Pharmacokinetic and Pharmacodynamic Relationship of Clinically Used Antiseizure Medications in the Maximal Electroshock Seizure Model in Rodents

Background/Objective: The assessment of the efficacy of antiseizure medications (ASMs) in animal models of acute seizures has played a critical role in these drugs’ success in clinical trials for human epilepsy. One of the most widely used animal models for this purpose is the maximal electroshock seizure (MES) model. While there are numerous published reports on the efficacy of conventional ASMs in MES models, there is a need to expand the understanding on the brain concentrations that are needed to achieve optimal levels of efficacy in this model. Methods: We evaluated six clinically available ASMs in both a mouse and a rat MES model by analyzing dose-response and concentration-response for brain and plasma exposure levels: carbamazepine (CBZ), phenytoin (PHT), valproic acid (VPA), lacosa-mide (LSM), cenobamate (CNB), and retigabine (RTG). Results: Our data indicate that these ASMs tend to be more effective in reducing seizures in the rat MES, with notable differences in drug metabolism and brain penetrance be-tween mice and rats. Conclusion: These findings highlight the value of considering concentration-response variations and species-specific differences when assessing the efficacy of both conventional ASMs and novel compounds exhibiting anticonvulsant activity.