Levetiracetam

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Abstract
Levetiracetam, the S-enantiomer of α-ethyl-2-oxo-1-pyrollidine acetamide, is approved for use as adjunctive therapy in adult patients with partial onset seizures. Oral levetiracetam 1000, 2000 and 3000 mg/day administered as adjunctive therapy for up to 18 weeks significantly increased responder rates and reduced seizure frequency compared with placebo in 3 well designed pivotal trials in adults with treatment-refractory partial seizures with or without secondary generalisation. Levetiracetam 3000 mg/day also significantly increased the number of seizure-free patients, but the effects of levetiracetam 1000 and 2000 mg/day on this end-point were unclear. Effects on seizure severity were not assessed in these trials. Although not yet approved as monotherapy or for use in paediatric patients, efficacy was observed with levetiracetam 3000 mg/day as monotherapy in adult patients with refractory partial seizures with or without secondary generalisation and with the 10 to 40 mg/kg/day dosage as adjunctive therapy in children with refractory partial seizures. However, these data are limited. Oral levetiracetam 1000, 2000 and 3000 mg/day as adjunctive therapy is generally well tolerated with an overall incidence of adverse events similar to that observed with placebo. The most commonly reported events in individual clinical trials were CNS-related and included somnolence, asthenia, headache and dizziness. Levetiracetam administered as adjunctive therapy does not appear to interact with other anticonvulsant drugs, and no clinically relevant interactions were observed between levetiracetam and digoxin, warfarin or probenecid; oral contraceptive protective efficacy was also not affected by levetiracetam. Conclusions: Levetiracetam is a new anticonvulsant agent with a favourable tolerability profile and a low potential for drug interactions. It has shown efficacy as adjunctive therapy in patients with treatment-refractory partial onset seizures with or without secondary generalisation in clinical trials. Direct comparative trials with other anticonvulsant agents are not yet available, but placebo-controlled clinical evidence to date suggests that levetiracetam (1000, 2000 and 3000 mg/day) is a useful option as adjunctive therapy in patients with this subtype of epilepsy. Although the exact mechanism of action of levetiracetam is yet to be defined, various theories have been proposed including changes in γ-aminobutyric acid (GABA) metabolism and turnover, inhibition of depolarising ion currents, calcium channel-dependent effects and dopaminergic activation. Levetiracetam appears to act via a specific binding site in the brain which is present predominantly in the membranes of the CNS, as observed in a single in vitro study. In this study, compounds structurally related to levetiracetam, but not conventional anti-convulsant drugs, showed some affinity for the same binding site. Levetiracetam was effective in animal models of partial seizures with or without secondary generalisation (especially in amygdala-kindled rats and pilocarpine- and kainic acid-induced seizures in rats). Levetiracetam appeared to be more effective in phenytoin nonresponders than phenytoin responders in 1 study. Oral or intraperitoneal levetiracetam inhibited tonic seizures induced audiogenically, electrically and chemically in most rodent models, but effects on clonic seizures appeared to be less marked. Levetiracetam is active in models of chronic epilepsy but not those of acute seizures. Levetiracetam appears to possess antiepileptogenic properties according to rodent studies. Intraperitoneal levetiracetam prevented the induced increases in seizure severity and duration of after discharges and inhibited induced clonic convulsions. No detrimental cognitive effects were observed with levetiracetam (500, 1000 or 1500 mg/day for 1 week) administered as adjunctive therapy to 10 patients with partial (with or without secondary generalisation) or generalised seizures. Tolerance did not develop after 14 or 28 days’ treatment with levetiracetam in 2 studies in rodent models with chemically induced seizures, but tolerance was observed after 10 to 21 days’ treatment in another study in amygdala-kindled rats. Levetiracetam (250 to 5000mg) is rapidly and almost completely absorbed after oral administration, and the absolute oral bioavailability is almost 100%. Maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increase dose-dependently over the 500 to 5000mg range, and steady state is achieved after 2 days. Levetiracetam is only minimally bound to plasma proteins (max and the AUC of levetiracetam were higher and t1/2β was longer at steady state. In patients with anuric end-stage renal impairment undergoing haemodialysis, the clearance of levetiracetam was reduced (by ≈70%) versus values in healthy volunteers and t1/2β during the period between dialysis treatments was increased to ≈25 hours. Mild to moderate hepatic impairment does not significantly affect the pharmacokinetics of levetiracetam. Changes in various parameters (e.g. AUC, t1/2β and total body clearance) were noted in patients with severe hepatic impairment but may have been associated with concomitant...