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    Mean ± SD plasma levetiracetam concentrations at various times after IV (white diamonds) and oral (black diamonds) administration of a single dose of levetiracetam (20 mg/kg) to 10 cats. Time of levetiracetam administration was designated as time 0.

  • 1.

    Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004; 101: 98619866.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Rigo JM, Hans G, Nguyen L, et al. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol 2002; 136: 659672.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Hanon E, Klitgaard H. Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusion model of focal cerebral ischemia. Seizure 2001; 10: 287293.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Wang H, Gao J, Lassiter TF, et al. Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit Care 2006; 5: 7178.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia 2000; 41: 12761283.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000; 55: 236242.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia 2000; 41: 11791186.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Boon P, Chauvel P, Pohlmann-Eden B, et al. Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy. Epilepsy Res 2002; 48: 7789.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Glauser TA, Ayala R, Elterman RD, et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006; 66: 16541660.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Sharpe DV, Patel AD, Abou-Khalil B, et al. Levetiracetam mono-therapy in juvenile myoclonic epilepsy. Seizure 2008; 17: 6468.

  • 11.

    Berkovic SF, Knowlton RC, Leroy RF, et al. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology 2007; 69: 17511760.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Brodie MJ, Perucca E, Ryvlin P, et al. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007; 68: 402408.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Hovinga CA. Levetiracetam: a novel antiepileptic drug. Pharmacotherapy 2001; 21: 13751388.

  • 14.

    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: 825830.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Benedetti MS, Coupez R, Whomsley R, et al. Comparative pharmacokinetics and metabolism of levetiracetam, a new anti-epileptic agent, in mouse, rat, rabbit and dog. Xenobiotica 2004; 34: 281300.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Dewey CW, Bailey KS, Boothe DW, et al. Pharmacokinetics of a single-dose intravenous levetiracetam administration in normal dogs. J Vet Emerg Crit Care 2008; 18: 153157.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Moore SA, Munana KR, Papich MG, et al. Levetiracetam pharmacokinetics in healthy dogs following oral administration of single and multiple doses. Am J Vet Res 2010; 71: 337341.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Walker MC, Patsalos PN. Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther 1995; 67: 351384.

  • 19.

    Volk HA, Matiasek LA, Feliu-Pascual AL, et al. The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. Vet J 2008; 176: 310319.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Platt SR, Adams V, Garosi LS, et al. Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy. Vet Rec 2006; 159: 881884.

    • Search Google Scholar
    • Export Citation
  • 21.

    Dewey CW, Guiliano R, Boothe DM, et al. Zonisamide therapy for refractory idiopathic epilepsy in dogs. J Am Anim Hosp Assoc 2004; 40: 285291.

  • 22.

    Bailey KS, Dewey CW, Boothe DM, et al. Levetiracetam as an adjunct to phenobarbital treatment in cats with suspected idiopathic epilepsy. J Am Vet Med Assoc 2008; 232: 867872.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Bailey KS, Dewey CW. The seizuring cat: diagnostic work-up and therapy. J Feline Med Surg 2009; 11: 385394.

  • 24.

    Bazil CW. New antiepileptic drugs. Neurologist 2002; 8: 7181.

  • 25.

    Pucci V, Bugamelli F, Mandrioli R, et al. High-performance liquid chromatographic determination of levetiracetam in human plasma: comparison of different sample clean-up procedures. Biomed Chromatogr 2004; 18: 3744.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Martens-Lobenhoffer J, Bode-Boger SM. Determination of levetiracetam in human plasma with minimal sample pretreatment. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 819: 197200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Morrell MJ, Leppik I, French J, et al. The KEEPER trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study. Epilepsy Res 2003; 54: 153161.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Steinhoff BJ, Somerville ER, Van Paesschen W, et al. The SKATE study: an open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy. Epilepsy Res 2007; 76: 614.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Thomas WB. Idiopathic epilepsy in dogs and cats. Vet Clin North Am Small Anim Pract 2010; 40: 161179.

  • 30.

    Quesnel AD, Parent JM, McDonell W. Clinical management and outcome of cats with seizure disorders: 30 cases (1991–1993). J Am Vet Med Assoc 1997; 210: 7277.

    • Search Google Scholar
    • Export Citation
  • 31.

    Dewey CW. Anticonvulsant therapy in dogs and cats. Vet Clin North Am Small Anim Pract 2006; 36: 11071127.

  • 32.

    Cochrane SM, Parent JM, Black WD, et al. Pharmacokinetics of phenobarbital in the cat following multiple oral administration. Can J Vet Res 1990; 54: 309312.

    • Search Google Scholar
    • Export Citation
  • 33.

    Center SA, Elston TH, Rowland PH, et al. Fulminant hepatic failure associated with oral administration of diazepam in 11 cats. J Am Vet Med Assoc 1996; 209: 618625.

    • Search Google Scholar
    • Export Citation
  • 34.

