Articles

Brivaracetam: A 3rd Generation Anti-Epileptic With Higher Efficacy And Better Safety Profile

Author: Dr. Mahesh Narayan Tiwari

M.S. M.Ch. (Neurosurgery) Consultant Neurosurgeon Shree Krishna Hospital, Kashipur Uttarakhand.

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Abstract

Epilepsy is the 4th most common and disabling chronic neurological disorder affecting 65 million people globally. Yet we have an incomplete understanding of the detailed pathophysiology and treatment options available for epilepsy. This article provides an overview of seizures and epilepsy, epidemiological consideration, antiepileptic’s drugs classification, Brivaracetam and its comparative studies with Levetiracetam.

Keywords: Seizure, Epilepsy, Brivaracetam, Levetiracetam, SV2A Receptor, Efficacy, Focal Seizures, Pharmacokinetics, Tolerability

 

Introduction

A “seizure” is defined as a sudden event causing alteration of neurological functions due to abnormal, excessive, hypersynchronous discharge from a group of CNS neurons in the brain.

“Epilepsy” is a chronic neurological disorder, defined as tendency to have recurrent and unprovoked seizures. However, a person is diagnosed with epilepsy if they have two or more unprovoked seizures, not caused by reversible medical conditions.

Epilepsy has numerous possible causes including an imbalance of neurotransmitters, tumors, strokes, and brain damage due to illness or injury and sometimes combination of these. In the majority of cases, there may be no detectable cause for epilepsy.

A seizure provoked by a reversible medical condition (e.g., high fever, hypoglycemia, alcohol withdrawal) does not fall under the definition of epilepsy because it is a temporary secondary condition, not a chronic state. Hence, all seizures cannot be considered as epilepsy.

 

Epidemiological consideration

Epilepsy is one of the most conventional neurological disorders, having an incidence of approximately 50 new cases per year per 100,000 populations (Hauser and Hersdorffer 1990). About 1% of the population suffers from epilepsy, and about one-third of patients have refractory or drug resistant epilepsy (i.e., seizures are uncontrolled even by two or more appropriately chosen antiepileptic medications). Various studies estimated that the overall prevalence of epilepsy in India is 5.59-10 per 1000 [1-5].

Males are getting affected in more numbers by epilepsy was reported in a study conducted in India by Bharucha et al. [6] in which prevalence rate of males (5.1 per 1000) was recorded significantly higher than that in females (2.2 per 100). ​

Approximately 75% of epileptic case starts during childhood, indicating the increased susceptibility of the developing brain to seizures.

 

Phases of Epilepsy

A seizure can be consisting of four different phases (figure 1): prodromal, early ictal (aura), ictal, and post-ictal [7, 8].

 

Figure 1: Different Phase of a Seizure

 

1. Prodromal: The prodromal phase serves as a warning sign of seizure onset for the patient, but unlike aura phase prodromal phase is not a part of the seizure.

About 20% of people with epilepsy experience a prodromal phase –an intuitive feeling or sensation that can occur several hours or even days before the actual seizure attack. Symptoms include confusion, discomfort, anxiety, irritability, headache, tremor, and anger or other mood swings.

 

1. Aura: For most of the epilepsy patients, the earliest sign of seizure activity is an aura. It acts as a warning or earliest sign of an on-coming seizure and the beginning of the ictal phase. The ictal phase includes the time between the starting (aura, if present) and the end of the seizure. Common symptoms include loss of vision or blurring, hallucinations, Deja vu (feeling of familiarity with a person, place, or thing without having experienced it), Jamais vu (feeling of unfamiliarity with a person, place, or thing despite having already experienced it), ringing sounds, strange offensive smells, bitter or acidic taste, nausea, numbness, tingling, dizziness, pain in head, arm & leg, subtle arm or leg jerking, strong feelings of joy, sadness, fear or anger.
2. Ictal Phase: The ictal phase express in different ways for different patient with epilepsy. They may experience a variety of symptoms, including but not limited to confusion, memory lapses, distractedness, sense of detachment, eye or head twitching movement in one direction, inability to move or speak, loss of bladder and/or bowel control, pale/flushed skin, hearing loss, strange sounds, vision loss, blurring vision, chewing or lip-smacking, unusual physical activity such as dressing/undressing, walking/running, pupil dilation, difficulty breathing, sweating, tremors, twitching, arm or leg stiffening, numbness etc.
3. Post-Ictal Phase: This is the recovery period after a seizure. Some people recover immediately, while others need sometime from minutes to days to become normal & feel like they’re back at their control. The duration of the post-ictal phase depends directly on the seizure type, severity, and region of the brain affected. Some of the typical symptoms include drowsiness, confusion, memory loss, nausea, body soreness, difficulty finding names or words, headaches/migraines, thirst, arm or leg weakness, hypertension, feelings of fear, embarrassment, or sadness.

