion influx and further hyperpolarizing the neuron, thus making it less likely to fire an action potential.

3. CYP450 Inhibition: Stiripentol is a potent inhibitor of several cytochrome P450 (CYP) enzymes, including CYP3A4, CYP2C19, and CYP2D6. This inhibition can increase the plasma concentrations of other anticonvulsant drugs like clobazam and valproate, which are often co-administered with Stiripentol. This pharmacokinetic interaction contributes to its anticonvulsant effect, but also necessitates careful monitoring for potential drug interactions and toxicity.

By increasing GABAergic inhibition and modulating the metabolism of other anticonvulsants, Stiripentol contributes to seizure control, particularly in the context of Dravet syndrome where multiple mechanisms are often needed to achieve adequate seizure reduction.

Clinical Uses

Stiripentol is primarily indicated for the treatment of seizures associated with Dravet syndrome in infants and young children. Dravet syndrome is a rare and severe form of epilepsy characterized by frequent, prolonged seizures, developmental delays, and an increased risk of sudden unexpected death in epilepsy (SUDEP). Stiripentol is almost always used in conjunction with other antiepileptic drugs, typically valproate and clobazam, due to the severity and complexity of Dravet syndrome seizures. Clinical trials have demonstrated that the addition of Stiripentol to valproate and clobazam significantly reduces the frequency of convulsive seizures in patients with Dravet syndrome compared to valproate and clobazam alone. The effectiveness of Stiripentol in other types of epilepsy is not well-established, and its use is generally reserved for Dravet syndrome because of the specific challenges in managing this condition and the demonstrated efficacy in clinical trials.

Dosage

Route of Administration: Oral

Adult Dosage (Off-label use, requires careful monitoring): The use of stiripentol in adults is off-label and typically not recommended unless under very specific circumstances and expert supervision. When used, the dosage needs to be highly individualized.

Pediatric Dosage (Specifically for Dravet Syndrome):

• Initial Dose: 50 mg/kg/day, administered in 2 or 3 divided doses.
• Titration: The dosage can be gradually increased based on clinical response and tolerability, typically in increments of 50 mg/kg/day every few days.
• Maximum Dose: 100 mg/kg/day, administered in 2 or 3 divided doses.
• Important Considerations: Dosage adjustments are frequently required based on drug interactions, particularly with valproate and clobazam. Monitoring of blood levels of other anticonvulsants is crucial. Stiripentol should always be administered with food to improve absorption.

Indications

The primary indication for Stiripentol is:

• Adjunctive treatment of seizures associated with Dravet syndrome in infants and young children (in conjunction with valproate and clobazam).

Contraindications

Stiripentol is contraindicated in the following situations:

• Hypersensitivity to stiripentol or any of the excipients.
• History of psychosis.
• Severe hepatic impairment (requires careful evaluation and monitoring if used).
• Porphyria (due to potential exacerbation of the condition).
• Concomitant use with drugs that are known to prolong the QTc interval on an electrocardiogram and can cause Torsades de Pointes.

FAQ

Q1: What is Stiripentol used for?

A: Stiripentol is used as an add-on treatment for seizures associated with Dravet syndrome, a severe form of epilepsy, in infants and young children. It is always used in combination with other antiepileptic medications like valproate and clobazam.

Q2: How does Stiripentol work?

A: Stiripentol is thought to enhance the effects of GABA, a neurotransmitter that inhibits brain activity, thereby reducing the likelihood of seizures. It also affects the metabolism of other anticonvulsants, increasing their levels in the blood.

Q3: What are the common side effects of Stiripentol?

A: Common side effects include drowsiness, ataxia (loss of coordination), hypotonia (decreased muscle tone), decreased appetite, weight loss, insomnia, and behavioral disturbances.

Q4: Does Stiripentol interact with other medications?

A: Yes, Stiripentol interacts with many medications, particularly other anticonvulsants like valproate and clobazam. It inhibits certain enzymes that metabolize these drugs, leading to increased blood levels and potential toxicity. Careful monitoring and dosage adjustments are necessary.

Q5: How should Stiripentol be taken?

A: Stiripentol should be taken with food to improve absorption. It’s crucial to follow the doctor’s instructions regarding dosage and administration.

Q6: Is Stiripentol a cure for Dravet syndrome?

A: No, Stiripentol is not a cure for Dravet syndrome. It helps to reduce the frequency and severity of seizures, but it does not eliminate the condition.

Q7: What should I do if my child misses a dose of Stiripentol?

A: Consult your doctor or pharmacist for specific instructions. Generally, if the missed dose is noticed within a few hours, it can be taken. However, if it’s close to the time for the next dose, skip the missed dose and continue with the regular schedule. Do not double the dose to catch up.

Q8: Are there any long-term side effects associated with Stiripentol use?

A: Long-term studies on Stiripentol are ongoing. Some potential long-term effects include persistent drowsiness, coordination problems, and effects on growth and development, particularly in children. Regular monitoring by a physician is important.