Abstracts

Rationale: The concomitant use of multiple antiepileptic drugs (AEDs) is not uncommon in the management of epilepsy. We have therefore investigated any potential for a pharmacodynamic (PD) interaction for the AEDs cannabidiol (CBD) with clobazam (CLB) or sodium valproate (VPA). Methods: The maximal electroshock seizure (MES) model of acute generalized seizure in mouse was employed to evaluate anticonvulsant properties of each AED alone and, subsequently, any CBD/AED PD interaction. Here, mice received an electrical stimulus using prevalidated fixed current intensity (30 mA, 0.2 sec duration) (Eur J Pharmacol 2009;602:298-305, Epilepsy Res 2010;90:188-198) that reliably produced tonic hindlimb extension indicative of generalized seizure in 100% of control animals. Using the brain exposure-response relationships derived from treatment with each AED alone, mice were then treated with three fixed ratios of CBD plus CLB or VPA (1:3, 1:1, and 3:1) calculated using Loewe’s equation of additivity (Naunyn Schmiedebergs Arch Pharmacol 2006;374:51-64) that yield a theoretically derived additive effect protecting 50% animals (EE50+ADD). The isobolographic method (Eur J Pharmacol 2009;602:298-305, Pharmacol Rev 2006;58(3):621-81) was then used to assess any additivity, antagonism, or synergy between CBD and CLB or VPA at each ratio. Exposures of drugs and their active metabolites were quantified in plasma and brain. Since assessment of any DDI relied upon brain exposure-response data, which accounted for efficacies of parent drugs and active metabolites, any contribution from PK interaction could be eliminated and any PD DDI between CBD and CLB or CBD and VPA alone determined. Results: CBD, CLB, and VPA caused brain exposure-dependent anticonvulsant effects upon the incidence of hindlimb extension when compared to vehicle. Log(brain exposure)-probit analysis provided robust data (R2>0.9) from which effective brain exposures protecting 50% animals (EE50) were derived (CBD: 7.9, CLB: 1.6 and VPA: 199.4; μM). The overall effect of parent drug plus any active metabolite was estimated in brain after normalizing metabolite anticonvulsant potency to that of parent. Data derived from administration of fixed ratio combinations were used to derive brain exposure-based isobolograms for [CBD+7-OH+CBD] versus [CLB+n-CLB] or [VPA], which revealed PD synergism between CBD/CLB and CBD/VPA at all three EE50+ADD ratios 1:3, 1:1 and 3:1. Conclusions: CBD administered with CLB or VPA produced PD synergism in the MES mouse model of acute generalized seizures that was independent of any PK interaction. Funding: GW Research Ltd