Pharmacokinetics of levetiracetam in infants and young children with epilepsy.

PURPOSE: To assess the single-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in infants and young children with epilepsy. METHODS: Eligible patients with a stable regimen of antiepileptic medications received a single oral dose of levetiracetam 20 mg/kg administered as a 10% oral solution followed by a 24-hour pharmacokinetic evaluation. RESULTS: Thirteen subjects (age 2.3-46.2 months) enrolled and received levetiracetam; 12 provided evaluable pharmacokinetic data. Levetiracetam was rapidly absorbed and reached peak plasma concentration (t(max)) 1.4 +/- 0.9 hours after dosing. The mean half-life (t(1/2)) of levetiracetam was 5.3 +/- 1.3 hours, and the apparent clearance was 1.46 +/- 0.42 mL/min/kg. Graphical differences were observed among three age subgroups (1 to <6 months, 6 to <24 months, and 24 to <48 months); however, statistical analysis was limited due to each subgroup's small sample size. No significant gender differences were detected. Treatment-emergent adverse events were seen in three patients (23.1%) but were not considered to be related to levetiracetam. CONCLUSIONS: The mean t(1/2) of levetiracetam was shorter and its apparent clearance was more rapid for infants and young children than that previously reported for adults. When determining dosage, age-dependent drug clearance should be considered; these findings suggest that a larger dose of levetiracetam (corrected for body weight) needs to be considered for infants and young children with epilepsy than that given to adults with epilepsy. A single dose of levetiracetam was well tolerated in this study population.

Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4- to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate.

PURPOSE: To assess the multiple-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in children with partial-onset seizures and determine whether it is affected by adjunctive carbamazepine or valproate. To correlate levetiracetam concentrations in plasma and saliva and to assess its safety and clinical response. METHODS: Design was an open-label, multicenter study. Twenty-one children (4-12 years old) with epilepsy taking carbamazepine (13) or valproate (8) received adjunctive levetiracetam. Levetiracetam was initiated at 20 mg/(kg day) and titrated at 2-week intervals to 40 and then 60 mg/(kg day). Twelve-hour pharmacokinetics were determined at the end of each 2-week period. Efficacy was estimated from the partial seizure frequency per week and Global Evaluation Scale. RESULTS: Levetiracetam was rapidly absorbed following oral dosing, with median t(max) of 0.5 h. Dose proportional increases were observed for C(max) and AUC((0-12)) over the dose range; t(1/2) was 4.9 h. Pharmacokinetics of levetiracetam and ucb L057 were not markedly different with concomitant carbamazepine or valproate; clearance was only 7-13% faster and AUC was decreased by only 15-24% in those on carbamazepine compared to valproate. Levetiracetam did not affect trough carbamazepine or valproate. Concentration in saliva and plasma were strongly correlated. Seizure frequency declined by 50% or more in 43% of subjects in the intent-to-treat population (n=21) and in 56% of those with seizures at baseline (n=16). Marked or moderate improvement occurred in 80% and 75% of patients based on Global Evaluation Scale ratings by investigators and parents/guardians, respectively. Levetiracetam was well tolerated. CONCLUSION: Levetiracetam exhibits simple pharmacokinetics in children, with rapid absorption and dose-proportional kinetics. Small but not clinically relevant differences were observed between subjects receiving carbamazepine and valproate, suggesting significant dose adjustment is usually not necessary. This substantiates prior assessments that levetiracetam clearance is higher in children than adults, necessitating a higher dose in children on a mg/kg basis, and suggests it is useful add-on therapy for children with partial-onset seizures regardless of baseline therapy.

Pharmacokinetics of levetiracetam in patients with moderate to severe liver cirrhosis (Child-Pugh classes A, B, and C): characterization by dynamic liver function tests.

