Monotherapy for partial epilepsy: focus on levetiracetam.

Levetiracetam (LEV), the S-enantiomer of alpha-ethyl-2-oxo-1-pyrollidine acetamide, is a recently licensed antiepileptic drug (AED) for adjunctive therapy of partial seizures. Its mechanism of action is uncertain but it exhibits a unique profile of anticonvulsant activity in models of chronic epilepsy. Five randomized, double-blind, placebo-controlled trials enrolling adult or pediatric patients with refractory partial epilepsy have demonstrated the efficacy of LEV as adjunctive therapy, with a responder rate (>/=50% reduction in seizure frequency) of 28%-45%. Long-term efficacy studies suggest retention rates of 60% after one year, with 13% of patients seizure-free for 6 months of the study and 8% seizure-free for 1 year. More recent studies illustrated successful conversion to monotherapy in patients with refractory epilepsy, and its effectiveness as a single agent in partial epilepsy. LEV has also efficacy in generalized epilepsies. Adverse effects of LEV, including somnolence, lethargy, and dizziness, are generally mild and their occurrence rate seems to be not significantly different from that observed in placebo groups. LEV also has no clinically significant pharmacokinetic interactions with other AEDs, or with commonly prescribed medications. The combination of effective antiepileptic properties with a relatively mild adverse effect profile makes LEV an attractive therapy for partial seizures.

Introduction

Levetiracetam (LEV), (S)-α-ethyl-2-oxo-pyrrolidine acetamide analog of piracetam (Shorvon 2001), is a new anticonvulsant agent with a favorable tolerability profile and a low potential for drug interactions (Dooley and Plosker 2000). LEV was synthesized in the early 1980s during a follow-up chemical program aimed at identifying a second-generation nootropic drug, and initial pharmacologic studies with LEV explored its ability to facilitate cholinergic neurotransmission (Klitgaard 2001). In 1991, pivotal clinical studies were initiated in epilepsy patients as adjunctive therapy in refractory partial onset seizures. In November 1999, the FDA approved LEV as a new antiepileptic drug (AED).

LEV has demonstrated efficacy and a favorable tolerability profile as adjunctive for partial seizures in adult and pediatric patients (Hovinga 2001; Shorvon and van Rijckevorsel). Moreover, there has been increasing evidence that LEV may also be useful in patients with generalized absence or myoclonic seizures, and in patients with Lennox-Gastaut syndrome (Kasteleijn-Nolst et al 1996; Labate et al 2006). LEV has become one of the most frequently prescribed new drugs for the treatment of partial seizures. It offers several advantages over traditional therapy, including twice daily dosing, a wide margin of safety with no requirements for serum drug concentration monitoring, and no interactions with other anticonvulsants. In addition, LEV appears to be well tolerated by most patients and may have less adverse effects on cognitive function than traditional agents (Dooley and Plosker 2000). This advantageous pharmacologic profile makes LEV an attractive first line or adjunctive therapy for epileptic seizures. This review focuses on the experience and use of LEV in partial epilepsy.

Experimental studies

The mechanism for the anticonvulsant effect of LEV still remains elusive. LEV is not chemically related to other anticonvulsants and its mechanism of action seems to be unrelated to known mechanisms of neurotransmission. Indeed, unlike other AEDs, LEV has no effect in the two classic rodent models for AEDs, the maximal electroshock seizure and the pentylenetetrazol (Gower et al 1992; Löscher and Hönack 1993). Moreover, the drug does not bind to receptors associated with excitatory or inhibitory neurotransmitters including γ-aminobutyric acid (GABA), glutamate, glycine, adenosine; it also has no effect on sodium or T-type calcium channel function, and does not affect GABA transaminase or glutamic acid decarboxylase (GAD) activity or second messenger systems (cyclic adenosine monophosphate) or protein kinase C (Löscher and Hönack 1993). Conversely, LEV seems to partially inhibit N-type high-voltage-activated Ca2+ currents and reduces the Ca2+ release from intraneuronal stores (Gower et al 1995; Klitgaard et al 1998; Löscher et al 1998; Rigo et al 2000; Niezpodziany et al 2001; Zona et al 2001). It also reverses inhibition of GABA and glycine gated currents induced by negative allosteric modulators (Rigo et al 2000), and effects voltage gated potassium channel conductance (Madeja et al 2001). LEV also has a specific stereoselective binding site in the CNS at the synaptic vesicle protein 2A (SV2A) (Dooley and Plosker 2000; Rigo et al 2000), and cannot be displaced from this site by other classic AEDs such as carbamazepine, phenytoin, valproate, and phenobarbital, although ethosuximide does show binding affinity. LEV has no binding to membranes outside of the CNS.

