Can pentylenetetrazole and maximal electroshock rodent seizure models quantitatively predict antiepileptic efficacy in humans?

PURPOSE Pentylenetetrazole and maximal electroshock rodent seizure models are commonly used to detect antiepileptic efficacy in drug development. The aim of this research was to evaluate the predictive capabilities of pentylenetetrazole and maximal electroshock models in estimating human exposures required for antiepileptic efficacy through a survey of current literature. METHODS A literature search was undertaken to identify articles describing pentylenetetrazole or maximal electroshock models in rat or mice, where at least one of nine pre-selected antiepileptic drugs based on evidence of efficacy were used. Exposures at the median doses of the approved human dose range for these drugs were compared to exposures at doses that inhibit maximal response by 50% (ED50s) from the pentylenetetrazole and maximal electroshock models. Ratios of the human to rodent exposures were calculated and summarised statistically and graphically. RESULTS Across the nine antiepileptic drugs investigated, the average (standard deviation) ratio of exposures comparing the median human efficacious dose to mice ED50 dose was 1.4 (3.9) for the pentylenetetrazole model and 3.8 (3.1) for the maximal electroshock model. In the rat, ratios in the maximal electroshock and pentylenetetrazole model were 4.1 (2.1) and a range of 1-2, respectively. CONCLUSION Based on the nine antiepileptic drugs investigated, the pentylenetetrazole model appeared to predict human exposures more accurately than the maximal electroshock model. There did not appear to be differences between rat and mice in either of the seizure models, therefore both species could be used equally. Both the pentylenetetrazole and maximal electroshock models are useful tools in screening compounds in early drug discovery.