    Hughes D, Moreau RE, Overal KL, et al. Acute hepatic necrosis and liver failure associated with benzodiazepine therapy in six cats (1986–1995). J Vet Emerg Crit Care 1996; 6: 1320.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Podell M, Fenner WR. Bromide therapy in refractory canine idiopathic epilepsy. J Vet Intern Med 1993; 7: 318327.

  • 36.

    Boothe DM, George KL, Couch P. Disposition and clinical use of bromide in cats. J Am Vet Med Assoc 2002; 221: 11311135.

  • 37.

    Ramael S, De Smedt F, Toublanc N, et al. 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. Clin Ther 2006; 28: 734744.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Doheny HC, Ratnaraj N, Whittington MA, et al. Blood and cere-brospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat. Epilepsy Res 1999; 34: 161168.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Loscher W, Honack D, Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J Pharmacol Exp Ther 1998; 284: 474479.

    • Search Google Scholar
    • Export Citation
  • 40.

    Knake S, Gruener J, Hattemer K, et al. Intravenous levetiracetam in the treatment of benzodiazepine-refractory status epilepticus. J Neurol Neurosurg Psychiatry 2008; 79: 588589.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Mazarati AM, Baldwin R, Klitgaard H, et al. Anticonvulsant effects of levetiracetam and levetiracetam-diazepam combinations in experimental status epilepticus. Epilepsy Res 2004; 58: 167174.

    • Crossref
    • Search Google Scholar
    • Export Citation

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Pharmacokinetics of levetiracetam after oral and intravenous administration of a single dose to clinically normal cats

Michelle Brogan Carnes MS, DVM1, Todd W. Axlund DVM, MS2, and Dawn M. Boothe DVM, PhD3
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  • 1 Animal Specialty Hospital of Florida, 10130 Market St, Ste 1, Naples, FL34112.
  • | 2 Ohio Veterinary Surgery and Neurology LLC, 1053 S Cleveland-Massillon Rd, Akron, OH 44321.
  • | 3 Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849.

Abstract

Objective—To determine whether therapeutic concentrations of levetiracetam can be achieved in cats and to establish reasonable IV and oral dosing intervals that would not be associated with adverse effects in cats.

Animals—10 healthy purpose-bred cats.

Procedures—In a randomized crossover study, levetiracetam (20 mg/kg) was administered orally and IV to each cat. Blood samples were collected 0, 10, 20, and 40 minutes and 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours after administration. Plasma levetiracetam concentrations were determined via high-performance liquid chromatography.

Results—Mean ± SD peak concentration was 25.54 ± 7.97 μg/mL. The mean y-intercept for IV administration was 37.52 ± 6.79 μg/mL. Half-life (harmonic mean ± pseudo-SD) was 2.95 ± 0.95 hours and 2.86 ± 0.65 hours for oral and IV administration, respectively. Mean volume of distribution at steady state was 0.52 ± 0.09 L/kg, and mean clearance was 2.0 ± 0.60 mL/kg/min. Mean oral bioavailability was 102 ± 39%. Plasma drug concentrations were maintained in the therapeutic range reported for humans (5 to 45 μg/mL) for at least 9 hours after administration in 7 of 10 cats. Only mild, transient hypersalivation was evident in some cats after oral administration.

Conclusions and Clinical Relevance—Levetiracetam (20 mg/kg) administered orally or IV to cats every 8 hours should achieve and maintain concentrations within the therapeutic range for humans. Levetiracetam administration has favorable pharmacokinetics for clinical use, was apparently tolerated well, and may be a reasonable alternative antiepileptic drug in cats.

Abstract

Objective—To determine whether therapeutic concentrations of levetiracetam can be achieved in cats and to establish reasonable IV and oral dosing intervals that would not be associated with adverse effects in cats.

Animals—10 healthy purpose-bred cats.

Procedures—In a randomized crossover study, levetiracetam (20 mg/kg) was administered orally and IV to each cat. Blood samples were collected 0, 10, 20, and 40 minutes and 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours after administration. Plasma levetiracetam concentrations were determined via high-performance liquid chromatography.

Results—Mean ± SD peak concentration was 25.54 ± 7.97 μg/mL. The mean y-intercept for IV administration was 37.52 ± 6.79 μg/mL. Half-life (harmonic mean ± pseudo-SD) was 2.95 ± 0.95 hours and 2.86 ± 0.65 hours for oral and IV administration, respectively. Mean volume of distribution at steady state was 0.52 ± 0.09 L/kg, and mean clearance was 2.0 ± 0.60 mL/kg/min. Mean oral bioavailability was 102 ± 39%. Plasma drug concentrations were maintained in the therapeutic range reported for humans (5 to 45 μg/mL) for at least 9 hours after administration in 7 of 10 cats. Only mild, transient hypersalivation was evident in some cats after oral administration.

