Disposition of Extended Release Levetiracetam in Normal Healthy Dogs After Single Oral Dosing

Abstract

BackgroundLevetiracetam is an anticonvulsant used for control of canine epilepsy. An extended release preparation should improve dosing convenience.ObjectivesTo determine the disposition of extended release levetiracetam in normal dogs after single dosing.AnimalsPharmacokinetic study: 16 healthy, adult dogs.MethodsUsing a partially randomized crossover study, levetiracetam (30 mg/kg) was administered intravenously (IV) and orally (PO) as extended release preparation with or without food. Blood was collected for 24 hours (IV) or 36 hours (PO). Serum levetiracetam was quantitated by immunoassay and data were subjected to noncompartmental analysis.ResultsPharmacokinetic parameters for fasted versus fed animals, respectively, were (mean ± SEM): C max = 26.6 ± 2.38 and 30.7 ± 2.88 μ/mL, T max = 204.3 ± 18.9 and 393.8 ± 36.6 minutes, t 1/2 = 4.95 ± 0.55 and 4.48 ± 0.48 hours, MRT = 9.8 ± 0.72 and 10 ± 0.64 hours, MAT = 4.7 ± 0.38 and 5.6 ± 0.67 hours, and F = 1.04 ± 0.04 and 1.26 ± 0.07%. Significant differences were limited to T max (longer) and F (greater) in fed compared to fasted animals. Serum levetiracetam concentration remained above 5 μ/mL for approximately 20 hours in both fasted and fed animals.Conclusions and Clinical ImportanceExtended release levetiracetam (30 mg/kg q12h), with or without food, should maintain concentrations above the recommended minimum human therapeutic concentration.

Pharmacokinetics of Single Oral Dose Extended‐Release Levetiracetam in Healthy Cats

“…This gradual change in serum concentration is proposed to result in fewer undesirable effects as well as to decrease the risk of therapeutic failure arising from subtherapeutic concentrations . Our findings are in agreement with those of previous studies comparing IRL and XRL in dogs and humans …”

“…At the time of sample analysis, serum samples were thawed at room temperature and then vortexed to assure homogeneity. Levetiracetam was detected and quantitated in feline serum by a Food and Drug Administration‐approved immunoassay for use in humans on a general chemistry analyzer, which is described elsewhere . The assay had been previously validated in cats .…”

“…The assay had been previously validated in cats . The upper and lower limits of quantitation are 100 and 2 μg/mL, respectively . The coefficient of variation using the manufacturer's quality controls for the time period our samples were analyzed was <14% for the low and <7% for the high‐range control.…”

Pharmacokinetics of the anticonvulsant levetiracetam in neonatal foals

“…The pharmacokinetics of levetiracetam have been extensively evaluated in human patients, dogs, cats, and, more recently, in adult horses [13,14,[22][23][24][25][26]. The results of the current study in foals are similar to those reported in adult horses [14] with minor differences in elimination half-life, volume of distribution and clearance that are likely attributable to agerelated differences in these mechanisms.…”

Disposition of levetiracetam in healthy adult horses

“…The package insert for the assay indicates a lack of cross‐reactivity with the major metabolite (L057/PBA) (ARK website). The accuracy and precision of the assay for quantitation of levetiracetam in serum was confirmed by comparing known amounts of LEV added to equine serum when measured by the immunoassay, as previously performed in dogs (Beasley & Boothe, ). LEV was detected in equine serum, to which the upper limit of quantitation was 150 μg/ml, and the lower limit of quantitation was 2 μg/ml.…”