LEV has very marked protection against seizures in audiogenic mice, mice kindled with corneal electroshock or PTZ, and amygdaloid kindled rats (Klitgaard et al 1998; Löscher et al 1998). It protects against spontaneous spike and wave discharges in the GAERS model and in pilocarpine or kainic acid induced focal seizures in rats (Klitgaard et al 1998; Löscher et al 1998). The extent of the antiepileptic efficacy in the audiogenic seizure model in mice was found to be correlated with the affinity for the binding site of a series of S-homologues of LEV (Noyer et al 1995). The dose-dependent ability of LEV to inhibit the development of kindling suggests a potential antiepileptogenic effect as well (Löscher et al 1998). LEV is the most effective of any of the pyrrolidone drugs in these epilepsy models. Its R-enantiomer has no antiepileptic activity.

The dose at which toxic effects on the rotarod test are produced is much higher than the effective antiseizure dose in both the GAERS model and the corneally kindled mice. The safety margin of LEV in these models is much greater than for other drugs (Harden 2001). In acute and chronic toxicity studies in animals, LEV shows generally low toxicity. Oral doses up to 5000 mg/kg acutely (maximum tested dose) are not lethal in mice and rats. LEV has not displayed any teratogenic, mutagenic, or carcinogenic properties (French et al 2001; Harden 2001).

Clinical pharmacokinetics

The pharmacokinetic properties of LEV have been studied in healthy adult volunteers, patients with epilepsy, and special populations, including pediatric and elderly patients and patients with renal or hepatic insufficiency (Pellock et al 2001; Radtke 2001). LEV is highly soluble in water. It is formulated for clinical use as 250-, 500-, and 1000-mg film-coated tablets. LEV is rapidly and almost completely absorbed after oral administration of doses ranging from 250 mg to 5000 mg, with peak serum concentrations occurring approximately 1 hour after a dose and steady state concentrations reached within 48 hours. Absorption of LEV is unaffected by the presence of food or antacids, although the rate of absorption may be slowed. It has been now produced an IV formulation of LEV whose infusion is bioequivalent to oral tablets and is well tolerated after 15 min and 5 min IV infusion in healthy subjects (Ramael et al 2006).

LEV exhibits minimal protein binding (<10%) and has a volume of distribution of 0.5–0.7 L/kg in adults, similar to the volume of distribution of intracellular and extracellular water. In addition, LEV exhibits linear, dose proportional, kinetics, with low intrasubject and intersubject variability, and a half-life of 6–8 hours (Pellock et al 2001; Radtke 2001).

LEV is eliminated through renal excretion, primarily as unchanged drug. LEV does not undergo hepatic metabolism (Nicolas et al 1999), even if a minor percentage undergoes hepatic metabolism via enzymatic hydrolysis and hydroxylation to inactive byproducts. Clearance is rapid, so that within 48 hours approximately 93% of an oral dose is eliminated. The elimination half-life of LEV in healthy adults ranges from 6 to 8 hours, in children is 5–7 hours and in elderly between 10 and 11 hours, regardless of dosage or frequency of administration. The prolonged elimination half life of LEV in the elderly is likely attributable to the age related decline in renal function. Average total body clearance is 0.96 mL/min/kg in adults, with a renal clearance of 0.6 ml/min/kg. After single oral dose administration of 20 mg/kg LEV in children between 6 and 12 years of age, total body clearance was about 30%–40% higher than in adults. Renal clearance of LEV is directly proportional to creatinine clearance. In adult patients with severe renal impairment (creatinine clearance <30 mL/min), LEV clearance is reduced by approximately 60% (Radtke 2001). Clearance of LEV is significantly reduced in patients with severe hepatic impairment and concomitant renal impairment (hepatorenal syndrome). No differences are seen in patients with mild to moderate hepatic impairment (Pellock et al 2001).

The recommended dosing regimen for LEV as add on therapy is twice daily doses of 500–1500 mg, for a total daily dosage of between 1000 mg and 3000 mg. Higher doses have been studied, but with little evidence of added effectiveness. The initial starting dose of 1000 mg/day has been shown to be clinically effective, but if sufficient seizure control is not obtained, doses can be increased up to 3000 mg/day. LEV has been shown to be effective as early as the first day of therapy, and this rapid effect is complemented by a sustained efficacy (French and Arrigo 2005). In patients with renal impairment, doses should be reduced in accordance with creatinine clearance (Keppra 2000a, b). Presently, there are no sufficient data to recommend treatment with LEV during pregnancy. In patients withdrawn from LEV, a gradual tapering of 1000 mg every 1–2 weeks has been successful and has not resulted in withdrawal seizures.