Conclusions and Clinical Relevance—Levetiracetam (20 mg/kg) administered orally or IV to cats every 8 hours should achieve and maintain concentrations within the therapeutic range for humans. Levetiracetam administration has favorable pharmacokinetics for clinical use, was apparently tolerated well, and may be a reasonable alternative antiepileptic drug in cats.

Levetiracetam (s-α-ethyl-2-oxo-1-pyrrolidine acetamide) is among the newest of the anticonvulsant drugs approved for use in humans, with proven efficacy for many types of seizure disorders. Although its mechanism of action is incompletely understood, it is novel, compared with that for the classical AEDs. Levetiracetam interacts with neuronal synaptic vesicular (SV2A) receptors, thereby modulating calcium-dependent exocytosis of neurotransmitters.1 It also suppresses the inhibitory effect of Zn2+ on γ-aminobutyric acid and glycine-gated currents.2 In addition to its anticonvulsant effects, levetiracetam has been found to be neuroprotective when administered prophylatically to rodents with experimentally induced cerebral ischemia and head trauma.3,4

The safety and efficacy of levetiracetam in humans have been extensively evaluated. During the clinical development of levetiracetam, 3 multicenter, double-blinded placebo-controlled trials conducted in the United States and Europe established its safety and efficacy as an adjunct treatment for refractory partial seizures in adults5–8 and children.9 Clinical trials have revealed levetiracetam to be effective as the sole treatment for control of myoclonic10 and primary generalized tonicclonic seizures11,12 in patients with idiopathic epilepsy. The most common adverse effects with administration of levetiracetam in adults are related to the CNS and include somnolence, fatigue, dizziness, and headache.13 In children, the most commonly reported adverse effects are aggressive behavior, nervousness, and hyperkinesia.13

In studies14–17 of pharmacokinetics of levetiracetam administered in accordance with recommended dose regimens to dogs, rodents, and rabbits, investigators have not reported adverse effects, which supports its potential safety. In all of the species evaluated, levetiracetam is almost exclusively excreted as the unchanged compound by the kidneys.15,18 In dogs, pharmacokinetics of levetiracetam support its long-term use as an anticonvulsant because it is well absorbed after oral administration, is minimally protein bound, distributes well into the brain, and has linear pharmacokinetics.14,15 Furthermore, it is excreted by the kidneys, which minimizes the risk of disease and interactions involving the liver. One potential disadvantage of levetiracetam in dogs is a T1/2 of approximately 3 to 4 hours, which necessitates administration every 8 hours.14–16

A number of novel, second-generation AEDs have been developed that are effective and tolerated well in humans. However, neither safety nor efficacy in humans can be used to predict effects in dogs or cats. Differences in pharmacodynamics (including therapeutic or adverse responses) or pharmacokinetics can be profound. Cost may also be a limiting factor. Among these newer drugs, gabapentin, zonisamide, and levetiracetam have been found to be of benefit as adjunctive treatments in refractory canine patients.19–21 Few scientific reports regarding the use of second-generation AEDs in cats are available. Levetiracetam has been used as an adjunct treatment22 and as the sole treatment23 in a limited number of cats; there was favorable efficacy and minimal adverse effects, which suggests the potential for safe use in this species. Although no important adverse effects have been reported in cats or other species, caution should be exercised when administering this drug to cats without knowledge of a scientifically derived dose. This may be particularly true for cats, a species for which unique pharmacokinetics and pharmacodynamics have been determined for many drugs. However, kinetic differences focus principally on metabolism, which suggests fewer adverse effects may be expected after administration of levetiracetam. Nonetheless, the potential risk for inappropriate use of an anticonvulsant drug mandates that use in any species, including cats, be supported with scientific studies, including pharmacokinetic studies.

The objective of the study reported here was to describe the time course of levetiracetam after a single dose administered IV or orally to cats to determine a dose and dosing interval that would achieve and maintain therapeutic concentrations described in humans (5 to 45 μg/mL)24 throughout the dosing interval. Furthermore, the study was intended to assess tolerability of levetiracetam after oral and IV administration of a single dose.

Materials and Methods

Animals—Ten healthy adult domestic shorthair cats were included in the study. There were 2 castrated males and 8 spayed females. Age of the cats ranged from 18 months to 5 years, and body weight ranged from 2.45 to 4.42 kg (mean, 3.44 kg). All procedures were approved by the Auburn University Institutional Animal Care and Use Committee.

A baseline health assessment that included physical and neurologic examinations, a CBC, serum biochemical profile, and urinalysis was performed. On the day prior to each period of the study, each cat was weighed and then sedated (15 mg of ketamine/kg, 0.4 mg of butorphanol/kg, and 0.03 mg of meditomidine/kg, IM) so that an indwelling catheter could be aseptically placed in a jugular vein. At the conclusion of each period of the study, the baseline health assessment was repeated and the indwelling catheter was removed.

