Seizures are the most common neurologic disorder encountered in small animal practice and have been reported to occur in 0.5% to 5.7% of dogs.1,2 Primary, or idiopathic, epilepsy (ie, recurrent seizures for which an underlying cause is not found) is diagnosed in approximately 80% of dogs with seizures.1,2 The mainstay of treatment for dogs with idiopathic epilepsy is AEDs, of which phenobarbital and potassium bromide are most commonly prescribed. However, between 20% and 30% of dogs with epilepsy are refractory to conventional medical therapy3 and, as such, continue to have recurrent seizure activity despite appropriate treatment with AEDs at established therapeutic serum concentrations. For this subset of patients, evaluation of new AEDs is vital to seizure management and improved quality of life.
Levetiracetam is a structurally novel AED that was approved as an adjuvant treatment for partial-onset seizures in humans in 1999. The mechanism of action of LEV has been postulated to involve inhibition of excitatory neurotransmitter release by binding to the synaptic vesicle protein SV2A.4 Following its approval for treatment of partial-onset seizures, LEV was demonstrated to be effective for treatment of a wide variety of seizure types in human patients, including simple partial, complex partial, and secondary generalized seizures.5 Furthermore, LEV is preferred in critical or geriatric patients because of minimal hepatic metabolism and primary renal excretion.4,6,7 Levetiracetam also has minimal effect on the disposition of other AEDs in humans, making it an ideal adjuvant medication for patients with refractory epilepsy.6,7 A therapeutic range for LEV administration in people has not been definitively established, but doses that achieve serum concentrations of 5 to 45 μg/mL have been proposed to be effective.8
On the basis of promising results in humans, LEV is being used with increasing frequency for the management of dogs with epilepsy.9 The pharmacokinetics of LEV in healthy dogs after administration of a single dose PO, IM, or IV have been reported.8,10,11 However, treatment of dogs with refractory epilepsy would require repeated dosing, and there is no published information on the pharmacokinetics of LEV after repeated oral administration. The objective of the study reported here was to measure the pharmacokinetics of LEV in healthy dogs after administration of a single oral dose and to determine whether the pharmacokinetics changed after repeated oral dosing.
Area under the concentration-versus-time curve
High-performance liquid chromatography
Keppra (250-mg tablet), UCB Pharma, Smyrna, Ga.
Quaternary solvent delivery system, Agilent 1100 series, Agilent Technologies, Wilmington, Del.
Agilent 1100 series autosampler, Agilent Technologies, Wilmington, Del.
Agilent variable wavelength detector, Agilent 1100 Series, Agilent Technologies, Wilmington, Del.
Agilent chemstation software, Agilent 1100 Series, Agilent Technologies, Wilmington, Del.
Zorbax Rx (C8, 4.6 × 150 mm, 5 μm), Agilent Technologies Inc, Wilmington, Del.
Solid-phase extraction cartridges, Varian Bond Elut CN-E (3-mL cartridges), Varian Inc, Lake Forest, Calif.
WinNonlin, version 5.0.1, Pharsight Corp, Mountain View, Calif.
UCB Pharma, Smyrna, Ga: Unpublished data, 1999.
Schwartz-Porsche D. Epidemiological, clinical and pharmacokinetic studies in spontaneously epileptic dogs and cats, in Proceedings. 4th Annu Vet Med Forum Am Coll Vet Intern Med, 1986;11-61–11-63.
Podell M, Fenner WR, Powers JD. Seizure classification in dogs from a nonreferral-based population. J Am Vet Med Assoc 1995; 206:1721–1728.
Schwartz-Porsche D, Loscher W, Frey HH. Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison. J Vet Pharmacol Ther 1985; 8:113–119.
Johannessen SI, Tomson T. Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed? Clin Pharmacokinet 2006; 45:1061–1075.
Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000; 55:236–242.
Nicolas JM, Collart P, Gerin B, et al. In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent. Drug Metab Dispos 1999; 27:250–254.
Gidal BE, Baltès E, Otoul C, et al. Effect of levetiracetam on the pharmacokinetics of adjunctive antiepileptic drugs: a pooled analysis of data from randomized clinical trials. Epilepsy Res 2005; 64:1–11.
Dewey CW, Bailey KS, Boothe DM, et al. Pharmacokinetics of single-dose intravenous levetiracetam administration in normal dogs. J Vet Emerg Crit Care 2008; 18:153–157.
Volk HA, Matiasek LA, Luján Feliu-Pascual A, et al. The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. Vet J 2008; 176:310–319.
Isoherranen N, Yagen B, Soback S, et al. Pharmacokinetics of levetiracetam and its enantiomer (R)-alpha-ethyl-2-oxo-pyrrolidine acetamide in dogs. Epilepsia 2001; 42:825–830.
Patterson EE, Goel V, Cloyd JC, et al. Intramuscular, intravenous and oral levetiracetam in dogs: safety and pharmacokinetics. J Vet Pharmacol Ther 2008; 31:253–258.
Yamaoka K, Nakagawa T, Uno T. Application of Akaike's information criteria (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 1978; 6:165–175.
Kampa N, Boström I, Lord P, et al. Day-to-day variability in glomerular filtration rate in normal dogs by scintigraphic technique. J Vet Med A Physiol Pathol Clin Med 2003; 50:37–41.