Levetiracetam

Description

Levetiracetam is a third-generation antiepileptic drug known under the proprietary brand name of Keppra® (UCB Pharma, Slough) in the UK and USA.

Generic formulation

MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):

• It is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns, such as patient anxiety and risk of confusion/ dosing error.

Indications

Epilepsy: monotherapy (not approved in USA) and adjunctive therapy of focal seizures with or without secondary generalization.

Recommendations summarized from NICE (2012)

• Seizure types: first line (myoclonic seizures, focal seizures), adjunctive (generalized tonic- clonic seizures, myoclonic seizures, focal seizures), on referral to tertiary care (absence seizures).
• Epilepsy types: first line (juvenile myoclonic epilepsy, benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, late-onset childhood occipital epilepsy), adjunctive (juvenile myoclonic epilepsy, epilepsy with generalized tonic- clonic seizures only, idiopathic generalized epilepsy, benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, late- onset childhood occipital epilepsy).

Dose titration

Epilepsy— monotherapy
250 mg od for 7– 14 days, 250 mg bd for 14 days, then increased by 250 mg bd every 14 days (max. maintenance dose 1500 mg bd).

Epilepsy— adjunctive therapy
250 mg bd for 14 days, then increased by 500 mg bd every 14–28 days (max. maintenance dose 1500 mg bd).
If levetiracetam has to be discontinued, it is recommended to withdraw it gradually (e.g. in patients weighing more than 50 kg: 500 mg decreases bd every 14– 28 days).

Plasma levels monitoring

Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam and, therefore, there is no need for plasma level monitoring of levetiracetam.

Cautions

Nil.

Adverse effects

Levetiracetam can be associated with adverse effects at the level of the nervous system and other systems.

Interactions

With AEDs
Nil

With other drugs

• Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/ prolonged blood methotrexate concentration to potentially toxic levels.
• There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with levetiracetam. Therefore, macrogol should not be taken orally for 1 hour before or after taking levetiracetam.

Special populations

Hepatic impairment
Halve dose in severe impairment with significant reduction in creatinine clearance

Renal impairment
Reduce maintenance dose according to degree of reduction in creatinine clearance

Pregnancy

• Post- marketing data from several prospective pregnancy registries of women exposed to levetiracetam monotherapy during the first trimester of pregnancy do not suggest a substantial increase in the risk for major congenital malformations, although a teratogenic risk cannot be completely excluded (especially in polytherapy with AEDs). Levetiractam is not recommended during pregnancy or in women of childbearing age not using contraception unless clinically necessary.
• Decrease in levetiracetam plasma concentrations has been observed during pregnancy (especially during the third trimester), suggesting that appropriate clinical management of pregnant women treated with levetiracetam should be ensured
• Levetiracetam is excreted in human breastmilk and, therefore, breastfeeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/ risk of the treatment should be weighed up.

Behavioural and cognitive effects in patients with epilepsy

Behavioural adverse event are often reported by patients with epilepsy taking levetiracetam. The most relevant ones are irritability and emotional lability. Marked behavioural changes with psychotic symptoms and episodes of severe aggression have occasionally been reported. On the contrary, levetiracetam is one of the safest AEDs in terms of interference with cognitive processes, despite occasional reports of decreased cognition.

Psychiatric use

Despite its widespread use in epilepsy, Levetiracetam does not have approved indications in psychiatry. Initial reports suggesting a possible role for Levetiracetam in the treatment of bipolar depression and anxiety disorders have not been confirmed by the findings of controlled trials. Evidence for the possible usefulness of levetiracetam for the treatment of patients with Tourette syndrome is equally inconsistent.

Description

Levetiracetam was first introduced in the US as an adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy. This second-generation analog of piracetam can be prepared by condensation of (S)-2-aminobutyramide with 4-chlorobutyryl chloride. Although its mechanism of action is not well established, it was shown that [³H]-levetiracetam reversibly binds to a specific site predominantly present in the membranes of the brain. Unlike conventional anticonvulsants such as phenytoin, carbamazepine, valproic acid, phenobarbital, diazepam and clonazepam, compounds structurally-related to levetiracetam, such as piracetam and aniracetam, also have affinity for this site. Levetiracetam reveals a broad and unique profile in animal seizure models, including promising antiepileptogenic properties. Besides being rapidly and almost completely absorbed in man (oral bioavailability>95%), it possesses a favorable pharmacokinetic profile since it is not hepatically metabolized but only partly hydrolized into the inactive carboxylic acid by enzymes in a number of tissues including blood cells, it is minimally bound to plasma proteins (<10%) and does not inhibit or induce hepatic enzymes. Therefore levetiracetam has a low potential for drug interaction, providing a useful alternative as adjunctive therapy to treat seizures refractory to conventional anticonvulsants.

Chemical Properties

White Crystalline Solid

Originator

UCB (Belgium)

Uses

Used as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy.

