Pharmacodynamic and Pharmacokinetic Characterization of Interactions between Levetiracetam and Numerous Antiepileptic Drugs in the Mouse Maximal Electroshock Seizure Model: An Isobolographic Analysis

Abstract

Approximately 30% of patients with epilepsy do not experience satisfactory seizure control with antiepileptic drug (AED) monotherapy and often require polytherapy. The potential usefulness of AED combinations, in terms of efficacy and adverse effects, is therefore of major importance. The present study sought to identify potentially useful AED combinations with levetiracetam (LEV) METHODS: With isobolographic analysis, the mouse maximal electroshock (MES)-induced seizure model was investigated with regard to the anticonvulsant effects of carbamazepine (CBZ), phenytoin, phenobarbital (PB), valproate, lamotrigine, topiramate (TPM), and oxcarbazepine (OXC), administered singly and in combination with LEV. Acute adverse effects were ascertained by use of the chimney test evaluating motor performance and the step-through passive-avoidance task assessing long-term memory. Brain AED concentrations were determined to ascertain any pharmacokinetic contribution to the observed antiseizure effect. LEV in combination with TPM, at the fixed ratios of 1:2, 1:1, 2:1, and 4:1, was supraadditive (synergistic) in the MES test. Likewise, the combination of LEV with CBZ (at the fixed ratio of 16:1) and LEV with OXC (8:1 and 16:1) were supraadditive. In contrast, all other LEV/AED combinations displayed additivity. Furthermore, none of the investigated LEV/AED combinations altered motor performance and long-term memory. LEV brain concentrations were unaffected by concomitant AED administration, and LEV had no significant effect on brain concentrations of concomitant AEDs. These preclinical data would suggest that LEV in combination with TPM is associated with beneficial anticonvulsant pharmacodynamic interactions. Similar, but less profound effects were seen with OXC and CBZ.