 

Types of Epilepsy

Seizure type depends on the part of the brain involved and how much of the brain is affected. The two broad classes of epileptic seizures are partial (simple and complex) and generalized seizures. There are several different types of seizures, fall under these categories (figure 2):

 

Figure 2: Classification of Seizures

 

1. Focal or partial seizures: In focal seizures abnormal electrical brain function occurs in one or more areas of one side of the brain. With focal seizures, particularly with complex focal seizures, patient may experience an aura before the seizure event. Focal seizures are of two types:

1. Simple focal seizures: Symptoms depends on the area of the brain involved. If occipital lobe (the back part of the brain that is involved with vision) is the region of the abnormal electrical brain function, sight may be altered, but more commonly affected part is muscles. The seizure activity is limited to an isolated muscle group, such as the fingers, or to larger muscles in the arms and legs. Patient is fully conscious in focal seizure and may also experience sweating, nausea, or become pale.
2. Complex focal seizures: Commonly occurs in the temporal lobe (the area of the brain that controls emotion and memory function) of the brain. Consciousness is usually lost during these seizures. Sometimes the patient stops being aware of what's going on around him or her, may look awake, but may have a variety of unusual behaviors. These behaviors may be in the form of gagging, lip smacking, running, screaming, crying, and/or laughing. When the person regains consciousness, he or she may complain of being tired or sleepy after the seizure.

1. Generalized seizures: It involves both sides of the brain. Consciousness is lost and experience a postictal state after the seizure occurs. Generalized seizures include the following types:

1. Absence seizures: Involve brief, lapses of consciousness and staring episodes. Signs include rapid eye blinking or twitching of mouth or face. Duration of the seizure is no longer than 30 seconds. Once the seizure is over the patient may not recall what just occurred and may go on with activities, acting as though nothing happened. Patient may have 100-200 episodes in a day. Absence seizures almost always start between ages 4 to 12 years.
2. Atonic seizures: With atonic seizures, there is a sudden loss of muscle tone and the patient may fall from a standing position or suddenly drop his or her head. During the seizure, the person feels difficulty in walking and become unresponsive.
3. Generalized tonic-clonic seizures: This is the classic form of generalized seizure and is characterized by five distinct phases. The body, arms, and legs will flex (contract), extend (straighten out), and tremor (shake), followed by a clonic phase (contraction and relaxation of the muscles) and the postictal period. Not all of these phases may be seen in every patient.
4. Myoclonic seizures: Involve quick movements or sudden jerking of a group of body muscles. These seizures may occur several times a day, or for several days in a row.

1. Infantile spasms: This is rare type of seizure disorder occurs in infants before six months of age. Mostly occur when the child is awakening, or when trying to go to sleep. The infant usually has brief episodes of movement of the neck, trunk, or legs that lasts for a few seconds. Infant may have 100 of episodes a day. This may affect infant growth and development.
2. Febrile seizures: This is associated with high fever and is not epilepsy. These seizures are more commonly seen in children between six months and five years of age, and may have a family history. Febrile seizures that last for less than 15 minutes are called simple, and do not have long-term neurological effects. Seizures lasting more than 15 minutes are called complex and there may be long-term neurological changes in the child.

 

Major Causes of Epilepsy

While the exact cause of the seizure may not be known, the most common are the following:

• In newborns and infants:

• Birth trauma
• Congenital problems
• Fever or infection
• Metabolic or chemical imbalances in the body

 

• In children, adolescents, and adults:

• Alcohol or drugs
• Head trauma
• Infection
• Congenital conditions
• Genetic factors
• Progressive brain disease
• Alzheimer's disease
• Stroke
• Unknown reasons

 

Some other possible causes of seizures may include the following:

• Brain tumor
• Neurological problems
• Drug withdrawal
• Medications
• Use of illicit drugs

 

Symptoms of Epilepsy

The patient may have different degrees of symptoms depending on the type of seizure. The following are common symptoms of a seizure or warning signs of seizures:

• Jerking movements of the arms and legs
• Stiffening of the body
• Loss of consciousness
• Breathing problems or breathing stops
• Loss of bowel or bladder control
• Falling suddenly for no visible reason, especially when associated with loss of consciousness
• Not responding to noise or words for brief periods
• Nodding the head rhythmically, when associated with loss of awareness or even loss of consciousness
• Periods of rapid eye blinking and staring
• During the seizure, the person's lips may become bluish and breathing may not be normal. The movements are often followed by a period of sleep or disorientation.

