Levetiracetam as an Adjunctive Therapy for Partial SeizuresIn December 1999, UCB Pharma, Inc. (Smyrna, Georgia) announced that the United States' Food and Drug Administration (FDA) has approved levetiracetam (Keppra™) as an antiepileptic drug indicated as an adjunctive (add-on) therapy in the treatment of partial onset seizures in adults with epilepsy. UCB Pharma, Inc. filed its New Drug Application for levetiracetam with the US FDA on 1 February 1999. Its approval within 10 months of the submission makes it the fastest antiepileptic drug (AED) approval to date in the USA. Levetiracetam is expected to be available in USA in the spring of 2000.
In CanadaIn a recent telephone interview, the medical spokesperson for UCB Pharma Inc. reported that application has been made to the Canadian government to license levetiracetam for distribution in Canada. The American arm of the Belgian chemical giant hopes to receive approval from our federal government in the second quarter of 2000. Levetiracetam has been approved in only a few countries.
PharmacokineticsPSL Group (authors of the
Doctor's Guide to the Internet) reports that levetiracetam's pharmacokinetic profile is its most distinctive feature. It quotes Tony Tebbutt, President of UCB Pharma, Inc., as saying that levetiracetam is "an important new treatment for the management of epilepsy because treatment is initiated with an effective daily dose and it contributes valuable additional seizure control without concern for interactions with concomitantly administered antiepileptic drugs."
Levetiracetam is reported to be absorbed rapidly after oral administration. Food does not affect the extent of bioavailability. Pharmacokinetics are linear and steady state is achieved after 2 days of multiple twice daily dosing. Levetiracetam is not protein bound (less than 10% bound). Its metabolism is not liver cytochrome P450 dependent, with 66% of the dose renally excreted unchanged. Plasma half-life is approximately 6-8 hours (longer in people with renal impairment, and in the elderly, due to age-related decrease in renal function). Levetiracetam is unlikely to produce or be subject to pharmacokinetic drug interactions. Studies show that levetiracetam's starting dose is also an effective daily dose, eliminating the need to begin taking the medication at sub-therapeutic levels because of side effects.
Clinical TrialsLevetiracetam was tested as adjunctive therapy in the treatment of partial onset seizures in adults in 3 multi-centre, randomized, double-blind, placebo-controlled clinical studies: 3,347 study participants have taken levetiracetam at some point during its development; 1,393 people with epilepsy participated in all phases of clinical studies.
In both the USA and Europe, 904 people with refractory partial onset seizures for at least 2 years participated. Participants remained on a steady dose of 1-2 AEDs and still experienced at least 4 seizures during each 4 weeks of the baseline period. After the baseline period of 8-12 weeks, participants were randomized into either a levetiracetam or placebo group. The 3 well-controlled clinical studies compared either 1,000 mg/day and 3,000 mg/day levetiracetam and placebo, 1,000 mg/day and 2,000 mg/day levetiracetam and placebo, or 3,000 mg/day levetiracetam and placebo given in equally divided doses twice daily. The 16-18-week treatment period comprised a 4-6-week titration period, and a 12-week fixed dose evaluation period during which concomitant AED regimens were held constant.
The primary measure of effectiveness was a comparison between groups of the reduction in weekly seizure frequency for the entire treatment period. Secondary measurements included the responder rate (incidence of at least a 50% reduction in seizure frequency).
In all 3 studies, persons taking 1000 mg/day, 2,000 mg/day or 3,000 mg/day of levetiracetam saw a statistically significantly greater reduction in weekly seizure frequency compared with those taking placebo. Those taking 1,000 mg/day levetiracetam had a reduction of 26.1% in Study 1, and 17.1% in Study 2. Those taking 2,000 mg/day levetiracetam had a reduction of 21.4% in Study 2. Those taking 3,000 mg/day levetiracetam had a reduction of 30.1% in Study 1, and 23.0% in Study 3.
The responder rate was statistically significantly greater in all who were taking levetiracetam. The responder rate for those taking 1,000 mg/day levetiracetam was 37.1% in Study 1, and 20.8% in Study 2. The responder rate at 2,000 mg/day levetiracetam was 35.2% in Study 2. At 3,000 mg/day levetiracetam, the responder rate was 39.6% in Study 1 and 39.4% in Study 3. Persons taking placebo had a 7.4%, 6.3%, and 14.4% responder rate in Studies 1, 2, and 3 respectively.
Levetiracetam was generally well tolerated by persons taking it in clinical studies. Adverse events included somnolence and fatigue, co-ordination difficulties and behavioural abnormalities. When taken with other AEDs in controlled studies, the most frequently reported adverse events were somnolence, asthenia (lack or loss of strength), infection and dizziness. Adverse events were usually mild to moderate in intensity. Most appeared predominantly during the first 4 weeks of treatment.
As a result of adverse events, 15% of persons receiving levetiracetam and 11.6% receiving placebo discontinued therapy or continued with a reduced dose. When comparing persons taking levetiracetam with those taking placebo, minor but statistically significant decreases in total mean RBC count (0.03 x 10
6/mm
2), mean haemoglobin (0.09 g/dL) and mean haematocrit (0.38 percent) were seen.
Levetiracetam is substantially excreted by the kidneys: caution is advised for persons with moderate and severe renal impairment and those on haemodialysis.
Levetiracetem is said to be effective, generally well tolerated and not associated with drug interactions when used in conjunction with other AEDs.
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about UCB Group
The UCB Group is a pharmaceuticals and chemical transnational conglomerate which is active in 3 principal industrial sectors: pharmaceuticals, films and chemicals (including agrochemicals). The group includes subsidiaries on every continent and in virtually every sector of the chemical industry.
