Daniël M. Jonker (1,2), Rob A. Voskuyl (1,2) and Meindert Danhof (1)
(1) Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratories, Leiden, The Netherlands; (2) Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands
Objective: Characterization of the pharmacodynamic interaction between the antiepileptic drugs tiagabine and lamotrigine on basis of the anticonvulsant effect in the cortical stimulation model in the rat.
Methods: The study was conducted according to a partial cross-over design, in which the plasma concentrations of both drugs were increased linearly in the absence and presence of a steady-state concentration of the second drug. The anticonvulsant effect was quantified by counts of 4 specific ictal signs (eye closure, forelimb clonus, forelimb extension and head jerk). These counts were related to the total plasma concentrations of both drugs with an inhibitory sigmoid model that was based on the density function for a Poisson distribution. This population model was implemented in NONMEM using the Laplacian method with the likelihood option. For each ictal sign, the tiagabine-lamotrigine interaction was assessed by response surface analysis based on a parametric interaction model [1].
Results: When given separately, both tiagabine and lamotrigine suppressed all ictal signs in a concentration-dependent manner, with the exception of eye closure, which was not suppressed by lamotrigine. The response surface analysis showed that the pharmacodynamic interaction between tiagabine and lamotrigine was synergistic for the ictal signs eye closure and head jerk. In contrast, the interaction was additive for the ictal signs forelimb clonus and forelimb tonus. These results were visualized by plotting the difference between the observed effect and the additive effect, showing that synergy for eye closure and head jerk was maximal at concentrations near the EC50 values of both drugs.
Conclusion: These findings show that the nature and magnitude of the pharmacodynamic interaction between tiagabine and lamotrigine differs between specific motor components of epileptic seizures.
Reference:
[1] Minto CF, Schnider TW, Short TG, et al. Response surface model for anesthetic drug interactions. Anesthesiology 2000;92:1603-1616.
Reference: PAGE 12 () Abstr 397 [www.page-meeting.org/?abstract=397]
Poster: poster