Pharmacokinetic evaluation—The study was conducted prospectively as a randomized, crossover design involving 2 periods with a 7-day washout between each period. Each cat initially received a single dose of levetiracetam (20 mg/kg) IV or orally in the first period and then received the same dose via the alternative route in the second period. For IV administration, the calculated dose of the commercial IV preparation of levetiracetama was diluted in 5 mL of sterile saline (0.9% NaCl) solution and administered over a 5-minute period through the indwelling catheter inserted in a jugular vein. The commercially available levetiracetam oral suspensionb was used for oral administration. A blood sample (3 mL) was collected from the jugular vein (via the indwelling catheter) and placed into collection tubes 0, 10, 20, and 40 minutes and 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours after administration. At least 2 catheter volumes of blood were aspirated and discarded prior to collection of each sample. After each sample was collected, indwelling catheters were flushed with heparinized saline solution. Blood samples were maintained on ice until centrifugation at 50 × g for 15 minutes at 4°C; plasma was harvested and stored frozen (−70°C) until analysis.

Evaluation for adverse effects—Each cat was monitored at each time point at which plasma samples were obtained for 24 hours after levetiracetam administration. Cats were observed for evidence of adverse drug reactions. In addition, a physical examination, CBC, serum biochemical profile, and urinalysis were performed for each cat immediately before and 24 hours after IV and oral administration.

Sample analysis—Plasma samples were thawed at 21°C and then mixed to assure homogeneity. Levetiracetam was detected in feline plasma via high-performance liquid chromatography by use of methods described elsewhere,25,26 with slight modifications (the column used was 250 mm instead of 150 mm). Sample preparation was accomplished by use of solid-phase extraction.c Samples were eluted from the columns with methanol. The eluent was dried (evaporated) under nitrogen gas and reconstituted with the mobile phase, which was a mixture composed of 5% acetonitrile, 6% methanol, and 89% 3mM potassium phosphate buffer containing triethylamine to adjust the pH to 6.5. Flow rate was set at 1.0 mL/min. Drug was detected by use of UV spectroscopy at 205 nm. Drug concentrations in samples were quantitated by comparing the UV signal in unknown samples with the signal for standards prepared by the addition of known amounts of levetiracetamd to feline plasma. Concentrations of the standard curve ranged from 1 to 300 μg/mL. The linear correlation coefficient was 0.9994. Control samples spanning the concentrations of the standard curve revealed results within 15% of the expected concentrations (intra-assay and interassay variability), which yielded a lower and upper limit of quantitation of 1 and 300 μg/mL, respectively.

Data analysis—Plasma levetiracetam concentrations obtained after IV or oral administration (logarithm of concentration vs time curves) were analyzed by use of noncompartmental linear regression analysis,e with AUC determined to infinity via the trapezoidal method. For IV administration, peak plasma concentrations were extrapolated to the y-intercept, whereas for oral administration, the actual Cmax detected at Tmax was calculated. In addition, MRT and T1/2 were determined. After IV administration, clearance and Vdss were also determined. Bioavailability after oral administration was determined by use of the equation (AUC after oral administration/AUC after IV administration) × 100.

Statistical analysis—Descriptive statistics were calculated by use of commercially available software.f Pharmacokinetic data were reported as the mean ± SD, except for T1/2, which was reported as the harmonic mean and its comparable measure of SD, pseudo-SD. The time that drug concentrations remained in the therapeutic range defined for humans (5 to 45 μg/mL) was determined. Student t testsg were used to compare elimination rate constants between routes of administration to detect a flip-flop effect.

Results

Adverse effects after oral or IV administration of a single dose of levetiracetam—All cats appeared to tolerate levetiracetam well; adverse effects were apparently limited to transient mild to moderate hypersalivation after oral administration. Laboratory data (results of a CBC, serum biochemical profile, and urinalysis) obtained 24 hours after administration were compared with preadministration data, and no clinically relevant changes or abnormalities were detected.

Pharmacokinetics after IV administration of a single dose of levetiracetam—Plasma concentrations of levetiracetam within the therapeutic range defined for humans were achieved at the first time point (10 minutes after administration) and remained within the therapeutic range for at least 9 hours in 7 of 10 cats (Figure 1; Table 1). Mean ± SD Cmax (ie, y-intercept) was 37.52 ± 6.79 μg/mL. Mean ± pseudo-SD for T1/2 was 2.86 ± 0.65 hours. Mean ± SD MRT was 4.57 ± 0.94 hours, Vdss was 0.52 ± 0.09 L/kg, and clearance was 2.0 ± 0.60 mL/kg/min.

Table 1—

Pharmacokinetics of levetiracetam in plasma after IV administration of a single dose of levetiracetam (20 mg/kg) to 10 cats.

