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A New Antiepileptic Drug J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.72.4.426 on 1 April 2002. Downloaded from 426 EDITORIAL Epilepsy potassium channel conductance,10 sug- ................................................................................... gesting that its mechanism of action dif- fers from other antiepileptic drugs. Lev- etiracetam also has a specific A new antiepileptic drug stereoselective binding site in the CNS,1 and cannot be displaced from this site by S D Shorvon, K van Rijckevorsel other classic anticonvulsant drugs (car- ................................................................................... bamazepine, phenytoin, valproate, phe- nobarbital), although ethosuximide does Levetiracetam, a pyrrolidone recently licensed as an show binding affinity. The extent of the antiepileptic efficacy in the audiogenic antiepileptic drug seizure model in mice was found to be correlated with the affinity for the bind- ecently a new antiepileptic drug, tonic seizures induced by maximal elec- ing site of a series of S-homologues of levetiracetam (LEV), was approved troshock or clonic seizures induced by levetiracetam. Levetiracetam has no for the add on treatment of partial pentylenetetrazol (PTZ) stimulation in binding to membranes outside of the R 2–4 epilepsy, both in the United States and in the classic rodent models. It however CNS. Europe. This is of potential importance, has very marked protection against because this drug is from a class not pre- seizures in audiogenic mice, mice kin- CLINICAL PHARMACOKINETICS viously used in epilepsy, although pira- dled with corneal electroshock or PTZ, The pharmacokinetic properties of lev- cetam, a compound with a structure and amygdaloid kindled rats. It protects etiracetam have been studied in healthy similar to that of levetiracetam, is useful against spontaneous spike and wave dis- adult volunteers, patients with epilepsy, in myoclonus. Both drugs are pyrro- charges in the GAERS model and in and special populations, including paedi- lidone derivatives, a class of drugs of pilocarpine or kainic acid induced focal atric and elderly patients and patients interest for both psychotropic and noo- seizures in rats.245 The dose dependent with renal or hepatic insufficiency. Lev- tropic applications and potentially as ability of levetiracetam to inhibit the etiracetam is rapidly and almost com- neuroprotectants. Levetiracetam (avail- development of kindling suggests a pletely absorbed after oral administra- able under the registered trademark of R potential antiepileptogenic effect as tion of doses ranging from 250 mg to UCB S.A., Keppra ) is the S-enantiomer 6 α well. Levetiracetam is the most effective 5000 mg, with peak plasma concentra- of -ethyl-2-oxo-1-pyrrolidine aceta- of any of the pyrrolidone drugs in these tions achieved in about 1 hour and mide (fig 1). Homologues sharing the S epilepsy models. Its R-enantiomer has steady state concentrations achieved in configuration include a range of other no antiepileptic activity. 48 hours. Absolute oral bioavailability is compounds, some of which also have The dose at which toxic effects on the nearly 100%. When taken with food, the antiepileptic action.1 The range and rotarod test are produced is much higher extent of absorption is not affected, extent of the compounds’ activity in than the effective antiseizure dose in although the rate of absorption may be experimental models of epilepsy and both the GAERS model and the corneally slowed. Levetiracetam is not significantly other conditions varies considerably kindled mice. The safety margin of bound to plasma proteins (<10%), and with minor changes to chemical struc- levetiracetam in these models is much its volume of distribution is about 0.6 ture, but the full extent of the range of greater than for other drugs. In acute l/kg, similar to the volume of distribution properties of these drugs in humans has of intracellular and extracellular water. not been explored. This article reviews and chronic toxicity studies in animals, levetiracetam shows generally low toxic- In addition, levetiracetam exhibits lin- http://jnnp.bmj.com/ the experimental and clinical data relat- ear, dose proportional, kinetics, with low ing to the antiepileptic action of levetira- ity. Oral doses up to 5000 mg/kg acutely (maximum tested dose) are not lethal in intrasubject and intersubject variability, cetam. 