 

Antiepileptic Drugs

Antiepileptic drugs are classified as first-generation (conventional), second-generation (newer) and third generation (newest) agents as mentioned in Table 1. The choice of drug depends on the type of seizure.

Antiepileptic drugs inhibit neural activity either by decreasing (↓) neural excitation or increasing (↑) neural inhibition.

 

Table 1: Antiepileptic drugs classification with indications and mode of action.

Classification	Agent	Indication	Mechanism of action
First-generation (conventional) antiepileptics	Valproate	First-line treatment for tonic-clonic seizures Partial (focal) seizures Absence epilepsy Status epilepticus [9] Myoclonic seizures Migraine prophylaxis Bipolar disorder	Inhibits GABA transaminase → increased GABA→ decreased neuronal excitability Inactivates Na+ channels
	Carbamazepine	First-line treatment for tonic-clonic generalized and focal seizures First-line treatment of trigeminal neuralgia	Inactivates Na+ channels
	Ethosuximide	First-line for absence seizures	Inhibition of voltage-gated calcium channels (T-type) in neurons of the thalamus
	Phenytoin, fosphenytoin	First-line treatment for tonic-clonic seizures Focal seizures Status epilepticus [9]	Inactivation of Na+ channels Zero-order elimination (i.e., constant rate of drug eliminated)
	Phenobarbital	First-line treatment in neonates Tonic-clonic generalized seizures Focal seizures Status epilepticus	GABA agonist →  increase GABA action
	Benzodiazepine	First-line for status epilepticus Second-line treatment for eclampsia	Indirect GABA agonist →  increase GABA action
Second-generation (newer) antiepileptic	Lamotrigine	First-line of focal seizures Second-line treatment for generalized seizures and absence seizures Mood stabilizer for treatment of bipolar disorder	Inhibition of voltage-gated Na+ channels → decrease glutamate release
	Levetiracetam	First-line treatment of focal seizures Generalized seizures	Blockage of SV2A receptor → GABA and/or glutamate release modulation and inhibition of voltage-gated Ca2+ channels
	Gabapentin	Second-line treatment for focal seizures Postherpetic neuralgia Peripheral (poly)neuropathy	Inhibition of presynaptic P/Q-type Ca2+ channels via action on the α2δ-subunit → decrease Ca2+ intracellular flow → decrease glutamate release [10] Does not bind to GABA receptors despite being a GABA analog
	Vigabatrin	Refractory focal seizures (adjunctive therapy) Monotherapy for infantile spasms West syndrome	Inhibits GABA transaminase irreversibly → increase GABA
	Topiramate	Focal and tonic-clonic seizures Migraine prophylaxis Idiopathic intracranial hypertension	Blockage of voltage-gated Na+ channels increase GABA
	Tiagabine	Focal seizures with or without impairment of consciousness (adjunctive therapy)	Inhibits GABA reuptake →  increase  GABA
3rd generation (newest) antiepileptic	Eslicarbazapine	Monotherapy or adjunctive therapy for Partial-onset seizures	Stabilises the inactive state of voltage-gated sodium channels
	Lacosamide	Adjunctive treatment of partial-onset seizure Diabetic neuropathic pain	Inhibition of sodium channels
	Brivaracetam	Adjunctive treatment of partial-onset seizures with or without secondary generalisation	Blockage of SV2A receptor → GABA and/or glutamate release modulation
	Perampanel	Adjunctive therapy for partial seizures and generalized tonic-clonic seizures	Selective non-competitive antagonist of AMPA receptors

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Brivaracetam

Brivaracetam is a propyl analogue of levetiracetam and a 3rd generation antiepileptic racetam derivative which granted USFDA approval in February 2016 as add-on therapy for treating focal seizures (also known as partial onset seizure) in adults and adolescents 16 years of age or older with epilepsy [11].

Mode of Action

The exact mode of action of brivaracetam is unknown; it binds to the human SV2A protein in the brain and reduces presynaptic neurotransmitter release. It has 15–30 fold higher and 20 times more selective binding affinity than levetiracetam. So, SV2A binding is believed to be the primary mechanism for brivaracetam anticonvulsant activity [12].

Pharmacokinetics Profile

Brivaracetam is rapidly absorbed with a median time to maximum concentration (tmax) of approximately 1 hour. High-fat food delays T max (3 hours) and decreases maximum concentration (Cmax), but has no effect on area under the plasma concentration–time curve (AUC), and there is only weak plasma binding of <20% [13-15].

