Newer therapies for epilepsy (Proceedings)

For many years, short and long-term therapy of epileptic disorders in dogs and cats has been based on the use of benzodiazepines (e.g. diazepam), barbiturates (e.g. phenobarbital) and bromide, either individually or with different combinations. While phenobarbital and bromide are still widely used for the long-term therapy of epilepsy in dogs and cats, newer agents have become available that can be used as adjunctive or sole therapy. These drugs, approved for epilepsy in humans, have appropriate safety, efficacy and pharmacokinetic characteristics to become real alternatives in dogs and cats. Furthermore, some of them are available in generic form, making cost less of a concern. This paper discusses some of these new drug alternatives for epilepsy treatment.

Objectives of the presentation

• To review current data on the safety and efficacy of newer antiepileptic agents in small animals.

Relevant therapeutic points

• The long-term objective of antiepileptic therapy is to reduce the frequency and intensity of seizures, keeping side effects as few as possible. 

• Liver toxicity and excessive sedation are often major limiting factors of therapy.

• Treatment success depends more on owner compliance than any other variable. Good candidate drugs benefit from half-lives that are long enough for convenient dose intervals (e.g. once-a-day administration).

• For drugs with narrow safety margins, therapeutic drug monitoring (TDM) is often helpful to determine safe and effective individual doses. This requires definition of a therapeutic window as well as the availability of sensitive and inexpensive bioassays.

• Drug interactions may largely affect safety and efficacy of antiepileptic drugs.

Drugs, dosages and indications

• Levetiracetam:

• Mechanism of action of this drug is not completely understood but it does not appear to affect GABA, NMDA receptors, or membrane channels. It seems to modulate calcium-dependent release of neurotransmitter by binding with a synaptic vesicle protein in neurons.

• In dogs, oral and intramuscular systemic availabilities are very high, 70-80% of the administered dose is excreted unchanged in the urine, and the elimination half-life from plasma is about 3-4 hours. This half-life is short for once-a-day administration. Recommended dose interval is 8 hours. Liver metabolism does not seem to play an important role, which opens the possibility to the use of this drug in hepatic impaired animals.

• The pharmacokinetic profile of the drug changes significantly in the presence of phenobarbital4. Levetiracetam half-life decreases by 50%, possibly requiring dosage adjustment.

• Since a relationship has not been established yet between plasma concentration and efficacy and the drug appears to be very safe, routine TDM is not recommended at this time.

• Published efficacy data indicates that levetiracetam is a safe alternative as adjunctive medication in dogs with refractory epilepsy5. Starting dose in both dogs and cats is 10-20 mg/kg PO q8h. Doses can be increased until efficacy is achieved.

• Effective serum levels in humans are 5-45 µg/mL.

• Gabapentin:

• It is a chemical analog of GABA but it does not interact with GABA receptors. Its action seems to be related to blocking N-type calcium-dependent channels, which are up-regulated in epileptic animals.

• It is well absorbed orally in dogs, with systemic availability about 80%. Time to peak plasma concentration is 1-3 hrs. Food does not seem to affect the oral disposition of the drug.

• It is eliminated preferentially by renal mechanisms in both humans and animals. In children, drug clearance is correlated with creatinine clearance, which is consistent with preferential renal elimination. For this reason, the drug can be used in dogs and cats with hepatic disease. Phenobarbital administration does not affect the disposition of gabapentin in humans. Terminal elimination half-life in dogs is 2-4 hours, which suggest that a 6 or 8-hr dose interval may be required to maintain therapeutic levels.

• Gabapentin seems to be very well tolerated in dogs. Normal neurons are not affected by gabapentin, so neurological side effects are less likely than with other drugs. Mild sedation and ataxia may occur10.

• Gabapentin has been used mostly for refractory seizures in dogs and cats at of 10-15 mg/kg PO every 6-8 hours and 5-10 mg/kg PO q8-12 hours, respectively. It is recommended to start therapy with the lower values in the range and titrate up. Efficacy as adjunctive therapy has been shown in several small studies in dogs. Information in cats is rather anecdotal.

• A gabapentin analog, pregabalin, appears to be effective as adjunctive therapy in dogs.

• Felbamate

• Seizure activity suppression occurs by antagonism at the NMDA receptor-ionophore complex.

• Systemic availability after oral administration in adult dogs is high.

• In dogs, up to 70% of the oral dose is excreted unchanged in the urine. The remaining 30% undergoes liver metabolism. Terminal elimination half-life ranges between 4 and 8 hours, which allows dosing every 8-12 hours.

• Felbamate has a wide margin of safety in dogs, therefore therapeutic drug monitoring is not currently recommended. Sedation during treatment is infrequent and hepatic dysfunction is typically reversible. However, the drug may need to be avoided in dogs with preexisting hepatic disease and serum biochemistry analysis is recommended twice a year.

• Efficacy for both focal and generalized seizures in dogs has been reported in small efficacy studies. Felbamate has been used as sole or adjunctive therapy in dogs. Clinical information in cats is lacking.

• Zonisamide

• Mechanism of action seems to involve blocking of calcium and sodium channels in the brain, scavenging of free radicals, enhancing GABA, and some other actions.

• Systemic availability by the oral route is approximately 70%.

• Zonisamide is eliminated by liver metabolism. The average half-lives in dogs and cats are 17-24 and 33 hours, respectively. Doses can be administered at 12-hr intervals. Concurrent administration with phenobarbital increases zonisamide metabolism, requiring dosage adjustment.

• Although the therapeutic window in animals has not been defined, the human range of 10-40 µg/mL is typically used. Trough concentrations can be checked 1 week after treatment initiation and at regular intervals after that.

• Zonisamide has a wide margin of safety and has shown to be efficacious in dogs. This drug has been used as adjunctive or sole therapy. In cats, toxicity is low and typical side effects include anorexia, diarrhea, and ataxia.

Table 1. Newer antiepileptic agents in small animals

Drug

Indication

Dose Range (mg/kg)

Human Therapeutic Window (µg/mL)

Drug Interactions

Levetiracetam

Add-on in refractory epilepsy

D: 10-20 q8 PO

C: 20 q8 PO

5-45

Phenobarbital (↑Cl)

Gabapentin

Add-on in refractory epilepsy

D: 10-15 q6-8 PO

C: 5-10 q8-12 PO

4-16

Felbamate

Add-on or Sole

D: 15-80 q8 PO*.

20-100

Zonisamide

Add-on or Sole

D: 5-10 q12 PO**

C: 10-20 q24 PO

10-40

*If ineffective, increase the dose by 15 mg/kg every 2 weeks until the drug is efficacious or excessive side effects occur.

** 10 mg/kg in dogs already receiving phenobarbital.

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