VariableMean ± SDMedian (range)
y-intercept (μg/mL)37.52 ± 6.7937.64 (28.05–51.86)
AUC (h•μg/mL)179.9 ± 38.6191.3 (96.7–217.1)
T1/2 (h)2.86 ± 0.65*3.10 (2.07–4.08)
MRT (h)4.57 ± 0.944.77 (3.09–6.09)
Clearance (mL/kg/min)2.0 ± 0.601.7 (1.5–3.4)
Vdss (L/kg)0.52 ± 0.090.51 (0.33–0.64)

Represents the harmonic mean ± pseudo-SD.

Figure 1—
Figure 1—

Mean ± SD plasma levetiracetam concentrations at various times after IV (white diamonds) and oral (black diamonds) administration of a single dose of levetiracetam (20 mg/kg) to 10 cats. Time of levetiracetam administration was designated as time 0.

Citation: American Journal of Veterinary Research 72, 9; 10.2460/ajvr.72.9.1247

Pharmacokinetics after oral administration of a single dose of levetiracetam—Plasma concentrations of levetiracetam within the therapeutic range defined for humans were achieved at the first time point (10 minutes after administration) and remained within the therapeutic range for at least 9 hours in 7 of 10 cats (Figure 1; Table 2). Mean ± SD Cmax was 25.54 ± 7.97 μg/mL, and mean Tmax was 1.67 ± 1.73 hours. Mean ± pseudo-SD T1/2 was 2.95 ± 0.95 hours. Mean ± SD MRT was 5.65 ± 1.25 hours, and oral bioavailability was 102 ± 0.39%. The elimination rate did not differ between IV and oral administration.

Table 2—

Pharmacokinetics of levetiracetam in plasma after oral administration of a single dose of levetiracetam (20 mg/kg) to 10 cats.

VariableMean ± SDMedian (range)
Cmax (μg/mL)25.54 ± 7.9726.77 (13.22–37.11)
AUC (h•μg/mL)172.9 ± 38.6169.9 (128.0–251.2)
T1/2 (h)2.95 ± 0.95*3.25 (1.86–4.63)
MRT (h)5.65 ± 1.255.09 (4.23–7.86)
Bioavaila bility1.02 ± 0.390.94 (0.69–2.05)
Tmax (h)1.67 ± 1.731.08 (0.33–4.0)

Represents the harmonic mean ± pseudo-SD.

Calculated as (AUC after oral administration/AUC after IV administration) × 100.

Discussion

Analysis of results of the study reported here suggested that levetiracetam (20 mg/kg) administered orally or IV to cats every 8 hours should achieve and maintain plasma concentrations within the therapeutic range for humans. The lack of clinically important adverse effects, in conjunction with favorable pharmacokinetics and potential efficacy,22 make use of levetiracetam a reasonable option for seizure management in cats.

Levetiracetam is a structurally novel AED that is used successfully in humans as the sole treatment or as adjunctive treatment for partial-onset seizures in humans.27,28 Levetiracetam has been proven effective after oral administration for the treatment of epilepsy in dogs19 and has promise for the treatment of epilepsy in cats.22 Treatment options for seizure disorders in cats are limited, which mandates a need for identification and description of new AEDs for use in cats. Currently, phenobarbital is the most commonly recommended anticonvulsant drug for the treatment of seizure disorders in cats. Although phenobarbital is generally safe and effective, its use is associated with adverse effects, including sedation, polyuria, polydipsia, polyphagia, facial pruritus, bone marrow dyscrasias, and coagulopathies.22,29–32 Additionally, unpredictable relationships between dose and plasma drug concentrations can make safe and effective seizure management much more challenging in cats.31 Diazepam is often cited as a second drug of choice for epilepsy in cats; however, up to 20% of cats are reportedly unresponsive to diazepam,30 and the development of acute fatal hepatic necrosis has been reported.29,33,34 Phenobarbital and diazepam are primarily metabolized by the liver, which may preclude their use in animals with hepatic dysfunction and generally increases the risk of drug interactions or hepatic disease. Bromide, a drug that has been used effectively in dogs,35 has proven variably effective for treatment of seizures in cats31,36; however, the risk for eosinophilic pneumonitis, which may develop in 30% to 40% of cats receiving bromide, precludes its routine use as an anticonvulsant in cats.36

