What is the role of levetiracetam (LEV) in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Answer

Levetiracetam (LEV) is a piracetam (S-enantiomer pyrrolidone) derivative. It was developed in the 1980s to enhance cognitive functions and for anxiolysis. [8, 85, 86, 87, 88, 89, 90, 91]

LEV is a unique antiepileptic drug (AED) in that it is ineffective in classic seizure models that screen potential compounds for antiseizure efficacy such as maximal electroshock and pentylenetetrazol in rats and mice. During preclinical evaluations, it was found to be effective in several models of seizures, including tonic and clonic audiogenic seizures in mice, tonic seizures in the maximum electroshock-seizure test in mice, and tonic seizures induced in rodents by chemoconvulsants.

Interestingly, LEV inhibits the development of pentylenetetrazol-induced amygdala kindling in mice, a situation in which other drugs such as phenytoin (PHT) and carbamazepine (CBZ) are inactive. The mechanism of action is possibly related to a brain-specific stereo-selective binding site, synaptic vesicle protein 2A (SV2A). SV2A appears to be important for the availability of calcium-dependent neurotransmitter vesicles ready to release their content. [4]

The lack of SV2A results in decreased action potential-dependent neurotransmission, while action potential-independent neurotransmission remains normal. [5, 6] In addition, it reduces bicuculline-induced hyperexcitability in rat hippocampal CA3 neurons, suggesting a mechanism that does not involve release of gamma-aminobutyric acid (GABA). LEV inhibits Ca2+ release from the inositol-trisphosphate (IP3)-sensitive stores without reducing Ca2+ storage, which could explain some of LEV’s antiepileptic properties.

LEV is absorbed rapidly after oral administration, with an oral bioavailability of approximately 100%. The peak concentration is reached approximately 0.6-1.3 hours after ingestion, and the rate of absorption is slowed by food. LEV does not bind to plasma proteins. The volume of distribution is approximately 0.5-0.7 L/kg.

LEV is minimally metabolized (approximately 27%), mainly by hydrolysis of the acetamide group. It does not involve the enzymes of the cytochrome P-450 system. The clinical relevance of the metabolites is likely to be negligible.

Approximately 66% is excreted unchanged in urine. LEV is cleared 48 hours after oral administration by glomerular filtration with partial tubular reabsorption. Although its elimination half-life is only 6-8 hours, its pharmacodynamic half-life is likely to be longer. In patients with renal insufficiency, the half-life may be increased up to 24 hours. The drug is removed during hemodialysis. LEV crosses the placenta, and fetal concentrations are similar to maternal levels.

No significant drug interactions have been identified. LEV does not inhibit cytochrome P-450 (CYP450) isoenzymes, epoxide hydrolase, or uridine diphosphate (UDP)-glucuronidation.

A multicenter, double-blind, responder-selected study evaluating LEV as monotherapy in patients with refractory partial epilepsy showed a 73.8% reduction of seizure frequency in 59.2% of the patients, and 18% of the monotherapy group remained seizure free.

Tolerability studies have demonstrated that LEV is very well tolerated. In the electroencephalographic (EEG) model, this drug induced a decrease in the number of frequent epileptiform discharges in most patients. An open-label study reported that 6 of 9 patients with juvenile myoclonic epilepsy refractory to valproate (VPA) or lamotrigine (LTG) became seizure free on LEV.

These results suggest that LEV might have a significant effect in generalized epilepsies. In March 2007, it was approved by the US Food and Drug Administration (FDA) as adjunctive treatment for primary generalized tonic-clonic seizures in adults and children aged 6 years and older.

The starting adult dosage is 500 mg twice a day, with weekly increments of 500-1000 mg/d to 3000 mg, if required. A slower titration rate of 250 mg twice a day with subsequent weekly dose increases by 500 mg is tolerated better.

Pediatric dosages are determined by seizure type and patient age. Use oral solution if weight is ≤20 kg. Pediatric recommendations for tonic-clonic seizures are as follows:

  • Younger than 6 years - Not established

  • Aged 6-15 years - 20 mg/kg/d PO divided bid; may increase daily dose by 20 mg/kg increments q2wk to recommended dose of 30 mg/kg bid

  • Aged 16 years and older - Administer as in adults

Pediatric recommendations for partial-onset seizures are as follows:

  • Younger than 1 month - Not established

  • 1-5 months: 14 mg/kg/d PO divided bid; may increase by 14 mg/kg/day increments q2wk to recommended dose of 21 mg/kg bid

  • 6 months through 3 years: 20 mg/kg/d PO divided bid: increase by 20 mg/kg/d increments q2wk to recommended dose of 25 mg/kg bid

  • Aged 4-15 years - 20 mg/kg/d PO divided bid; may increase by 20 mg/kg/d increments q2wk to recommended dose of 30 mg/kg bid

  • Aged 16 years and older - Administer as in adults

Pediatric recommendations for myoclonic seizures are as follows:

  • Younger than 12 years - Not established

  • Aged 12 years and older - Administer as in adults

The drug is best given twice daily. LEV is available in tablets of 250 mg, 500 mg, 750 mg, and 1000 mg. Intravenous (IV) and oral solutions are also available.

LEV is well tolerated. The most significant adverse effects are somnolence, asthenia, and dizziness. A number of patients reported infection, usually related to upper respiratory tract; however, none of these patients discontinued the drug, and it was not associated with changes in WBC count.

In the phase II studies and open extension studies that represent approximately 2258 patient-years exposure of to LEV, adverse effects were reported in more than 10% of cases. They included headache (25%), accidental injury (25%), convulsion (23%), infection (23%), asthenia (22%), somnolence (22%), dizziness (18%), pain (15%), pharyngitis (11%), and a flu-like syndrome (10%).

No serious acute idiosyncratic reactions have been reported, and no evidence of visual field disturbance has been reported. LEV has no strong tendency to exacerbate seizures, unlike this paradoxical effect recorded in some patients treated with other AEDs.

LEV is very useful in patients with hepatic or renal insufficiency and patients on concomitant medications, because it has no drug interactions. Current data support a good safety profile and efficacy in different patient populations, causing LEV to become one of the preferred AEDs in elderly patients. An IV preparation is available and a good alternative to treat seizures in the acute setting.

Efficacy in status epilepticus has not been established. The antiepileptogenic effect observed in kindling models makes it a potential agent for the prevention of epilepsy in conditions such as traumatic brain injury. However, no clinical studies have been performed to confirm this hypothesis.


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