Levetiracetam (LEV) is one of the newest AEDs, marketed worldwide only since 2000. It was initially approved in the US only as adjunctive therapy for partial-onset seizures. However, more recent trials earned it approval as adjunctive therapy for primary generalized tonic-clonic seizures and myoclonic seizures of juvenile myoclonic epilepsy, and a recent comparative monotherapy trial earned it approval for use as initial monotherapy in the European Union, though not in the US. In addition, the recent approval and marketing of an intravenous preparation has added to the versatility of this AED.
LEV is rapidly and almost completely absorbed after oral intake, with peak plasma concentrations approximately one hour after oral administration. Food reduces the peak plasma concentration by 20% and delays it by 1.5 hours, but does not reduce LEV bioavailability (Patsalos 2000, 2003). There is a linear relationship between LEV dose and LEV serum level over a dose range of 500–5000 mg (Radtke 2001). LEV protein binding, at less than 10%, is not clinically relevant. LEV metabolism is not dependent on the liver cytochrome P450 enzyme system. LEV is predominantly excreted unchanged through the kidneys, with only about 27% metabolized. The main metabolic pathway is hydrolysis of the acetamide group in the blood (Radtke 2001). The resultant metabolite generated is inactive. LEV plasma half-life is 7 ± 1 hours in adults, but can be prolonged by an average of 2.5 hours in the elderly, most likely due to decreased creatinine clearance with age (French 2001; Hirsch et al 2007). In patients with impaired renal function, a dose adjustment is needed, dependent on the creatinine clearance (French 2001). The absence of hepatic metabolism and of protein binding predict absence of pharmacokinetic interactions (Nicolas et al 1999). Indeed, no pharmacokinetic interactions were observed with phenytoin, warfarin, digoxin, or oral contraceptives (Browne et al 2000; Levy et al 2001; Patsalos 2000, 2003; Ragueneau-Majlessi et al 2001, 2002; Abou-Khalil et al 2003; Coupez et al 2003). However, some studies have suggested lower LEV levels or higher LEV clearance in patients taking enzyme-inducing AEDs (May et al 2003; Perucca et al 2003; Hirsch et al 2007). Autoinduction probably does not occur with LEV, but one study involving short intensive monitoring suggested a drop in serum levels after the fifth day of administration (Stefan et al 2006).
Intravenous levetiracetam. The intravenous formulation of LEV was demonstrated bioequivalent to the oral formulation (Ramael et al 2006b). In the initial study 1,500 mg of LEV were injected over 15 minutes (Ramael et al 2006b). The infusion was well tolerated and adverse effects were similar to those with oral LEV, though somnolence was more common with the intravenous administration. In a second study, higher doses and faster infusion rates were used (2,000, 3,000, and 4,000 mg over 15 min; 1,500, 2,000, and 2,500 mg over 5 min) (Ramael et al 2006a). The most common adverse experiences, dizziness and somnolence, were not clearly related to dose or infusion rate. As expected, the peak plasma level was reached at 5 or 15 minutes, corresponding to the end of the infusion, but otherwise the pharmacokinetic profile was similar to that of oral LEV. LEV infusion over 15 minutes was demonstrated to be a practical alternative in epilepsy patients unable to take the oral medication (Baulac et al 2007).
Pharmacology in children, infants, and neonates. Pharmacokinetics in children were studied in 15 boys and nine girls 6–12 years old who received a single dose of LEV, 20 mg/kg as an adjunct to their stable regimen of a single concomitant AED (Pellock et al 2001). The half-life was 6 ± 1.1 hours. The C-max and area under the curve were lower in children than in adults and renal clearance was higher. The apparent body clearance was 1.43 ± 0.36 mL/min/kg, 30%–40% higher in children than in adults. In another study in younger children and infants, the same dose/Kg was administered as a 10% oral solution to thirteen subjects aged 2.3–46.2 months. The mean half-life was 5.3 ± 1.3 hours in this younger group (Glauser et al 2007). The half-life is likely longer in neonates. Two studies estimated LEV half-life in the neonate at 18 hours (Allegaert et al 2006; Tomson et al 2007).
Pharmacokinetics during pregnancy. Maternal plasma concentrations measured during the third trimester were compared to a “baseline” before pregnancy or after delivery in two small studies (Tomson et al 2007; Westin et al 2008). Both studies found plasma concentrations to be significantly lower during the third trimester in comparison with baseline. The mean concentration-to-dose ratio in the third trimester was 50%–30% of that at baseline. This suggested that the elimination of LEV may be enhanced during pregnancy. However, there was great variability between patients, such that the change in serum concentration could not be accurately predicted.
Serum levels. LEV has linear kinetics, such that in any individual the serum concentration is proportional to the dose (Patsalos 2004). However, the effective serum level for LEV is not known. One study in 69 patients taking 500–3000 mg/day found that the trough plasma concentration ranged from 1.1 to 33.5 μg/mL (Lancelin et al 2007). Similar mean concentrations were found in patients experiencing adverse effects and those without adverse effects (11.2 vs 10.9 μg/mL). The mean plasma concentrations in responders and non-responders were 12.9 and 9.5 μg/mL. The difference was not significant, but the authors suggested that 11 μg/mL could be a threshold concentration for a therapeutic response. The vast majority of patients in this study had refractory epilepsy, making it difficult to study the effective plasma concentration of LEV. Such a study is best conducted in patients with new onset epilepsy. A trial comparing LEV and carbamazepine in newly diagnosed patients did not report plasma concentrations (Brodie et al 2007). However, it found that most patients were seizure-free at the lowest LEV dose of 1000 mg/day. In the therapeutic drug monitoring study mentioned earlier, a daily dose of 1000 mg/day was associated with a mean trough level of 6.5 ± 2.4 μg/mL (Lancelin et al 2007). Even though a therapeutic and toxic LEV concentration are not defined, measuring the serum concentration is helpful to assess compliance. In addition, if a baseline serum concentration is obtained during a period of good seizure control, the serum concentration can be repeated with breakthrough seizures to assess if a drop in concentration played a role. Finally, monitoring serum concentration through the course of pregnancy can help with calculating the recommended dose adjustments needed to correct for increased clearance.
Putative mechanism of action. LEV is different in its mechanism from that of other AEDs, because it is not effective in the standard animal models used to screen for anticonvulsant activity, while it is effective in the chronic kindling model (Loscher and Honack 1993; Klitgaard et al 1998). It was recently established that the most relevant LEV mechanism of action is through binding to the synaptic vesicle protein SV2A (Lynch et al 2004). The SV2A binding affinity of LEV derivatives correlated strongly with their binding affinity in the brain, as well as with their ability to protect against seizures in the audiogenic mouse model (Lynch et al 2004). Similar findings were noted in the mouse corneal kindling model and the GAERS rat model of generalized absence epilepsy (Kaminski et al 2008). The specific effect of LEV binding to SV2A appears to be a reduction in the rate of vesicle release (Yang et al 2007). LEV has other mechanisms of action that likely play a comparatively smaller role: reversing the inhibition of neuronal GABA- and glycine-gated currents by the negative allosteric modulators zinc and ?-carbolines (Rigo et al 2002), and partial depression of the N calcium current (Niespodziany et al 2001; Lukyanetz et al 2002). At present, the mechanisms of action have not yet helped identify a specific clinical efficacy profile for LEV.