Analysis of results of the present study suggested that the disposition and apparent tolerance of levetiracetam in clinically normal cats support its clinical use at a dose of 20 mg/kg. Its disposition in cats is similar to that in dogs but differs from that in humans. The mean ± SD T1/2 in cats for oral (2.95 ± 0.95 hours) and IV administration (2.86 ± 0.65 hours) is comparable to that for IV administration in dogs (3.6 ± 0.8 hours14 and 4.0 ± 0.82 hours16) and is considerably shorter than that in humans (7.16 ± 1.13 hours).37 Differences in T1/2 between cats and humans probably reflect differences in clearance, whereas the mean Vdss is similar between dogs, cats, and humans (0.52 ± 0.09 L/kg, 0.45 ± 0.13 L/kg, and 0.56 ± 0.09 L/kg, respectively). Mean clearance is higher in cats (2.0 ± 0.6 mL/min/kg), compared with mean clearance in humans (0.85 ± 0.15 mL/min/kg) and dogs (1.5 ± 0.3 mL/min/kg).14,37 The short half-life indicates that levetiracetam concentrations in cats may be expected to decrease by approximately 50%, 75%, and 87% at 2, 4, and 6 hours after administration, respectively, which suggests a need for dosing intervals ≤ 6 hours. However, the pharmacodynamic response to levetiracetam may outlast its presence in plasma, perhaps because of a longer maintenance of concentrations in CSF that has been determined in rats, for which the half-life in the CSF is approximately twice that of plasma.38 Furthermore, levetiracetam has antiepileptogenic activity in rats that persists long after elimination of the drug from plasma.39

The mean ± SD bioavailability was 102 ± 35%, which suggested substantial variation. One cat was a noticeable outlier, with bioavailability calculated at 200%. If results for this cat were removed from the data set, the mean bioavailability would have been 90 ± 15%. Data for this cat were carefully evaluated, and it was noticed that its AUC and Cmax after IV administration were the lowest. This may suggest that its Vdss was much larger, compared with that of the other cats; however, the Vdss should normalize when the drug is given orally (ie, the total amount of drug in the body should not be impacted by an increase in Vdss). On the basis of these data, a possible explanation for the variation is that this cat may have been underdosed for IV administration (eg, part of the dose was inadvertently administered SC), but this was unlikely because of the fact that the AUC was normally distributed. In consideration of this, the bioavailability approached 100%, which is consistent with results of other studies14–16 in dogs.

In a recent study,22 investigators evaluated the efficacy of levetiracetam (20 mg/kg, PO) as an adjunctive treatment to the administration of phenobarbital in cats with refractory seizures. Results of that study22 suggested that levetiracetam may be a useful adjunctive treatment for refractory epilepsy because 7 of 10 cats had a reduction in seizure frequency of > 50%. Those investigators also reported a limited pharmacokinetic analysis after oral administration. Although only 3 time points were used for plasma drug concentrations in that study,22 which resulted in the need for some extrapolation of data, the reported pharmacokinetics for oral administration of levetiracetam were similar to the data in the study reported here. The repeatability of both studies to evaluate the pharmacokinetics after oral administration of levetiracetam to epileptic cats and after oral and IV administration to clinically normal nonepileptic cats further validates these results and underscores the potential for safe use of levetiracetam in this species.

A therapeutic range for plasma concentrations of levetiracetam has not been defined in cats or dogs. In humans, the therapeutic range is not firmly established but has been reported as 5 to 45 μg/mL on the basis of a typical dosing regimen of 500 to 1,500 mg every 12 hours.24 Monitoring of therapeutic concentrations of levetiracetam is not routinely performed in humans because a clear relationship between plasma concentrations and efficacy has not been established.13 For the purposes of the present study, the reported therapeutic range for humans (5 to 45 μg/mL) was used as a basis for the comparison of the pharmacokinetics of levetiracetam in cats. Mean ± SD Cmax of levetiracetam achieved in the present study was 37.52 ± 6.79 μg/mL after IV administration and 25.54 ± 7.97 μg/mL after oral administration. Mean plasma concentrations in 7 of 10 cats were within the therapeutic range for humans for at least 9 hours. On the basis of the T1/2, a dosing interval of 6 hours may be ideal for cats; however, this is impractical for most pet owners and will result in poor compliance. At a Cmax of 25 μg/mL, with 2 half-lives elapsing during a dosing interval, trough concentrations will be in the low part of the therapeutic range. An initial dose of 20 mg/kg administered IV or orally every 8 hours should be adequate for most cats, given that most of the cats in the present study maintained levetiracetam plasma concentrations within the therapeutic range for humans throughout the dosing interval as well as the fact that the pharmacodynamic effect of levetiracetam appears to outlast its presence in plasma. However, for some cats, a trough concentration in the low part of the therapeutic range may be inadequate. To enhance efficacy and maintain an 8-hour dosing interval, every doubling of the dose will add 1 half-life to the dosing interval. Thus, to obtain a target plasma concentration of 10 to 12 g/mL, a dose of approximately 40 mg of levetiracetam/kg every 8 hours may be necessary.

The potential for toxicosis associated with levetiracetam administration is low. In dogs, oral administration of 2,000 mg/kg and IV administration of 1,200 mg/kg result in mild adverse reactions, including salivation, vomiting, tachycardia, and restlessness.h In 2 studies of the efficacy of levetiracetam (20 mg/kg, PO, q 8 h), 1 of 18 dogs had mild sedation19 and 2 of 10 cats had transient lethargy and inappetance.22 In another study16 conducted to evaluate the pharmacokinetics and tolerability of levetiracetam (60 mg/kg, IV) in 6 dogs, investigators reported no substantial adverse effects. To our knowledge, there are no data on the toxic effects of levetiracetam in cats; however, on the basis of the disposition of the drug in cats and the data available on toxicoses in dogs, doubling or tripling the dose in cats may prove to be safe and effective. Additional studies are needed to evaluate this possibility.

