Authors :
Presenting Author: Rohini R. Rana, PhD – Jazz Pharmaceuticals, UK Ltd.
William H. Hind, PhD – Jazz Pharmaceuticals, UK Ltd.
Pabitra H. Patra, PhD – Transpharmation Ltd.
Saga Johansson, PhD – Jazz Pharmaceuticals, UK Ltd.
Karthik Rajasekaran, PhD – Jazz Pharmaceuticals, Inc.
H. Steve White, RPh, PhD – University of Washington
David J. Virley, PhD – Jazz Pharmaceuticals, UK Ltd.
Rationale:
Antiseizure medications (ASMs) are often used in combination to improve seizure control and tolerability in people with epilepsy. Previously, we identified a synergistic antiseizure pharmacodynamic drug-drug interaction (PD-DDI) between cannabidiol (CBD) and clobazam using the maximal electroshock seizure (MES) model in mice.1 Cenobamate (CNB) has been shown to enhance the antiseizure activity of other ASMs using the DBA/2 mouse model.2 The current study investigates PD-DDIs for CBD and CNB in the mouse MES model.
Methods:
The MES model1 of acute generalized seizures was used in male C57BL/6J mice to evaluate antiseizure properties of CBD alone, CNB alone, and in combination. Mice were treated with either CNB (1–30 mg/kg intraperitoneally [IP]; 30 min) or plant-derived highly-purified CBD (Epidiolex® active pharmaceutical ingredient, 10–100 mg/kg IP; 60 min), before receiving a validated, fixed-current-intensity electrical stimulus via corneal stimulation (30 mA, 0.2 sec). Antiseizure efficacy was determined by inhibition of tonic hind-limb extension, indicative of generalized tonic-clonic seizures, compared with vehicle-treated animals. Exposures of CBD, its active metabolite 7-OH-CBD, and CNB were quantified in plasma and brain samples collected immediately after the seizure test using liquid chromatography/tandem mass spectrometry bioanalysis. The overall effect of CBD + 7-OH-CBD was estimated after normalizing 7-OH-CBD potency to that of CBD1. Based on effective brain exposures that produce 50% antiseizure effects (b-EE50) for each ASM alone, mice were treated with 3 fixed ratios of CBD and CNB (1:3, 1:1, and 3:1) calculated using Loewe’s equation that yielded a theoretical additive effect (b-EE50+ADD). The isobolographic method for DDI analysis was then used to quantitatively assess synergism, additivity, or antagonism between CBD and CNB.3 Rotarod evaluation was conducted on all CBD and CNB ratios to evaluate potential effects on motor coordination.
Results:
CBD and CNB each produced brain exposure–dependent antiseizure effects in the MES test (n=10 per dose group; b-EE50: CBD 14.89 μM, CNB 12.30 μM). Isobolographic analysis based on equieffective b-EE50 values revealed PD synergism between CBD and CNB at all 3 b-EE50+ADD ratios (1:3, 1:1, and 3:1). PD synergy was also reflected by Combination Index < 1 and Exposure Reduction Index > 1 values. Synergistic antiseizure effects were noted in the absence of any significant pharmacokinetic interactions or reduced motor coordination.
Conclusions:
This study demonstrates a novel synergistic PD-DDI between CBD and CNB in the mouse MES model of acute generalized seizures and provides a scientific rationale for exploring the clinical efficacy of combining these ASMs.
References
1. Rana RR, et al. Exp Neurol. 2023;360:114286.
2. Leo A, et al. Eur J Pharmacol. 2024:962:176222.
3. Luszczki JJ, et al. Eur J Pharmacol. 2009;602:298-305.
Funding:
Jazz Pharmaceuticals, Inc.