Abstracts

Rationale: Lacosamide (LCM) is a functionalized amino acid that shows a more potent and effective anticonvulsant profile in animal models when compared to conventional antiepileptics. New antiepileptic drugs (AEDs) are initially licensed as add-on treatment, often with no evidence to suggest which existing therapies they should be employed with. In addition, approximately 30% of patients with epilepsy are prescribed polytherapy regimes. There is, thus, a clear need to develop a rational basis for AED polytherapy. The objective of this study was the isobolographic evaluation of the interaction between LCM and a number of other AEDs.Methods: The anticonvulsant effect of LCM with other AEDs (carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), gabapentin (GBP) and levetiracetam (LEV)) at fixed ratios of 1:3, 1:1 and 3:1 was evaluated in the 6 Hz-induced seizure model in mice. The protective action of an AED was defined as the absence of seizure. Furthermore, motor side effects of AED combinations was assessed in the rotarod test.Results: All studied AEDs produced dose-dependent anticonvulsant effects against 6 Hz induced seizures. Combinations of LCM with CBZ, LTG, TPM, GBP or LEV were supraadditive (synergistic). All other LCM/AED combinations displayed additive effects with a tendency towards supraadditivity. Furthermore, no enhanced adverse effects were induced by combinations of LCM with these AEDs as assessed in the rotarod test.Conclusions: The isobolographic analysis revealed that combinations of LCM with novel AEDs (TPM, GBP, LTG or LEV) or with CBZ are associated with supraadditive anticonvulsant effects. Similar but less profound supraadditive effects were seen with LCM in combination with PHT or VPA. In contrast, infra-additive effects were seen on motor side effects for combinations in comparison to equipotent doses of AEDs alone. (Research funding provided by Schwarz Biosciences).