Levetiracetam is the first of the second-generation AEDs to be formulated as an injectable preparation. Its tolerability and disposition in cats make it suitable for use in clinical settings. This is particularly advantageous for cats that cannot be administered the drug orally because of medical or behavioral reasons. Interestingly, the authors of a recent report40 described the successful use of the injectable preparation of levetiracetam in the treatment of 18 benzodiazepine-refractory human patients with status epilepticus. In another study41 in rats with experimentally induced status epilepticus, investigators concluded that IV administration of levetiracetam significantly enhanced the anticonvulsant effects of diazepam administered IV. These data and the disposition of levetiracetam in cats suggest that IV administration of levetiracetam may also be considered as an adjunctive treatment for status epilepticus in cats.

On the basis of the present study, levetiracetam should be considered as an alternative AED for seizure control in cats. The clinical use of levetiracetam in cats as an alternative to standard AEDs, such as phenobarbital, is supported by the fact that levetiracetam has no known clinically relevant drug-drug interactions,23 does not alter mentation or cause substantial sedation, appears to be tolerated well, and, because of its short half-life, does not accumulate. Because of these factors, any delay in response reflects pharmacodynamic rather than pharmacokinetic accommodation. In the present study, 10 healthy cats tolerated well a single 20 mg/kg dose of levetiracetam administered orally and IV. Plasma concentrations remained within the therapeutic range for humans for at least 9 hours in 7 of 10 cats, which suggested the possibility of daily administration at 8-hour intervals. It is anticipated that some cats may require higher doses of levetiracetam to maintain plasma concentrations in the upper part of the therapeutic range for humans. The increased dose is not anticipated to cause clinical problems. Future studies are warranted to determine the overall efficacy of levetiracetam in control of seizures in cats as well as for the development of a therapeutic range for plasma concentrations of levetiracetam in cats.

ABBREVIATIONS

AED

Antiepileptic drug

AUC

Area under the curve

Cmax

Maximum concentration

MRT

Mean residence time

T1/2

Elimination half-life

Tmax

Time to maximum concentration

Vdss

Volume of distribution at steady state

a.

Verdru P, Wajgt A, Schiemann Delgado J, et al. Efficacy and safety of levetiracetam 3000 mg/d as adjunctive treatment in adolescents and adults suffering from idiopathic generalized epilepsy with myoclonic seizures (abstr). Epilepsia 2005;46:54–55.

b.

Keppra 100 mg/mL injectable solution, UCB Pharma Inc, Smyrna, Ga.

c.

Keppra 100 mg/mL oral suspension, UCB Pharma Inc, Smyrna, Ga.

d.

Cartridges Strata C8 (55 μm; 70 A), 100 mg/mL, part No. 8B-S005-EAK, Phenomenex, Torrance, Calif.

e.

Keppra, UCB Pharma Inc, Smyrna, Ga.

f.

WinNonlin Professional, version 4.1, Pharsight Corp, Mountain View, Calif.

g.

Microsoft Office Excel 2003, Microsoft Corp, Redmond, Wash.

h.

UCB Pharma Inc, Smyrna, Ga: Unpublished data, 2001.

References

  • 1.

    Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004; 101: 98619866.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Rigo JM, Hans G, Nguyen L, et al. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol 2002; 136: 659672.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Hanon E, Klitgaard H. Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusion model of focal cerebral ischemia. Seizure 2001; 10: 287293.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Wang H, Gao J, Lassiter TF, et al. Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit Care 2006; 5: 7178.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia 2000; 41: 12761283.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000; 55: 236242.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia 2000; 41: 11791186.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Boon P, Chauvel P, Pohlmann-Eden B, et al. Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy. Epilepsy Res 2002; 48: 7789.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Glauser TA, Ayala R, Elterman RD, et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006; 66: 16541660.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Sharpe DV, Patel AD, Abou-Khalil B, et al. Levetiracetam mono-therapy in juvenile myoclonic epilepsy. Seizure 2008; 17: 6468.

  • 11.

    Berkovic SF, Knowlton RC, Leroy RF, et al. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology 2007; 69: 17511760.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Brodie MJ, Perucca E, Ryvlin P, et al. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007; 68: 402408.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Hovinga CA. Levetiracetam: a novel antiepileptic drug. Pharmacotherapy 2001; 21: 13751388.

  • 14.