BRV is extensively metabolized, primarily by hydrolysis of the acetamide group to the carboxylic acid metabolite by an amidase, followed by hydroxylation by cytochrome P450 (CYP)2C9 to form a hydroxy-acid metabolite [16-17].

More than 95% of the brivaracetam dose is eliminated in the urine within 72 hours, 8.6% is eliminated unchanged, and the rest is excreted as metabolites [15,18]. Mean half-life (t½) is ~9 hours and plasma clearance is 3.4 L/ hour following a single BRV 50 mg oral dose in healthy participants [19].

Adverse Reaction

The following serious adverse reactions are observed with brivaracetam:

• Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs) including brivaracetam, increase the risk of suicidal thoughts or behavior in patients taking these drugs.
• Neurological Adverse Reactions: Brivaracetam causes somnolence, fatigue, dizziness, and disturbance in coordination. Patients should be monitored for these signs and symptoms.
• Psychiatric Adverse Reactions: Brivaracetam causes psychiatric adverse reactions but offers better tolerability than levetiracetam [20].
• Hypersensitivity (Bronchospasm and Angioedema): Brivaracetam can cause hypersensitivity reactions. Bronchospasm and angioedema have been reported in patients taking brivaracetam.
• Withdrawal: Similar to other antiepileptic drugs, brivaracetam should also be withdrawn gradually because of the risk of seizure recurrence. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

Drug-Drug Interactions

Rifampin: Co-administration with rifampin decreases plasma concentrations because of CYP2C19 induction. Brivaracetam dose should be increases up to 100% while receiving concomitant treatment with rifampin.

Carbamazepine: Though available research did not reveal any safety concerns, but if tolerability issues arises carbamazepine dose reduction should be considered.

Phenytoin:  Brivaracetam can increase plasma concentrations of phenytoin; hence phenytoin levels should be monitored when co-administered to or discontinued from ongoing phenytoin therapy.

 

Brivracetam versus Levetiracetam

• Onset of brain activity: Brivaracetam (BRV) displays a fast and unrestricted passage across the blood-brain barrier. The passive diffusion permeability is superior to levetiracetam (LEV), with no evidence of transporter-mediated extrusion from the brain, leading to faster onset of brain activity [21].
• Protection: BRV demonstrates a more pronounced effect on inhibition of neuronal hyper synchronization than selectracetam (SEL) [21]. In contrast with LEV and SEL, BRV shows seizure protection in the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazol (PTZ) tests, although at high doses; and also has significant protection against the partial seizure phase in animal models of focal epilepsy [21].
• Potency: BRV demonstrated higher potency than LEV in various animal seizure models, which includes MES and PTZ tests in cornea-kindled mice, hippocampus-kindled rats, and the 6 Hz seizure model in mice and also in models of primary generalized epileptogenesis [22]. Furthermore, potent efficacy was evident in a model status epilepticus [23].
• Affinity: Studies observed that BRV has a 15- to 30-fold increased affinity for synaptic vesicle protein 2A (SV2A) compared with LEV [24]. The differential effect of the allosteric SV2A modulator on the binding of LEV and BRV indicates that they influence different conformations of the SV2A protein [21], which determines that LEV and BRV bind to SV2A at closely-related sites but interact with these sites differently [25].
• Dosing: Studies that compare BRV and LEV using high-frequency neuronal stimulation suggest that BRV augments synaptic depression and thereby decreases synaptic transmission at 100-fold lower concentrations than LEV [26].
• Selective SV2A ligand and adverse effects: Studies support the absence of any relevant contribution of conventional anti-epileptic drugs (AED) mechanisms to the anti-epileptic properties of BRV and suggest it represents the first, selective SV2A ligand for epilepsy treatment [21]. The selectivity of BRV may be associated with fewer clinical adverse effects and is even supported by findings obtained from a study showing that epilepsy patients experiencing non-psychotic behavioral adverse events related to LEV had benefited from switching to BRV [27].

 

Conclusion

Brivaracetam is a third-generation anti-epileptic drug. It is different from levetiracetam based on the higher affinity, selectivity, and differential interaction with SV2A. Its higher lipophilicity correlates with significant potential and complete seizure suppression and more rapid brain penetration in preclinical models. These properties of brivaracetam propose its favorable potential as an anti-epileptic drug that might provide broad-spectrum efficacy, along with a better tolerability profile and fast onset of action. Brivaracetam represents the first selective SV2A ligand for epilepsy treatment and will significantly contribute to the existing range for anti-epileptics.

 

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