An Assessment of Acute Pharmacodynamic Drug-drug Interactions (PD-DDIs) Between Cannabidiol (CBD) and Cenobamate (CNB) in a Mouse Model of Generalized Tonic Seizures
Rohini R. Rana1, William H. Hind1, Pabitra H. Patra2, Saga Johansson1, Karthik Rajasekaran3, H. Steve White4, David J. Virley1
1Jazz Pharmaceuticals, UK Ltd., 2Transpharmation Ltd., 3Jazz Pharmaceuticals, Inc., 4University of Washington
Objective:

To evaluate PD-DDIs between plant-derived highly purified CBD (Epidiolex®, active pharmaceutical ingredient) and CNB in a mouse maximal electroshock seizure (MES) model.

Background:

Synergistic antiseizure PD-DDIs between CBD and antiseizure medications (ASMs) like clobazam have been observed in mouse seizure models. CNB has been shown to enhance the antiseizure activity of other ASMs using the DBA/2 mouse model.

Design/Methods:

Male C57BL/6J mice were treated with CBD (10–100 mg/kg intraperitoneally [IP]; 60 min) or CNB (1–30 mg/kg IP; 30 min) before receiving a validated, fixed-current electrical corneal stimulation (30 mA, 0.2 sec) followed by immediate brain and plasma sample collection. Antiseizure efficacy was determined by inhibited tonic hind-limb extension, indicative of generalized tonic-clonic seizures, compared with vehicle-treated animals. CBD, its active metabolite 7-OH-CBD, and CNB exposures were quantified by mass spectrometry bioanalysis. Overall effect of CBD + 7-OH-CBD was estimated after normalizing 7-OH-CBD potency to CBD. 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, yielding a theoretical additive effect (b-EE50+ADD). Synergism, additivity, or antagonism between CBD and CNB was assessed using the isobolographic method for DDI analysis. Rotarod evaluation was conducted on all CBD: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 b-EE50+ADD ratios. PD synergy was also indicated by Combination Index <1 and Exposure Reduction Index >1 values. Synergistic antiseizure effects were observed without any significant pharmacokinetic interactions or impaired motor coordination.

Conclusions:

The study reveals evidence for pharmacodynamic synergism between CBD and CNB.

10.1212/WNL.0000000000215410
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.