Uses

A compound which inhibits burst firing without affecting normal neuronal excitability

Uses

The (S)-enantiomer of Etiracetam (E932970) and the ethyl analog of Piracetam (P500800). Used as an anticonvulsant.

Uses

The (S)-enantiomer of the ethyl analog of Piracetam. Used as an anticonvulsant.

Definition

ChEBI: A pyrrolidinone and carboxamide that is N-methylpyrrolidin-2-one in which one of the methyl hydrogens is replaced by an aminocarbonyl group, while another is replaced by an ethyl group (the S enantiomer). An anticonvulsa t, it is used for the treatment of epilepsy in both human and veterinary medicine.

Manufacturing Process

(a) Preparation of the (R)-α-methyl-benzylamine salt of (S)-α-ethyl-2-oxo-1- pyrrolidineacetic acid
8.7 kg (50.8 moles) of racemic ()-α-ethyl-2-oxo-1-pyrrolidineacetic acid are suspended in 21.5 liters of anhydrous benzene in a 50 liter reactor. To this suspension is added gradually a solution containing 3.08 kg (25.45 moles) of (R)-(+)-α-methyl-benzylamine and 2.575 kg (25.49 moles) of triethylamine in 2.4 liters of anhydrous benzene. This mixture is then heated to reflux temperature until complete dissolution. It is then cooled and allowed to crystallize for a few hours. 5.73 kg of the (R)-α-methyl-benzylamine salt of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid are thus obtained. Melting point: 148°-151°C. Yield: 77.1%.
This salt may be purified by heating under reflux in 48.3 liters of benzene for 4 hours. The mixture is cooled and filtered to obtain 5.040 kg of the desired salt. Melting point: 152°-153.5°C. Yield: 67.85%.
(b) Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid
5.04 kg of the salt obtained in (a) above are dissolved in 9 liters of water. 710 g of a 30% sodium hydroxide solution are added slowly so that the pH of the solution reaches 12.6 and the temperature does not exceed 25°C. The solution is stirred for a further 20 minutes and the α-methylbenzylamine liberated is extracted with a total volume of 18 liters of benzene. The aqueous phase is then acidified to a pH of 1.1 by adding 3.2 liters of 6 N hydrochloric acid. The precipitate formed is filtered off, washed with water and dried. The filtrate is extracted repeatedly with a total volume of 50 liters of dichloromethane. The organic phase is dried over sodium sulfate and filtered and evaporated to dryness under reduced pressure. The residue obtained after the evaporation and the precipitate isolated previously, are dissolved together in 14 liters of hot dichloromethane. The dichloromethane is distilled and replaced at the distillation rate, by 14 liters of toluene from which the product crystallizes. The mixture is cooled to ambient temperature and the crystals are filtered off to obtain 2.78 kg of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid. Melting point: 125.9°C. [α]D20 = -26.4° (c = 1, acetone). Yield: 94.5%.
(c) Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide
34.2 g (0.2 mole) of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid are suspended in 225 ml of dichloromethane cooled to -30°C. 24.3 g (0.24 mole) of triethylamine are added dropwise over 15 minutes. The reaction mixture is then cooled to -40°C and 24.3 g (0.224 mole) of ethyl chloroformate are added over 12 minutes. Thereafter, a stream of ammonia is passed through the mixture for 4 ? hours. The reaction mixture is then allowed to return to ambient temperature and the ammonium salts formed are removed by filtration and washed with dichloromethane. The solvent is distilled off under reduced pressure. The solid residue thus obtained is dispersed in 55 ml toluene and the dispersion is stirred for 30 minutes and then filtered. The product is recrystallized from 280 ml of ethyl acetate in the presence of 9 g of 0.4 nm molecular sieve in powder form 24.6 g of (S)-α-ethyl-2-oxo-1- pyrrolidineacetamide are obtained. Melting point: 115°-118°C. [α]D25 = -89.7° (c = 1, acetone). Yield: 72.3%.

brand name

Keppra (UCB).

Therapeutic Function

Antiepileptic, Nootropic

Biological Functions

Levetiracetam (Keppra) has recently been approved for the treatment of partial-onset seizures. It appears to be safe and effective; its exact therapeutic profile has yet to be determined. It does not appear to share any of the mechanisms of action of agents that have been discussed to this point. It does have a highly specific brain binding site, but the significance of this observation to its mechanism of action has not been elucidated.

General Description

LEV is an analog of the nootropic agent, piracetam. Onlythe S-isomer has any anticonvulsant activity. Unlike piracetam, LEV does not have any affinity for the AMPA receptor thereby has no nootropic activity forthe treatment of Alzheimer disease. LEV also has no affinityfor GABA receptors, BZD receptors, the various excitatoryamino acid related receptors, or the voltage-gated ionchannels.For this reason, its mechanism of anticonvulsantaction remains unclear, but it appears to exert itsantiepileptic action by modulating kainite/AMPA-inducedexcitatory synaptic currents, thus decreasing membraneconductance.Furthermore, the anticonvulsant activity ofthis drug appears to be mediated by the parent moleculerather than by its inactive metabolite,(S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (i.e., via the hydrolysis of amidegroup).Like gabapentin, LEV has few drug interactionswith other AEDs thereby can be used in combination to treatrefractory epilepsy.

