LEVETIRACETAM

(S)-alfa-ethyl-2-oxo-l-pyrrolidine-acetamide is a pyrrolidine derivative

Chemical properties

• Levetiracetam is a white powder ,wholly soluble in water.

• racemically pure S-enantiomer . • The R-enantiomer devoid of anticonvulsant

properties in animals

Preclinical data

• levetiracetam is not active against acute seizures, namely the maximal electroshock (MES) and pentylenetetrazol (PTZ) seizure tests

• Levetiracetam also appears to lack anticonvulsant activity in other acute seizure tests utilizing chemoconvulsant agents,

• levetiracetam does possess activity chronic epilepsy, such as kindled and genetic animals

• reduces seizure severity, duration of motor seizures as well as after discharge duration in fully amygdala-kindled rats

• effective in genetic animal models of epilepsy, such as the genetic absence epilepsy rat from Strasbourg (GAERS) (resembling human spike-wave conditions)

• Wide safety margin between the effective dose (ED50; dose protecting 50% of animals from seizures) and the dose impairing rotarod performance(TD50; dose causing 50% of animals to lose equilibrium on the rotarod).

mechanism of action

• inhibits a specific high-voltage activated calcium channel, the N-type

• inhibit the release of calcium from intracellular stores .

• oppose the inhibitory action of zinc and beta-carbolines on GABAA- and glycine-gated currents

• inhibits burst firing without affecting normal neuronal excitability

• inhibit hypersynchronization of epileptiform activity, which distinguishes levetiracetam from other AEDs

• stereoselective, saturable and reversible binding site specific for levetiracetam in the CNS,SV2A

Pharmacokinetics

• water-soluble compound, which is rapidly and almost completely absorbed after oral administration

• Administration with food does not reduce the extent, but may slow the rate of absorption .

• Bioavailability approaches 100% . • Peak plasma concentrations are reached in 1-2 h.• The pharmacokinetics are linear,• Levetiracetam is <10% protein bound.

• Sixty-six per cent of the dose is excreted unchanged in the urine.

• Twentyseven per cent of the dose is metabolized by an enzymatic hydrolysis of the acetamide group, mainly to L057

• This process occurs diffusely in the body, and is not hepatically mediated.

• no inhibition of drug-metabolizing enzymes including CYP3A4, CYP1A2, CYP2C19, CYP2C9, CYP2E1, CYP2D6, epoxide hydrolase and various uridine glucuronyltransferases

• The metabolites of levetiracetam are renally excreted. • Because there is no hepatic metabolism, • and because levetiracetam does not induce or inhibit

hepatic enzymes, • it does not interfere with the metabolism of other AEDs, • nor do other AEDs interact with its metabolism or

elimination. • Probenecid increases plasma levels of the levetiracetam

metabolite L057 2.5-fold, by a reduction in renal clearance

children

• The half-life of levetiracetam in children, as for most drugs, is shorter than adults.

• After a single oral dose of 20mg/kg, values for Cmax and AUC equated for a 1-mg/kg dose were -30-40% lower than adults, whereas renal clearance was higher.

• The half-life was ~6h

elders

Elderly individuals may have altered drug metabolism, • gastric mucosal atrophy • decreased gastric motility leading to altered absorption,• change in hepatic and renal function, • altered albumin levels. • Studies demonstrated a prolonged half-life, which could be

explained entirely by reduced creatinine clearance • The elimination half-life is approximately 10-llh, compared to

7.7h in younger normal subjects • Adjustments in dosage should be made based on estimated

creatinine clearance, taking body mass into account.

Liver failure

• Mild to moderate (Child-Pugh class A or B) hepatic

impairment do not alter the clearance of levetiracetam, and no dosage adjustments are required.

• However, in severe hepatic failure (Child-Pugh class C) there is a reduced clearance, most likely due to concomitant renal insufficiency .

• Adjustments in dose should therefore be made based on renal rather than hepatic function.

Renal failurepatients with renal failure on dialysis, a dose of 500-1000 mg oncedaily is recommended, with a supplemental dose of 250-500 mgafter dialysis treatment

31 -Betts T, Waegemans T, Crawford 32 Cereghino JJ etal. 33

Shorvon SD etal.41 -Ben-Menachem E, Falter U.

• The efficacy of levetiracetam in treatment of primary generalized epilepsy including tonic-clonic, absence and myoclonic epilepsy was reported in a recent small case series.

• effective in juvenile myoclonic epilepsy (JME). Among 30 patients with resistant JME who received levetiracetam, 62% became seizure free

• reports suggest that levetiracetam is potentially efficacious in photosensitive epilepsy

• patients with progressive myoclonic epilepsy have experienced dramatic improvements with the addition of levetiracetam to their regimen

• useful in the treatment of other epilepsies including atypical absence and atonic seizures

indications

Adjunctive to • Partial onset seizures in adults,children >4 yrs• Myoclonus in adults,children>12 yrs ,JME• Primary GTCS in adults,children>6 yrs

Side-effects• Somnolence ,20.4% of patients on lOOOmg of levetiracetam vs. 18.8% on

3000 mg, as compared to 13.7% of placebo patients• asthenia. 14.7% vs. 9.1 % of placebo• nausea,• dizziness and headache.• Infections including upper respiratory tract (rhinitis and pharyngitis) and

urinary tract infections• agitation, hostility, anxiety, apathy, emotional lability, depersonalization and

depression,13.3% of levetiracetam patients compared to 6.2% in placebo• suicidal behaviour was reported in 0.5% vs. none for placebo group• In a pooled analysis, >25% worsening of seizures occurred during add-on

trials in the placebo group (26%) than in the levetiracetam-treated group (14%)

• Anemia,leukopenia

• Idiosyncratic adverse effects• Teratogenicity• Adverse effects of levetiracetam in paediatric

patients• Overdosage• Tolerance

50- Bourgeois B etal. 57- Wannag E, Eriksson A, Brockmeier, 59- Faircloth VC etal. 60- Strunc M, Levisohn P.

Clinical therapeutics

• highly water soluble,• Levetiracetam is not metabolized by the liver. • It is free of non-linear metabolic kinetics, autoinduction and drug-

drug interactions • it lacks protein binding (<10%), which avoids the problem of

displacement of highly protein-bound drugs. • potentially broadspectrum effects • low rate of side-effects• The starting dose of levetiracetam is typically 500 mg BID,• The dose can be titrated by 500-1000 mg every 1-2 weeks until

maximum benefit• children aged 6-12 years used mean doses of 40mg/kg/day

FORMS

• TABLETS OF 250 mg, 500 mg, 1000mg, • Solution form• Parenteral form(phase iv trails )