The pharmacokinetics of levetiracetam in healthy dogs concurrently receiving phenobarbital

Abstract

Levetiracetam (LEV) is a commonly used add-on medication in dogs with refractory epilepsy. The objective of this study was to determine if the pharmacokinetics of LEV are altered by concurrent administration of phenobarbital (PB). Six healthy dogs received a single oral dose of LEV (16.7-27.8 mg/kg). Blood samples were collected at baseline and intermittently for 24 h. The study was repeated after the dogs received oral PB (2.0-3.3 mg/kg) twice daily for 21 days. Plasma LEV levels were evaluated by high pressure liquid chromatography, and data analyzed using a compartmental model. Compared with values determined when LEV was administered alone, concurrent administration of PB resulted in a decrease in LEV peak concentration (C(max) ) from 32.39 ± 6.76 to 18.22 ± 8.97 (P = 0.0071), a decrease in elimination half-life (T(1/2) ) from 3.43 ± 0.47 to 1.73 ± 0.22 (P = 0.0005), and an increase in oral clearance from 124.93 ± 26.93 to 252.99 ± 135.43 ml/h/kg (P < 0.0001). Concurrent PB administration significantly alters the pharmacokinetics of LEV in the dog, indicating that dosage adjustments might be necessary when the drug is administered with PB.

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

“…The AUC for regular release was 44.8 μ × h/mL and with extended release 230 μ × h/mL. This AUC for regular release is short when compared to previously published data,7, 9, 10, 11, 12, 14, 15 which may reflect the short sampling period.…”

“…Favorable characteristics include a unique mechanism of action13 (binding to the synaptic vesicle protein 2A), minimal metabolism,14 few documented drug‐drug interactions,15 and multiple administration routes (IV, PO, IM, per rectum) 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. Currently, based on previous studies in dogs, an average 3‐hour half‐life requires 8‐hour dosing intervals.…”

Status epilepticus in dogs and cats, part 2: treatment, monitoring, and prognosis

“…However, concurrent phenobarbital use increases levetiracetam clearance. Monitoring of serum levetiracetam concentrations and dose adjustments may be needed when the drugs are used together …”

Pharmacokinetic evaluation of immediate- and extended-release formulations of levetiracetam in dogs

“…11 Ideally, interactions among anticonvulsant medications and ER formulations of levetiracetam would be assessed before conclusions are made regarding the benefits of ER formulations in the treatment of dogs with seizures. Although the sample size was sufficient for detection of significant differences in pharmacokinetic properties among the formulations, the fact that only 6 dogs were included and that those dogs were healthy limited application of the findings to the general population of dogs with seizures.…”