Levetiracetam

(levetiracetam)

Brands

Keppra

Availability

  • Tablets: 250 mg, 500 mg, 750 mg, 1000 mg
  • Oral Solution: 100 mg/mL

Pharmacology

Levetiracetam is an antiepileptic drug that shows anticonvulsant action. It is used in the treatment of partial (focal) and generalized seizures.  While its mechanism of action is not entirely known, it has been shown to suppress Ca2+ mobilization from endoplasmic reticulum by binding to neural synaptic vesicle protein SV2A 3 in the brain which helps to prevent seizure activity. In addition, levetiracetam and its major metabolite are less than 10% bound to plasma proteins therefore making it less likely to have any significant interactions with other drugs competing for protein binding sites. 6 It does not inhibit voltage-dependent Na+ channels, nor does it affect GABAergic transmission, and it does not bind to GABAergic or glutamatergic receptors.7 Essentially levetiracetam does not affect normal neurotransmission.

A study has also shown that both serum and CSF levetiracetam concentrations rose essentially linearly and dose-dependently, suggesting that transport across the blood-brain barrier is not rate limiting over the levetiracetam concentration range observed in that study, while it was apparent that the elimination half-life values for serum and CSF both were dose-independent with CSF being greater of the two. This indicates that serum-free levetiracetam concentration is not protein bound. 5

Levetiracetam has almost complete absorption, orally, with broad tissue distribution. It is not extensively metabolized by the liver. The drug’s acetamide group is enzymatically hydrolyzed to the inactive carboxylic acid metabolite as such it does not induce any hepatic cytochrome P450 enzymes. Approximately 93% 4 of the dose, in rats, is excreted unchanged by way of the kidneys in urine.4,11 In addition, Levetiracetam has been shown to be excreted in maternal milk. Caution in administering should be utilized in rats having renal impairment, as well as with rats that are nursing.

In animal studies, levetiracetam shows evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. However, studies done in rats at 6 times the human maximum dose showed no evidence of impaired fertility, reproductivity, or carcinogenicity.10 Consider use of levetiracetam in pregnant or nursing rats only if benefit outweighs risk.

In conclusion, while levetiracetam is shown to have a wide margin of safety, there is little information available pertaining to the ideal therapeutic dose range and frequency in pet rats making dosing empirical at this time. While not considered a first-choice drug in treating seizures in rats, it has been shown to be useful where seizures have been refractory to first line treatment regimens.

Indications

*Note: Usage in rats is “off label” or “extra label.” Always follow veterinary direction for use and dosage.

Can be used in rats for the following:

  • Primary maintenance therapy for generalized seizures
  • Add-on therapy for the management of partial (focal) seizures that are refractory to conventional treatment such as:  phenobarbital, potassium bromide, gabapentin, allowing dosages to be reduced
  • As pulse therapy for cluster seizures
  • As possible treatment (similar to the use of gabapentin) for neuropathic pain2,8

Drug Interactions or Contraindications

  • Caution when co-administering ketamine, opioids (e.g., buprenorphine), benzodiazepines with levetiracetam as this may increase CNS depression.
  • Caution in dosing and frequency should be considered for rats having renal impairment.

Adverse Reactions

CNS:  sedation, weakness

GI:  inappetence, constipation, diarrhea

Other: Changes in behavior (though none to this point has been identified in the rat).

Dosage Recommendations

Dose is empirical as of this writing.

5 mg/kg  PO,  BID  12  Dosage range used successfully in pet rats by Adele Wharton MRCVS, CertGP (F&L) Veterinary Surgeon.   Dose and frequency to be determined by treating veterinarian based on type of seizure activity in the individual rat.

Considerations

  • Avoid abrupt withdrawal from Levetiracetam tablets in order to reduce the risk of increased seizure frequency and status epilepticus.
  • It is important for pet owner to keep record of any seizure activity, in the event medication efficacy needs to be reviewed by the veterinarian, such as:  increased frequency, duration, or type of seizure activity.
  • Levetiracetam appears to work synergistically (in combination) with NSAIDs. In the event rat is being maintained on levetiracetam for seizures and requires medicating for pain with an NSAID dosing may need to be adjusted as directed by veterinarian. 9
  • Store tablets and oral solution at room temperature away from light.

Consultant

Adele Wharton, MRCVS, CertGP (F&L) Veterinary Surgeon

References

  1. Gower, A. T., Hirsch, E., Boehrer, A., Noyer, M., & Marescaux, C. (1995). Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy. Epilepsy Research, 22(3), 207–213. https://doi.org/10.1016/0920-1211(95)00077-1
  2. Hedley, J. (2020). BSAVA Small Animal Formulary Part B: Exotic Pets. (10th ed.). BSAVA.
  3. Al-Shorbagy, M. Y., El Sayeh, B. M., & Abdallah, D. M. (2013). Additional antiepileptic mechanisms of levetiracetam in lithium-pilocarpine treated rats. PLoS ONE, 8(10), e76735. https://doi.org/10.1371/journal.pone.0076735
  4. Strolin Benedetti, M., Coupez, R., Whomsley, R., Nicolas, J. M., Collart, P., & Baltes, E. (2004). Comparative pharmacokinetics and metabolism of levetiracetam, a new anti-epileptic agent, in mouse, rat, rabbit and dog. Xenobiotica, 34(3), 281–300. https://doi.org/10.1080/0049825042000196749
  5. Doheny, H. C., Ratnaraj, N., Whittington, M. A., Jefferys, J. G. R., & Patsalos, P. N. (1999). Blood and cerebospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat. Epilepsy Research, 34(2–3), 161–168. https://doi.org/10.1016/s0920-1211(98)00104-1
  6. Levetiracetam – FDA prescribing information, side effects and uses. (n.d.). Retrieved September 12, 2021, from https://www.drugs.com/pro/levetiracetam.html
  7. Deshpande, L. S., & DeLorenzo, R. J. (2014). Mechanisms of levetiracetam in the control of status epilepticus and epilepsy. Frontiers in Neurology, 5https://doi.org/10.3389/fneur.2014.00011
  8. Micov, A., Tomić, M., Popović, B., & Stepanović-Petrović, R. (2010). The antihyperalgesic effect of levetiracetam in an inflammatory model of pain in rats: mechanism of action. British Journal of Pharmacology, 161(2), 384–392. https://doi.org/10.1111/j.1476-5381.2010.00877.x
  9. Tomić, M. A., Micov, A. M., & Stepanović-Petrović, R. M. (2013). Levetiracetam interacts synergistically with nonsteroidal analgesics and caffeine to produce antihyperalgesia in rats. The Journal of Pain, 14(11), 1371–1382. https://doi.org/10.1016/j.jpain.2013.06.003
  10. Keppra XR [package insert]. Smyrna, GA: UCB, Inc.; 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022285s025lbl.pdf
  11. Plumb, D. (2008). Sildenafil Citrate. Plumb’s Veterinary Drug Handbook (6th ed., pp. 532-533). Stockholm, Wis.: PharmaVet ;.
  12. Vinogradova, L. V., & van Rijn, C. M. (2008). Anticonvulsive and antiepileptogenic effects of levetiracetam in the audiogenic kindling model. Epilepsia, 49(7), 1160–1168. https://doi.org/10.1111/j.1528-1167.2008.01594.x

Cross-references

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