11 mice and rats. Levetiracetam has not dis- and a half life of 6 to 8 hours. Levetira- cetam does not undergo hepatic metabo- EXPERIMENTAL STUDIES played any teratogenic, mutagenic, or carcinogenic properties. lism, nor does it induce or inhibit Levetiracetam shows an unusual profile 12 The mechanism of action of levetira- cytochrome P-450 enzymes. Levetira- of antiepileptic activity in experimental cetam is to a limited extent metabolised animal models of partial and generalised cetam (or indeed the other -acetam (by hydrolysis) by a serine esterase on September 24, 2021 by guest. Protected copyright. epilepsy.2 Unlike other antiepileptic drugs) is not clearly understood, and it does not seem to involve any conven- enzyme in blood and other tissues and drugs, levetiracetam has no effect on excreted through the kidneys un- tional modulation of the three main changed or as inactive metabolites.11 mechanisms relevant for the action of Renal clearance of levetiracetam is classic antiepileptic drugs.7 The drug directly proportional to creatinine clear- does not bind to receptors associated ance. Clearance of levetiracetam is sig- with excitatory or inhibitory neurotrans- nificantly reduced in patients with se- mitters (for example, γ-aminobutyric O vere hepatic impairment and N acid (GABA), glutamate, glycine, adeno- concomitant renal impairment (hepato- sine), has no effect on sodium or T-type CH3CH2 renal syndrome). No differences are seen calcium channel function, and does not in patients with mild to moderate affect GABA transaminase or glutamic C hepatic impairment. In studies with eld- acid decarboxylase (GAD) activity or erly patients, the elimination half life of second messenger systems (cyclic ad- levetiracetam is prolonged to 10 to 11 CONH2 enosine monophosphate, protein kinase 2 H C). By contrast, it has recently been reported that levetiracetam reduces high ........................................ Figure 1 Levetiracetam is a pyrrolidone voltage activated Ca2+ currents,8 reverses derivative and is chemically designated Abbreviations: LEV, levetiracetam; PTZ, (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide. It inhibition of GABA and glycine gated pentylenetetrazol; GABA, γ-aminobutyric acid; has a molecular weight of 170.21 and currents induced by negative allosteric GAD, glutamic acid decarboxylase; SUDEP, 9 molecular formula of C8H14N2O2. modulators, and effects voltage gated sudden and unexplained death in epilepsy www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.72.4.426 on 1 April 2002. Downloaded from EDITORIAL 427 Table 1 Pooled responder rates for those patients who completed titration and were evaluated on a stable dose (evaluation period), and for all patients randomised (the intent to treat population) during the complete treatment period Intent to treat population, total treatment period titration Evaluation period on stable dose included Levetiracetam Levetiracetam Placebo 1000 mg/day 2000 mg/day 3000 mg/day Placebo 1000 mg/day 2000 mg/day 3000 mg/day (n=301) (n=195) (n=95) (n=269) (n=312) (n=204) (n=106) (n=282) >50% responder rate 12.6 27.7 31.6 41.3 9.4 28.6 35.2 39.5 >75% responder rate 3.3 11.8 16.8 22.3 2.6 10.8 16.2 22.4 Seizure freedom* 0.6 3.9 2.1 8.2 0.3 2.9 2.8 6.0 *Seizure-free during the analysed period (evaluation period or total treatment period). hours and is likely attributable to the age 32.5 for patients receiving levetiracetam 69 patients (71%) who were selected for related decline in renal function. After compared with 7 for patients receiving the monotherapy phase were success- single oral dose administration of 20 placebo (p<0.001). The responder rate fully down titrated, and 36 of 69 (52%) mg/kg levetiracetam in children between (the proportion of patients experiencing completed the monotherapy phase. The 6 and 12 years old, total body clearance a 50% or greater reduction in seizure fre- median percentage reduction compared was about 30% to 40% higher than in quency compared with baseline) during with baseline was 73.8% (p=0.037), the adults, and the half life was roughly 6 the evaluation period was 27.7% (54/ 50% responder rate was 59.2% (29/49), hours.13 195), 31.6% (30/95), and 41.3% (111/ and nine patients (18.4%) remained sei- Because it does not undergo hepatic 269) for patients receiving 1000, 2000, zure free during monotherapy. metabolism and is not significantly and 3000 mg/day respectively, compared protein bound, levetiracetam has a very with 12.6% (38/301) of patients who Long term efficacy studies low potential for pharmacokinetic inter- received placebo (fig 2; p>0.001, all Long term analysis of results from the 12 actions. Findings from studies in vitro, doses versus placebo). The percentage of 1422 patients with epilepsy from the first 14–16 clinical trials in patients, and specific patients experiencing a 75% or greater day of exposure to levetiracetam or 17 18 studies with digoxin, phenytoin, war- reduction in seizures was 11.8% (23/ placebo in phase I, II, or III studies show farin, valproic acid, and oral 195), 16.8% (16/95), and 22.3% (60/269) estimated retention rates (Kaplan-Meier 11 contraceptives support this assertion. of patients receiving 1000 mg, 2000 mg, analysis) of about 60% after 1 year and 3000 mg of levetiracetam respec- (number of patients at risk=826), 44% CLINICAL ANTIEPILEPTIC EFFECT tively, compared with 3.3% (10/301) of after 2 years (number of patients at Add on therapy in partial epilepsy placebo treated patients (p<0.001, all risk=489), and 32% after 4 years The efficacy of levetiracetam as add on doses versus placebo). In addition, 5.7% (number of patients at risk=175), for up therapy has been assessed in three (32/559) of patients treated with leveti- to 8 years (number of patients at prospective, double blind, placebo con- 19 racetam became seizure free, compared risk=1).
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