Development of Tolerance During Chronic Treatment of Kindled Rats With the Novel Antiepileptic Drug Levetiracetam

Abstract

Purpose: 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 thresh-old 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.