    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: 825830.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Benedetti MS, Coupez R, Whomsley R, et al. Comparative pharmacokinetics and metabolism of levetiracetam, a new anti-epileptic agent, in mouse, rat, rabbit and dog. Xenobiotica 2004; 34: 281300.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Dewey CW, Bailey KS, Boothe DW, et al. Pharmacokinetics of a single-dose intravenous levetiracetam administration in normal dogs. J Vet Emerg Crit Care 2008; 18: 153157.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Moore SA, Munana KR, Papich MG, et al. Levetiracetam pharmacokinetics in healthy dogs following oral administration of single and multiple doses. Am J Vet Res 2010; 71: 337341.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Walker MC, Patsalos PN. Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther 1995; 67: 351384.

  • 19.

    Volk HA, Matiasek LA, Feliu-Pascual AL, et al. The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. Vet J 2008; 176: 310319.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Platt SR, Adams V, Garosi LS, et al. Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy. Vet Rec 2006; 159: 881884.

    • Search Google Scholar
    • Export Citation
  • 21.

    Dewey CW, Guiliano R, Boothe DM, et al. Zonisamide therapy for refractory idiopathic epilepsy in dogs. J Am Anim Hosp Assoc 2004; 40: 285291.

  • 22.

    Bailey KS, Dewey CW, Boothe DM, et al. Levetiracetam as an adjunct to phenobarbital treatment in cats with suspected idiopathic epilepsy. J Am Vet Med Assoc 2008; 232: 867872.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Bailey KS, Dewey CW. The seizuring cat: diagnostic work-up and therapy. J Feline Med Surg 2009; 11: 385394.

  • 24.

    Bazil CW. New antiepileptic drugs. Neurologist 2002; 8: 7181.

  • 25.

    Pucci V, Bugamelli F, Mandrioli R, et al. High-performance liquid chromatographic determination of levetiracetam in human plasma: comparison of different sample clean-up procedures. Biomed Chromatogr 2004; 18: 3744.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Martens-Lobenhoffer J, Bode-Boger SM. Determination of levetiracetam in human plasma with minimal sample pretreatment. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 819: 197200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Morrell MJ, Leppik I, French J, et al. The KEEPER trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study. Epilepsy Res 2003; 54: 153161.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Steinhoff BJ, Somerville ER, Van Paesschen W, et al. The SKATE study: an open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy. Epilepsy Res 2007; 76: 614.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Thomas WB. Idiopathic epilepsy in dogs and cats. Vet Clin North Am Small Anim Pract 2010; 40: 161179.

  • 30.

    Quesnel AD, Parent JM, McDonell W. Clinical management and outcome of cats with seizure disorders: 30 cases (1991–1993). J Am Vet Med Assoc 1997; 210: 7277.

    • Search Google Scholar
    • Export Citation
  • 31.

    Dewey CW. Anticonvulsant therapy in dogs and cats. Vet Clin North Am Small Anim Pract 2006; 36: 11071127.

  • 32.

    Cochrane SM, Parent JM, Black WD, et al. Pharmacokinetics of phenobarbital in the cat following multiple oral administration. Can J Vet Res 1990; 54: 309312.

    • Search Google Scholar
    • Export Citation
  • 33.

    Center SA, Elston TH, Rowland PH, et al. Fulminant hepatic failure associated with oral administration of diazepam in 11 cats. J Am Vet Med Assoc 1996; 209: 618625.

    • Search Google Scholar
    • Export Citation
  • 34.

    Hughes D, Moreau RE, Overal KL, et al. Acute hepatic necrosis and liver failure associated with benzodiazepine therapy in six cats (1986–1995). J Vet Emerg Crit Care 1996; 6: 1320.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Podell M, Fenner WR. Bromide therapy in refractory canine idiopathic epilepsy. J Vet Intern Med 1993; 7: 318327.

  • 36.

    Boothe DM, George KL, Couch P. Disposition and clinical use of bromide in cats. J Am Vet Med Assoc 2002; 221: 11311135.

  • 37.

    Ramael S, De Smedt F, Toublanc N, et al. 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. Clin Ther 2006; 28: 734744.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Doheny HC, Ratnaraj N, Whittington MA, et al. Blood and cere-brospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat. Epilepsy Res 1999; 34: 161168.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Loscher W, Honack D, Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J Pharmacol Exp Ther 1998; 284: 474479.

    • Search Google Scholar
    • Export Citation
  • 40.

    Knake S, Gruener J, Hattemer K, et al. Intravenous levetiracetam in the treatment of benzodiazepine-refractory status epilepticus. J Neurol Neurosurg Psychiatry 2008; 79: 588589.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Mazarati AM, Baldwin R, Klitgaard H, et al. Anticonvulsant effects of levetiracetam and levetiracetam-diazepam combinations in experimental status epilepticus. Epilepsy Res 2004; 58: 167174.

    • Crossref
    • Search Google Scholar
    • Export Citation

Contributor Notes

Presented in abstract form at the 26th Annual American College of Veterinary Internal Medicine Forum, San Antonio, Tex, June 2008.

Address correspondence to Dr. Carnes (mcarnes@ashfl.com).