Levetiracetam pharmacokinetics in healthy dogs following oral administration of single and multiple doses

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.

Section: Discussioncontrasting

confidence: 52%

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confidence: 99%

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confidence: 99%

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

Boothe

2015

“…Pharmacokinetic studies with oral and parenterally administered levetiracetam in dogs have demonstrated that this drug undergoes rapid absorption and has excellent tolerance and bioavailability via oral, intramuscular, and subcutaneous routes of administration 16, 21, 22, 23, 24, 25, 26, 27 Although the serum half‐life for these routes is similar to that of rectally administered diazepam metabolites, the resident half‐life of levetiracetam in the cerebrospinal fluid can be considerably longer. In view of its excellent bioavailability and longer duration of action in the CNS, levetiracetam is a good candidate for parenteral administration to dogs experiencing an episode of CS.…”

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confidence: 99%

Levetiracetam Rectal Administration in Healthy Dogs

Peters

Schubert

Clemmons

et al. 2014

BackgroundLevetiracetam is used to manage status epilepticus (SE) and cluster seizures (CS) in humans. The drug might be absorbed after rectal administration and could offer a practical adjunct to rectal administration of diazepam in managing SE and CS.HypothesisLevetiracetam is rapidly absorbed after rectal administration in dogs and maintains target serum concentrations for at least 9 hours.AnimalsSix healthy privately owned dogs between 2 and 6 years of age and weighing 10–20 kg.MethodsLevetiracetam (40 mg/kg) was administered rectally and blood samples were obtained immediately before (time zero) and at 10, 20, 40, 60, 90, 180, 360, and 540 minutes after drug administration. Dogs were observed for signs of adverse effects over a 24‐hour period after drug administration.Results C LEV at 10 minutes was 15.3 ± 5.5 μg/mL (mean, SD) with concentrations in the target range (5–40 μg/mL) for all dogs throughout the sampling period. C max (36.0 ± 10.7 μg/mL) and T max (103 ± 31 minutes) values were calculated and 2 disparate groups were appreciated. Dogs with feces in the rectum at the time of drug administration had lower mean C max values (26.7 ± 3.4 μg/mL) compared with those without (45.2 ± 4.4 μg/mL). Mild sedation was observed between 60 and 90 minutes without other adverse effects noted.Conclusions and Clinical ImportanceThis study supports the use of rectally administered levetiracetam in future studies of clinical effectiveness in the management of epileptic dogs.

“…Metabolic tolerance is present when progressive dose increases without concurrent parallel increase in serum drug concentration occurs, most likely because of other drugs that are p450 enzyme inducers or genetic variations. Conversely, phenobarbital will increase clearance of several other AEDs, including levetiracetam,59, 60 zonisamide61 and clorazepate 62…”

Section: How Should Monitoring Be Performed?mentioning

confidence: 99%

2015 ACVIM Small Animal Consensus Statement on Seizure Management in Dogs

Podell

Volk

Berendt

et al. 2016

131

This report represents a scientific and working clinical consensus statement on seizure management in dogs based on current literature and clinical expertise. The goal was to establish guidelines for a predetermined, concise, and logical sequential approach to chronic seizure management starting with seizure identification and diagnosis (not included in this report), reviewing decision‐making, treatment strategies, focusing on issues related to chronic antiepileptic drug treatment response and monitoring, and guidelines to enhance patient response and quality of life. Ultimately, we hope to provide a foundation for ongoing and future clinical epilepsy research in veterinary medicine.