Correlation analysis between anticonvulsant ED 50 values of antiepileptic drugs in mice and rats and their therapeutic doses and plasma levels

Abstract

Objective Although there are several animal models of epilepsy, the extrapolation of antiepileptic drug (AEDs) performance to epileptic patients from anticonvulsant activity results in animals is not straightforward. Consequently, the aim of this work was to perform a correlation analysis between therapeutic daily doses ( D) and average steady-state plasma concentrations ( C ss,av) of AEDs and their activity in common anticonvulsant animal models. Methods AED activity in anticonvulsant animal models was expressed as maximal electroshock seizure (MES) test ED 50 values in mice and rats and ED 50 values in audiogenic seizure-susceptible mice (AGS ED 50). Data were examined, by use of linear and logarithmic approaches, for an association between C ss,av (mg/L or μmol/L) and D (mg or mmol) for each AED in epileptic patients as the dependent variable ( Y) and its MES ED 50 in mice and rats and AGS ED 50 in mice (mg/kg or μmol/kg) as the independent variable ( X). Results Linear correlation analyses between C ss,av (mg/L) and ED 50 (mg/kg) for 11 AEDs gave the following correlation coefficients ( R 2): 0.68 (mice, MES); 0.73 (rat, MES); 0.64 (AGS). Switching the units from milligrams to micromoles improved the correlation significantly and gave the following R 2 values: 0.88 (mice, MES); 0.90 (rat, MES); 0.76 (AGS). The linear correlation between C ss,av and ED 50 was better than that between D and ED 50. Conclusions The results of this analysis suggest that the relationship between C ss,av and ED 50 is useful in predicting target concentration ranges in humans. The Y intercepts of the C ss,av-versus-ED 50 and D-versus- ED 50 plots were similar in all three animal models and ranged between 12 and 17 mg/L and between 570 and 890 mg, respectively, indicating that for all AEDs analyzed except valproic acid and ethosuximide, the therapeutic plasma concentration is in the range 10–20 mg/L.