Abstract Details

Title An Assessment of Acute Pharmacodynamic Drug-drug Interactions (PD-DDIs) Between Cannabidiol (CBD) and Cenobamate (CNB) in a Mouse Model of Generalized Tonic Seizures

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) P3 - Poster Session 3 (5:00 PM-6:00 PM)

Poster/Presentation
Number 10-001

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-EE_50+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-EE_50+ADDratios. 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.

Authors/Disclosures
Karthik N. Rajasekaran, PhD (Jazz Pharmaceuticals) PRESENTER	Dr. Rajasekaran has received personal compensation for serving as an employee of Jazz Pharmaceuticals.
Rohini Rana, PhD	Dr. Rana has received personal compensation for serving as an employee of Jazz Pharmaceuticals.
William Hind, PhD	Dr. Hind has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Dr. Hind has stock in Jazz Pharmaceuticals. Dr. Hind has received intellectual property interests from a discovery or technology relating to health care.
Pabitra Hriday Patra	Dr. Patra has nothing to disclose.
Saga Johansson	Saga Johansson has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Saga Johansson has stock in Jazz pharmaceuticals.
H S. White, PhD	Prof. White has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jazz Pharmaceuticals. Prof. White has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB Pharm. The institution of Prof. White has received research support from NIH. The institution of Prof. White has received research support from Neurelis.
David J. Virley, PhD	Dr. Virley has received personal compensation for serving as an employee of Jazz Pharmaceuticals . Dr. Virley has stock in Jazz Pharmaceuticals . Dr. Virley has received intellectual property interests from a discovery or technology relating to health care.

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