Biological Activity

Antiepileptic that displays distinctive properties from conventional antiepileptic drugs. Displays potent seizure protection in animal models of chronic epilepsy but lacks activity in acute seizure models. Binds synaptic vesicle protein 2A (SV2A) and inhibits Na + -dependent Cl - /HCO 3 - exchange.

Biochem/physiol Actions

Levetiracetam is a pyrrolidine with antiepileptic activity. Stereoselective binding of levetiracetam was confined to synaptic plasma membranes in the central nervous system with no binding occurring in peripheral tissue. Levetiracetam inhibits burst firing without affecting normal neuronal excitability, which suggests that it may selectively prevent hyper-synchronization of epileptiform burst firing and propagation of seizure activity.

Mechanism of action

The mechanism of action for S-(–)-levetiracetam is unknown. It does not appear to interact with any of the recognized excitatory or inhibitory neural mechanism. A CNS-specific binding site for S-(–)-levetiracetam has been identified as the synaptic vesicle protein (SV2A). Knockout animals without SV2A proteins accumulated presynaptic Ca2+ during consecutive action potentials that destabilized synaptic circuits and induced epilepsy. Thus, it appears that SV2A plays a major role in the antiepileptic properties of S-(–)-levetiracetam, which acts by modulating the function of SV2A and the regulation of Ca2+ mediated synaptic transmission. These data support previous indications that S-(–)-levetiracetam possesses a mechanism of action distinct from that of other antiepileptic drugs. Three SV2 isoforms (SV2A, SV2B, and SV2C) have been identified, each of which has a unique distribution in brain, suggesting synapse-specific functions as well as antagonism of neuronal synchronization.

Pharmacokinetics

S-(–)-levetiracetam displays rapid and complete absorption, although food slows the rate but not the extent of absorption. It exhibits linear pharmacokinetics and is minimally protein bound. Approximately 60% of an oral dose is excreted into the urine unchanged and 24 to 30% as its carboxylic acid metabolite, with an elimination half-life in adults of approximately 7 hours. Although S-(–)-levetiracetam is not metabolized by hepatic CYP450, UGT, or epoxide hydrolase, it is esterase hydrolyzed to its carboxylic acid metabolite (loss of amido group), which is not affected by the hepatic metabolizing enzymes.

Clinical Use

S-(–)-levetiracetam is a pyrrolidone derivative unrelated to the structures of other AEDs. It is indicated as an adjunct in the treatment of partial onset seizures in adults, and it has shown some benefit in clinical trials for generalized tonic-clonic seizures (GTC) and myoclonic seizures in adults and children.

Side effects

The risk of clinically relevant drug interactions is minimal with S-(–)-levetiracetam, because it does not alter the pharmacokinetics of coadministered drugs by inhibition or induction of hepatic enzymes. Toxic effects include mild to moderate somnolence, asthenia, ataxia, and dizziness; these effects seldom require discontinuance. An increase in the incidence of behavioral abnormalities in children and in adults having a previous history of neuropsychiatric problems has been noted. Its use in the elderly or in patients with renal impairment will require an individualization of dose, and an additional dose is needed after renal dialysis. Levetiracetam was associated with developmental toxicity in the offspring of pregnant animals.

Veterinary Drugs and Treatments

Levetiracetam may be useful as a third antiseizure medication in dogs that are not well controlled with phenobarbital and bromides or when either bromides or phenobarbital are not tolerated. Some evidence suggests that in dogs suffering from phenobarbital liver toxicity, the addition of levetiracetam will allow reduction of their phenobarbital dosage without increasing seizure frequency.
Levetiracetam may also be useful as add-on therapy in cats.

storage

Store at RT

References

1) Wright?et al.?(2013)?Clinical Pharmacology and Pharmacokinetics of Levetiracetam; Front. Neurol.?4?192 2) De Smedt?et al.?(2007)?Levetiracetam: the profile of a novel anticonvulsant drug – part I: preclinical data; CNS Drug Rev.?13?43 3) Klitgaard and Verdru (2007)?Levetiracetam: the first SV2A ligand for the treatment of epilepsy; Drug Discov.?21537 4) Lynch?et al.?(2004)?The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam; Proc. Natl. Acad. Sci. USA?101?9861 5) Nagarkatti et al. (2008)?Levetiracetam inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture; Neurosci. Lett.?436?289 6) Bonnet?et al.?(2019)?Levetiracetam mediates subtle pH-shifts in adult human pyramidal cells via an inhibition of the bicarbonate-driven neuronal pH-regulation – Implications for excitability and plasticity modulation; Brain Res.?1710?146