Establishing the predictive validity of preclinical seizure models across broad developmental and epileptic encephalopathies (DEEs).

Testing anticonvulsant activity in preclinical seizure models is central to developing new antiseizure medications (ASMs). However, the predictive validity of these models across the spectrum of epilepsy indications remains uncertain. The Praxis Analysis of Concordance (PAC) framework was recently developed to assess translational concordance between preclinical seizure models and clinical efficacy in focal onset and generalized epilepsies. Here, we sought to extend the PAC framework to evaluate concordance across broad DEEs, including genetic epilepsies.

Thirty-two approved ASMs were evaluated across established preclinical seizure and genetic epilepsy models using reported TD₅₀ and ED₅₀ values. Protective index values were calculated and a weighted scale representing relative antiseizure efficacy was used to grade preclinical ASM response for each ASM in each seizure and genetic epilepsy model. Clinical use and perceived efficacy were similarly evaluated across epilepsy indication. Predictive validity of preclinical models was assessed using the PAC scoring matrix, with concordance scores assigned ranging from complete discordance (-1) to complete concordance (1) between preclinical and clinical ASM responses. Scores were then summed and normalized to generate a global translational concordance score for each model.

Findings from our PAC-DEE framework revealed variable concordance across models, with preliminary analyses suggesting certain preclinical seizure models exhibit predictive validity for specific DEEs. In general, genetic models demonstrated greater concordance than preclinical seizure models.

Findings from the PAC-DEE study extend our insights into the predictive validity of commonly used seizure models across broad DEEs and underscore the importance of appropriate model selection in ASM drug discovery. Together with previous findings in focal and generalized epilepsy, these findings are anticipated to have important implications for accelerating research efforts and promoting efficient resourcing for novel ASM drug development across the epilepsy spectrum.