BACKGROUND: Levetiracetam is an antiepileptic drug approved for use as adjunctive therapy in adults with partial-onset seizures. We sought to investigate possible changes in the pharmacokinetics of levetiracetam and its metabolite ucb L057 in patients with liver cirrhosis, who may require dose adjustments. METHODS: A single dose of levetiracetam was administered to 5 healthy subjects and to patients with Child-Pugh class A (n = 5), B (n = 6), or C (n = 5) alcohol-induced cirrhosis. The pharmacokinetics of levetiracetam and ucb L057 was measured and correlated with biochemical liver function parameters, with creatinine clearance, and with kinetics of caffeine, lidocaine, and d -sorbitol as probes for specific liver functions. RESULTS: Dynamic liver function tests revealed a deterioration of liver function. The pharmacokinetics of levetiracetam and its metabolite did not differ between healthy subjects and those with class A or B cirrhosis. However, in patients with class C cirrhosis, levetiracetam total clearance was reduced by 57% (90% confidence interval [CI], 43%-67%; P < .001). The geometric mean ratio of the area under the plasma concentration-time curve for levetiracetam, Child-Pugh class C versus control, was 2.41 (90% CI, 1.80-3.23), and the geometric mean of the half-life ratio was 2.27 (90% CI, 1.74-2.97). This was explained by the deterioration of renal function in patients with severe hepatic disease. CONCLUSIONS: In pharmacokinetic studies of hepatic impairment, including all classes of cirrhosis may be more revealing than including only selected classes of liver failure. No dose adjustment of levetiracetam is necessary in patients with mild to moderate liver impairment; however, patients with severe cirrhosis should initially receive only half of the commonly recommended dose.

Levetiracetam: relative bioavailability and bioequivalence of a 10% oral solution (750 mg) and 750-mg tablets.

Levetiracetam, an antiepileptic drug, is used worldwide as an adjunctive treatment for partial-onset seizures. The availability of a new oral solution formulation would provide an additional treatment option for patients who have difficulty swallowing tablets. A phase I single-center, randomized, open-label, two-way crossover, single-dose study was conducted to confirm that a 10% oral solution of levetiracetam was bioequivalent to the 750-mg oral tablet and to characterize its pharmacokinetics. Each of 24 healthy subjects received a single oral 750-mg dose of the randomized levetiracetam formulation (7.5 mL of 10% solution or 750-mg tablet) on day 1 and a single oral dose of the alternate formulation on day 8. Serial blood samples were collected from 0 to 36 hours after each dose administration for determination of plasma levetiracetam concentrations. Pharmacokinetic parameters were calculated, and bioequivalence of the two formulations was evaluated. The mean levetiracetam plasma concentration-time curves and pharmacokinetic parameters essentially were identical for the oral 10% solution and tablet and consistent with previously reported levetiracetam pharmacokinetics. The 90% confidence limits of the geometric mean ratio of the two formulations for area under the plasma concentration-time curve from time 0 to infinity, area under the plasma concentration-time curve from time 0 to last measurable time point, and maximum plasma concentration were within the 80% to 125% range, demonstrating bioequivalence of the two formulations. Both levetiracetam formulations were well tolerated. The levetiracetam 10% oral solution is a bioequivalent, well-tolerated alternative to the tablet formulation in patients who have difficulty swallowing.

Levetiracetam, a new antiepileptic agent: lack of in vitro and in vivo pharmacokinetic interaction with valproic acid.

PURPOSE: The novel antiepileptic drug (AED) levetiracetam (LEV; Keppra) has a wide therapeutic index and pharmacokinetic characteristics predicting limited drug-interaction potential. It is indicated as an add-on treatment in patients with epilepsy, and thus coadministration with valproic acid (VPA) is likely. These studies were performed to determine whether coadministration of LEV with VPA might result in pharmacokinetic interactions. METHODS: In vitro assays were performed to characterize the transformation of LEV into its main in vivo metabolite UCB L057. The reaction was examined for its sensitivity to clinically relevant concentrations of VPA. An open-label, one-way, one-sequence crossover clinical trial was conducted in 16 healthy volunteers to assess further the possibility of any relevant pharmacokinetic interaction. RESULTS: Human whole blood and, to a lesser extent, human liver homogenates were demonstrated to hydrolyze LEV to UCB L057, its main metabolite. The reaction possibly involves type-B esterases and is not affected by 1 mM VPA (i.e., 166 microg/ml). Pharmacokinetic parameters of a single dose of LEV (1,500 mg) coadministered with steady-state concentrations of VPA (8 days of 500 mg, b.i.d.) did not differ significantly from the pharmacokinetics of LEV administered alone [area under the curve (AUC) of 397 and 400 microg/h/ml, respectively]. Furthermore, LEV did not affect the steady-state pharmacokinetics of VPA. CONCLUSIONS: These findings suggest the absence of a pharmacokinetic interaction between VPA and LEV during short-term administration, and suggest that dose adjustment is not required when these two drugs are given together.