Development of tolerance during chronic treatment of kindled rats with the novel antiepileptic drug levetiracetam.
OBJECTIVE
Levetiracetam (LEV) is an interesting novel antiepileptic drug with proven efficacy in both animal models and patients with partial epilepsy. To study whether the efficacy of the drug changes during chronic treatment, we evaluated the anticonvulsant activity of LEV during prolonged daily administration in amygdala-kindled rats.


METHODS
On the basis of the anticonvulsant potency and duration of action after acute doses, LEV was administered in fully kindled rats three times daily at 108 mg/kg i.p. for 3 weeks. For the study of anticonvulsant efficacy, the afterdischarge threshold was determined before, during, and after the drug treatment period. To determine whether the pharmacokinetics of the drug change during prolonged treatment, LEV levels were repeatedly determined in plasma during the treatment period.


RESULTS
LEV markedly increased the afterdischarge threshold and decreased the seizure severity and duration after initial dosing, but a marked loss of anticonvulsant efficacy developed during chronic treatment. This loss of efficacy was not due to alterations in drug elimination, indicating the development of functional tolerance to LEV during repeated administration. After the termination of treatment, no withdrawal signs (e.g., changes in behavior, body temperature, body weight, or seizure threshold) were observed.


CONCLUSIONS
The data demonstrate that chronic administration of LEV leads to a significant reduction in anticonvulsant efficacy in the kindling model of temporal lobe epilepsy. Whether this experimental observation has clinical relevance must await monotherapy trials with long-term follow-up of patients who initially responded to LEV.
Löscher
W
W
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany. wloscher@pharma.tiho-hannover.de
Hönack
D
D
D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy*; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D000077287:Levetiracetam; D010889:Piracetam / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000209:etiology
D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam