Single-dose bioavailability of levetiracetam intravenous infusion relative to oral tablets and multiple-dose pharmacokinetics and tolerability of levetiracetam intravenous infusion compared with placebo in healthy subjects.
BACKGROUND
Antiepileptic drugs are usually administere dorally, but alternative routes of drug delivery may be required when oral administration is not feasible.


OBJECTIVE
The purpose of this study was to evaluate the single-dose bioavailability of an IV formulation of levetiracetam relative to oral tablets and the multiple-dose tolerability and pharmacokinetics of this formulation compared with placebo in healthy subjects.


METHODS
This study consisted of 2 phases. Subjects entered the first phase, which was a single-dose, randomized, open-label, 2-way crossover bioavailability comparison of a 15-minute IV infusion of levetiracetam 1,500 mg and three 500-mg oral tablets. Subjects then entered the second phase, a multiple-dose, randomized, double-blind, placebo-controlled (2:1), parallel-group tolerability and pharmacokinetic study, in which they received 9 successive doses of levetiracetam 1,500 mg IV or placebo at 12-hour intervals. Plasma levetiracetam concentrations were determined by gas chromatography with nitrogen-phosphorus detection. The comparison of bioavailability was based on the 90% CIs around the geometric mean ratios for AUC and C(max) (IV/oral).


RESULTS
Eighteen subjects (9 men, 9 women) participated in the study. All subjects were white. Their mean (SD) age was 35.0 (9.3) years, mean weight 73.3 (14.2) kg, and mean body mass index 23.9 (2.5) kg/m(2). After a single dose, the IV infusion and oral tablet were similar in terms of C(max) (50.5 and 47.7 microg/mL, respectively) and AUC (392.4 and 427.9 pg x h/mL). The geometric mean IV/oral ratios were 92.2 (90 % CI, 89.0-95.6) for AUC and 103.7 (90% CI, 91.6-117.4) for C(max) indicating that the IV and oral formulations were bioequivalent. After multiple twice-daily infusions, steady state was reached within 48 hours. Seventeen (94%) of 18 subjects had >or=1 treatment-emergent adverse event after single-dose administration. During the single-dose phase, the incidence of treatment-emergent adverse events was 89% (16/18) for the IV formulation and 72% (13/18) for the oral tablets; during the multiple-dose phase, the incidence of treatment-emergent adverse events was 67% (8/12) in the IV levetiracetam group and 33% (2/6) in the placebo group. The most common adverse events in the single-dose phase were somnolence (61% IV vs 28% oral) and postural dizziness (17% vs 39%, respectively). The most common adverse events with IV levetiracetam in the multiple-dose phase were also somnolence (33% vs 17% placebo) and postural dizziness (25% vs 0% placebo).


CONCLUSIONS
In these healthy subjects, single doses of levetiracetam 1,500 mg administered as a 15-minute IV infusion and as oral tablets were bioequivalent. General and local tolerability during multiple dosing were good. Steady state was reached within 48 hours. Despite the limitations of a study of short duration and small size conducted in healthy subjects, the findings suggest that use of a 15-minute IV infusion of levetiracetam should be further investigated.
Ramael
Steven
S
SGS Life Sciences Services, Research Unit Stuivenberg, Antwerp, Belgium. steven_ramael@sgs.com
De Smedt
Florence
F
Toublanc
Nathalie
N
Otoul
Christian
C
Boulanger
Pierre
P
Riethuisen
Jean-Michel
JM
Stockis
Armel
A
D000284:Administration, Oral; D000328:Adult; D000465:Algorithms; D000704:Analysis of Variance; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013997:Time Factors
D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam