Abstracts

Rationale: To identify potential interactions between pharmaceutical grade CBD (Epidiolex) and AEDs by monitoring of serum AED levels during active titration of CBD in patients with treatment refractory epilepsy enrolled in an open label safety study. CBD is investigated as a potential add-on AED through a State of Alabama sponsored compassionate use open label safety study. As part of the study protocol, serum AED levels were checked frequently (in many cases at every study visit) to identify any interactions between CBD and AEDs. In a smaller sample of subjects from this study and in other data, it was shown that there is an interaction between clobazam and CBD. Through anecdotal observations and current data regarding CBD mechanism and metabolism, we hypothesized that there would be interactions between CBD and clobazam and valproate, though all AEDs taken by study subjects were analyzed. Methods: Flexible CBD dose adjustment schedule was implemented starting at 5 mg/kg/day and increased to tolerability and seizure control every two weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Baseline AED levels were drawn as part of the inclusion criteria. AEDs had to be at a stable dose for 1 month prior to enrollment. AED levels were obtained at almost all study visits during dose titration and maintenance. AED doses were adjusted at the discretion of the investigators if it was felt an adverse effect, lab abnormality, or drug level increase or decrease was related to a potential interaction between CBD and the AED in question. In particular, clobazam and valproate doses were frequently adjusted due to complaints of sedation and alteration in the liver function tests, respectively. At the time of this analysis, 81 subjects were enrolled in the study (39 adults, 42 children). Of the AEDs taken by study subjects, there were sufficient data points to analyze potential interactions between CBD and 19 AEDs (Table 1). Data were analyzed using the Mixed Procedure to determine if there was a significant change in each serum AED level as the dose of CBD was increased. Analysis was performed among all subjects and within individual pediatric and adult arms (if applicable). Results: Increase in serum levels of topiramate (p < 0.01), rufinamide (p < 0.01), and desmethyclobazam (p < 0.01, active metabolite of clobazam), and decrease in levels of clobazam (p < 0.01) with increasing CBD dose was seen in combined pediatric and adult arms. In addition, a significant increase in serum levels of zonisamide (p=0.02) and eslicarbazepine (p=0.04) with increasing CBD dose was seen in the adult arm only. There were no significant interactions seen between CBD and the other AEDs investigated (see Table 1). Conclusions: Significant drug interactions were identified between CBD and clobazam, rufinamide, topiramiate, zonisamide, and eslicarbazepine. This study emphasizes the importance of monitoring AED levels during treatment with CBD. In the future, these data will need to be correlated with reported side effects and/or lab abnormalities to determine if they are clinically significant. Funding: This study is funded by the State of Alabama through "Carly's Law" (SB174).