A comparison of the effects of lamotrigine on neuroma-induced action potential firing and normal behaviour in rat: implications for establishing a pre-clinical 'therapeutic index'

The effects of lamotrigine on rat neuroma and behavioural paradigms were evaluated to determine a pre-clinical therapeutic index. Lamotrigine blocked neuroma-induced burst pattern firing at a free plasma concentration of 13.7 +/- 1.7 muM (n = 5). Oral dosing of lamotrigine (50-200 mg/kg) had no significant effects on behaviour but measurements of plasma concentrations of free drug showed non-linear oral absorption and lower than predicted drug levels (5-27 muM). Given intravenously (10-100 mg/kg), lamotrigine did affect behaviour at a free plasma concentration of 42.0 muM (n = 2). By comparing free plasma concentrations, a therapeutic index of 3 was calculated, which is lower than published data based on comparing oral doses. We propose that a therapeutic index should only be derived with reference to plasma drug concentrations to prevent non-linear or incomplete drug absorption from confounding accurate estimation. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.