Annual Meeting Abstracts: View
(Abst. 2.309), 2014
THE EFFECT OF EPIDIOLEX (CANNABIDIOL) ON SERUM LEVELS OF CONCOMITANT ANTI-EPILEPTIC DRUGS IN CHILDREN AND YOUNG ADULTS WITH TREATMENT-RESISTANT EPILEPSY IN AN EXPANDED ACCESS PROGRAM
Authors: Daniel Friedman, Maria Roberta Cilio, Nicole Tilton, Joseph Sullivan, Julie Hedlund, Evan Rosenberg, Judith Bluvstein and Orrin Devinsky
Content: Rationale: Preclinical and anecdotal evidence suggests that cannabidiol (CBD) has anticonvulsant effects and shows promise as a novel treatment for refractory epilepsy. However, in vitro studies and animal studies suggest that CBD may inhibit cytochrome P450 enzymes, specifically CYP2C and CYP3A classes, which may cause theoretical pharmacokinetic interactions with multiple drugs, including anti-epileptic drugs (AEDs). Here we report the effect of the addition of CBD to the levels of co-administered AEDs in patients with treatment-resistant epilepsy (TRE) enrolled in an expanded access treatment program. Methods: Children and young adults with severe, childhood-onset TRE participating in an expanded access compassionate use of CBD at two sites (NYU and UCSF) were enrolled in a prospective observational study after obtaining informed consent. Patients then received a purified 98% CBD extract, of known and constant composition (Epidiolex: GW Pharmaceuticals), at a dose of 5 mg/kg/day in addition to their baseline AED regimen. The daily dose was gradually increased by 2-5mg/kg increments at 1-2 intervals until intolerance occurred or a maximum dose of 25 mg/kg/day was achieved. Laboratory testing for hematologic, liver, kidney function, and concomitant AED levels was performed at baseline and every 4 weeks during the 12-week observation period. Results: Thirty-three subjects (17 were female [51.5%]; median age 10 age, range 3.7-26.2) had serum AED concentrations measured at baseline and at least once following the addition of CBD. The median number of concomitant AEDs was 3 (range 1-4). The most common AEDs were: clobazam (54.5% of subjects), valproate (36.4%), levetiracetam (30.3%), felbamate (21.2%), lamotrigine (18.2%) and zonisamide (18.2%). Following the addition of CBD, there was a median change in clobazam levels of 8.3% (range: -64 to 478%, N=17), a median change in valproate levels of 8.4% (range: -21 - 38%, N=11), a median change in levetiracetam levels of 9.8% (range: -23 - 46%, N=8), median change in felbamate levels of -8.6% (range: -41-100%, N=7), and median change in lamotrigine levels of -21% (range: -42 - 2.3%, N=6). The % changes from baseline for all AEDs are summarized in Figure 1. Of patients taking clobazam, 7 (41%) required a dose reduction following the addition of CBD because of excessive sedation attributed to elevated serum levels or the effect of combined medications. Conclusions: In patients with TRE on multi-AED regimens, the addition of CBD may be associated with changes in serum concentrations of concomitant AEDs. Particularly, a subset of patients experienced an increase in serum clobazam concentrations requiring dose adjustment, suggesting possible effects of CYP2C19 inhibition by CBD, a major metabolic pathway of clobazam. Further studies are needed to delineate the pharmacokinetic interactions between CBD and AEDs and frequent monitoring of serum AED levels is warranted in patients using CBD-containing products, including medicinal cannabis.