Importance of Monitoring Clobazam and N-Desmethylclobazam Levels in Treatment with Cannabidiol (CBD) for Epilepsy (S14.001)

Objective: To assess the potential interaction between pharmaceutical grade CBD formulation (Epidiolex) and clobazam in patients with treatment-refractory epilepsy enrolled in an open-label safety study. Background: CBD use through State-sponsored program allowed us to evaluate the possible drug-drug interactions between CBD and clobazam. We hypothesized that with increasing CBD dose the level of clobazam and its metabolite N-desmethylclobazam would rise leading to increase in adverse events including sedation. Methods: Of the 51 patients enrolled in the program, 17 received concomitant CBD and clobazam (11 adults (mean age 22.9 ± 4.2 years, 6 females) and 6 children (mean age 11.8 ± 4.8 years, 3 females). All subjects were treated with CBD starting at 5 mg/kg/day that was increased to tolerability and seizure control every two weeks by 5 mg/kg/day up to a maximum of 25 mg/kg/day. Clobazam and N-desmethylclobazam levels were checked at most visits. Clobazam dose was decreased if there was report of sedation; frequently before the levels were available. Spearman rho (non-normal distribution) and linear regression analyses were used. Results: Plasma clobazam/N-desmethylclobazam levels were obtained at 83/85 visits. We noted positive correlation between CBD dose and N-desmethylclobazam level (rho=0.234; p=0.033) and negative correlation between CBD dose and clobazam level (rho=-0.314; p=0.004). We also observed positive correlations between clobazam dose and clobazam (rho=0.711; p=0.000) and N-desmethylclobazam (rho=0.464; p=0.000) levels. 6/11 (55[percnt]) adults and 5/6 (83[percnt]) children complained of sedation, with subsequent reduction in clobazam dose. Regression analysis indicates that while controlling for increases in CBD and decreases in the clobazam dose, the level of clobazam declined non-significantly (β=-0.179; p=0.193) while the level of N-desmethylclobazam rose significantly (β=0.725; p=0.000). Conclusions: A clear interaction between CBD and clobazam was identified. This study highlights the importance of monitoring clobazam and N-desmethylclobazam levels when treating patients with CBD.