Pharmacodynamic analysis of the anticonvulsant effects of tiagabine and lamotrigine in combination in the rat.
OBJECTIVE
The pharmacodynamic interaction between the antiepileptic drugs (AEDs) tiagabine (TGB) and lamotrigine (LTG) was characterized on basis of the anticonvulsant effect in the cortical stimulation model in the rat.


METHODS
The study was conducted according to a partial crossover design, in which both drugs were infused intravenously to achieve linear increases in the plasma concentration in the absence and presence of a steady-state concentration of the second drug. The anticonvulsant effect was quantified by counts of four specific ictal signs (eye closure, forelimb clonus, forelimb extension, and head jerk). A potential pharmacokinetic interaction was accounted for by determination of total plasma concentrations of both drugs.


RESULTS
When given separately, both TGB and LTG suppressed all ictal signs in a concentration-dependent manner, with the exception of eye closure, which was not suppressed by LTG. The interaction between both drugs was estimated by response surface analysis by using the difference between the observed effect and the additive effect to identify synergistic drug concentrations. This analysis showed that the pharmacodynamic interaction between TGB and LTG is synergistic for the ictal signs of eye closure and head jerk. In contrast, the interaction was additive for the ictal signs of forelimb clonus and forelimb tonus.


CONCLUSIONS
This study demonstrates the usefulness of ictal-component analysis for studying the pharmacodynamic interaction between AEDs. Quantification of both the nature and the magnitude of the interaction between TGB and LTG led to the identification of two ictal signs that were synergistically suppressed. This approach offers a theoretical basis to identify and optimize drug combinations that are useful to treat refractory epilepsy.
Jonker
Daniël M
DM
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratories, Leiden, The Netherlands.
Voskuyl
Rob A
RA
Danhof
Meindert
M
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D004569:Electroencephalography / Q000187:drug effects; D004597:Electroshock; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D009557:Nipecotic Acids / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000517:prevention & control*; D000078308:Tiagabine; D014227:Triazines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D000927:Anticonvulsants; D009557:Nipecotic Acids; D014227:Triazines; D000077213:Lamotrigine; D000078308:Tiagabine