Abstracts

Patients that do not respond well to monotherapy, may benefit from a drug combination. However, the selection of optimal drug combinations and the optimization of doses remain a matter of trial and error. Combinations of drugs with different modes of action are commonly assumed to offer the highest chance of producing synergism, but this hypothesis is not proven.
In this study in rats, tiagabine and lamotrigine were selected, because of their selectivity of action on different targets, respectively being inhibition of presynaptic GABA reuptake and Na-channel blockade (thereby reducing Glu-release). In each experiment, one drug was administered intravenously to achieve an increasing plasma concentration over time in the absence or presence of the other drug at steady state. This design enabled a full characterization of the pharmacokinetic-pharmacodynamic (PK-PD) interaction. Seizure activity was elicited repeatedly via electrodes implanted on the motor cortex and recorded on video. Rather than scoring seizures as all-or-none events, the occurrence of 4 individual ictal components within the total pattern was assessed: eye blinking, clonic forelimb flexion, forelimb extension and head jerk (violent backward movement of head and body). The PD interaction was characterized by relating drug concentrations in individual animals to the occurrence of ictal components.
PK interaction was characterized by monitoring concentrations of both drugs in arterial blood samples. The increase of tiagabine levels was significantly faster in the presence of steady state lamotrigine than in its absence, but no other PK interactions were detected.
The PK-PD relationship between the drug concentrations and the 4 ictal components was defined by estimation of drug potencies (EC[sub]50[/sub]) and Hill slopes (n[sub]H[/sub]). The EC[sub]50[/sub] of tiagabine for suppressing both forelimb components and head jerk was 86[plusmn]28 ng/ml and for lamotrigine 6910[plusmn]1430 ng/ml. Against eye blinking, tiagabine was less potent (EC[sub]50[/sub]: 486[plusmn]173 ng/ml) and lamotrigine did not affect this component at all. The combination of tiagabine and lamotrigine was significantly more potent in suppressing head jerk and eye blinking. Relative to the additive (no interaction) response, this effect corresponded to an increase of response up to 31% that was localized around the EC[sub]50[/sub] values of the individual drugs. For both forelimb components, there was no statistically significant difference from the additive response.
The combination of tiagabine and lamotrigine suppresses ictal components synergistically and selectively in the rat. We suggest that this combination at low doses may alter the nature of seizures by suppressing some ictal signs more strongly than others. The present study provides proof-of-principle that synergistic drug combinations can effectively be identified and characterized through the joint application of ictal component analysis and advanced PK-PD modelling.
[Supported by: Nationaal Epilepsie Fonds]