Drug interactions

Because of its advantageous pharmacokinetic, LEV does not appear to interact with other AEDs (Nicolas et al 1999), and the overall pharmacokinetic parameters of LEV during polytherapy with AEDs are comparable to those of subjects receiving LEV alone. The pharmacokinetic profile of LEV is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, oral contraceptives ethinylestradiol, and warfarin (Browne et al 2000; French et al 2001; Levy et al 2001; Radtke 2001; Shorvon and van Rijckevorsel 2002). Similarly, the addition of LEV does not significantly alter serum concentrations of all these drugs. Pooled analysis confirmed these findings (Gidal et al 2005). The possible interaction between LEV and tiagabine, topiramate, and zonisamide has not been investigated. A recent experimental study illustrated a pharmacokinetic contribution other than pharmacodynamic interaction between LEV and felbamate (Luszczki et al 2007).

Side effects

The most commonly reported adverse effects during clinical trials with LEV in adults were primarily related to the CNS and included somnolence (15% of patients), asthenia (15%), headache (14%), infection (13%), dizziness (9%), and ataxia (3%) (Ben-Menachem and Falter 2000; Cereghino et al 2000; Shorvon et al 2000). These adverse effects were seen most frequently in the first month of therapy and typically lessened or resolved with continued treatment. In the pooled analysis, there was no evidence of a dose dependent relation within the recommended dose range of 1000–3000 mg/day (Gidal et al 2005). Patients receiving LEV also reported a slightly higher incidence of symptoms of upper respiratory infection, which was not associated with leucopenia or dose reduction. In clinical trials, from one to 4% of patients have withdrawn because of these effects (Ben-Menachem and Falter 2000; Cereghino et al 2000; Shorvon et al 2000; Tsai et al 2006). Similar adverse effects, but higher percentages, were reported in pediatric populations (Glauser et al 2002, 2006).

In pre-marketing studies of LEV, up to 13% of patients have experienced adverse neuropsychiatric symptoms. In most of these patients, the symptoms have been mild, including agitation, hostility, apathy, anxiety, emotional lability, and depression. Nonetheless, about 1% of pediatric or adult patients have experienced serious neuropsychiatric symptoms including hallucinations, suicidal ideations, or psychosis, after beginning LEV (Kossoff et al 2001; Mula et al 2003). There was a significant association between psychiatric adverse events and previous history of febrile convulsions or status epilepticus, while a past personal or family history of psychiatric disorders was more important in predicting the features of psychiatric adverse events rather than their occurrence. Moreover, psychiatric adverse events were not related to the starting dose, titration schedule of LEV or the rate of seizure freedom. In these reports, symptoms occurred mostly within the first month of therapy, but they could develop at any time during treatment. Dose reduction or discontinuation has led to resolution of symptoms in the cases reported. Overall, these studies illustrated that a close clinical monitoring with regard to psychiatric adverse events is related to the psychiatric profile of the patient (Kossoff et al 2001; Mula et al 2003). Conversely, LEV has no major adverse effects on cognitive function (Neyens et al 1995).

Clinical antiepileptic effect

Add on therapy in partial epilepsy

The efficacy of LEV as add on therapy has been assessed in 5 prospective, double blind, placebo controlled trials in patients with uncontrolled partial seizures (Ben-Menachem and Falter 2000; Cereghino et al 2000; Shorvon et al 2000; Glauser et al 2006; Tsai et al 2006). Four of these studies enrolled adult patients with at least 2 refractory partial seizures per 4 weeks (Ben-Menachem and Falter 2000; Cereghino et al 2000; Shorvon et al 2000; Tsai et al 2006). The fifth study was carried out in children aged 4–16 years (Glauser et al 2006). Doses of LEV evaluated in adults included 1000, 2000, and 3000 mg/day given in twice-daily regimens. Dose titration was of 4 weeks, followed by 12–14 weeks of maintenance. At all dosages evaluated in these three studies, LEV was significantly more effective than placebo. The median percentage reduction from baseline was 32.5% for patients receiving LEV compared with 7% for those receiving placebo (p < 0.001). During the evaluation period, the responder rate, that is the proportion of patients experiencing a 50% or greater reduction in seizure frequency compared with baseline, was 27.7% (54/195), 31.6% (30/95), and 41.3% (111/269) for patients receiving 1000, 2000, and 3000 mg/day respectively, compared with 12.6% (38/301) of patients who received placebo (p > 0.001, all doses versus placebo). The percentage of patients experiencing a 75% or greater reduction in seizures was 11.8% (23/195), 16.8% (16/95), and 22.3% (60/269) of patients receiving 1000 mg, 2000 mg, and 3000 mg of LEV respectively, compared with 3.3% (10/301) of placebo treated patients (p < 0.001, all doses versus placebo). In addition, 5.7% (32/559) of patients treated with LEV became seizure free, compared with 0.6% (2/301)in the placebo group (p < 0.001) (Cereghino et al 2000).

A statistically significant reduction in seizure frequency for all different subtypes of partial seizures (simple partial, complex partial, and secondarily generalized seizures) was found with LEV treatment. In addition a pooled analysis derived from the three studies in adults demonstrates a specific independent reduction of secondary generalized seizures (median percentage reduction: 68.5%) (Leppik et al 2003).

A large multicenter, randomized, placebo-controlled trial illustrated that LEV as adjunctive therapy administered at 60 mg/kg/day is also efficacious and well tolerated in children with drug-resistant partial seizures (Glauser et al 2006). During the treatment period, 198 patients received either placebo or LEV add-on therapy and were up-titrated to a target dose of 60 mg/kg/day. There was a significant (26.8%; p < 0.0002; 95% CI 14.0%–37.6%) reduction in partial onset seizure frequency per week for LEV adjunctive therapy over placebo adjunctive therapy. A 50% or greater reduction of partial seizure frequency per week was attained in 44.6% of the LEV group (45/101 patients), compared with 19.6% (19/97 patients) receiving placebo (p = 0.0002).

Monotherapy

Although LEV is well tolerated with a favorable pharmacokinetic profile, few works demonstrated successful conversion to monotherapy in patients with refractory epilepsy, and few studies with small number of patients demonstrate its effectiveness as a single agent in partial epilepsy (Ben-Menachem and Falter 2000; Alsaadi et al 2005; Brodie et al 2007). In a multicenter double-blind, responder selected study (Ben-Menachem and Falter 2000), it was evaluated the efficacy and tolerability of LEV monotherapy in selected patients with refractory focal epilepsy: in the LEV monotherapy group the median percent reduction in partial seizure frequency compared with baseline was 73.8% with a responder rate of 59.2%.

In an open study, LEV was efficacious as monotherapy in 46 patients with newly diagnosed naïve epilepsy or with chronic difficult to control epilepsy who were followed for 1 year (Alsaadi et al 2005). In this study, the majority (82%) of the patients remained on LEV for at least 1 year with more than 50% of patients remaining seizure free. Moreover, a recent randomized double-blind trial involving 579 patients comparing LEV with controlled-release carbamazepine illustrated that both AEDs have produced equivalent seizure freedom rates in newly diagnosed epilepsy at optimal dosing in a setting mimicking clinical practice (Brodie et al 2007). Importantly, no other newer AED has been shown to be equivalent to an older generation AED (Brodie et al 2007). Furthermore, long-term evaluation of the patients enrolled in these trials, as well as several others, suggests that LEV is both efficacious and well tolerated by most patients. Based on compiled results, retention rates are estimated to be 60% at 1 year and 32% at 5 years (Krakow et al 2001).

IV therapy

LEV IV infusion is bioequivalent to oral tablets and is well tolerated after 15-min (2000–4000) and 5-min (1500–2500) IV infusions in healthy subjects (Ramael et al 2006a, b). Among the newer agents LEV has been the first to be approved for IV application. The results of a small, multicenter, open-label study (Baulac et al 2007) suggest that a 15-min infusion (500–1500 mg, bid) is well tolerated in patients with partial onset seizures when administered over a 4-day period. The observed adverse events were mild to moderate and the most frequently reported ones were headache and fatigue. None of the subjects discontinued because of adverse events and no serious adverse events were reported. These results support dosing flexibility and easy conversion from oral to IV LEV, and back, in patients with partial-onset seizures temporarily unable to take the drug orally.

Conclusions

LEV is a novel antiepileptic drug which has been approved as adjunctive treatment for adults with partial onset seizures. Its effectiveness was established in five multicenter, well-controlled pivotal trials. In addition, LEV is well tolerated with a favorable pharmacokinetic profile that includes minimal protein binding, lack of hepatic metabolism, and twice a day dosing. These features and others make it ideal for use as monotherapy (French et al 2004a, b). The majority of studies on LEV monotherapy effect in focal epilepsies in children, in adults, and in the elderly are based on retrospective evaluation of small series of patients with a short-term follow up; only one study compares LEV to an traditional AED; more additional randomized double-blind monotherapy trials are needed to confirm these findings.