Abstract
Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP; UAB CBD Program. Epilepsia 2017;58:1586–1592.
OBJECTIVE: To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs. METHODS: In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmeth-ylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate. RESULTS: Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01). SIGNIFICANCE: Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.
Commentary
The algorithms behind Google auto-complete may be idiosyncratic, but at least for this writer on his laptop computer today, when “how to treat epilepsy” is entered into the search bar, the three top phrase-finishing suggestions for treatment methods are “without medications,” “naturally,” and “with CBD.”
Indeed, no practicing epileptologist can legitimately be surprised nowadays when a patient, family member, or care-giver asks about the use of “medical marijuana” for epilepsy. Like questions about the driving regulations in one's state, the risk of sudden unexpected death in epilepsy (SUDEP), or the teratogenicity of antiepileptic drugs (AEDs), the queries about cannabinoid treatment likely elicit an already prepared response from most of us that distills a large amount of background knowledge into an easily digestible lesson, hopefully tailored to the individual patient's circumstances. With regard to cannabidiol (CBD), for example, we may choose to inform patients of the positive studies of its efficacy in certain refractory syndromes (1, 2), the relative lack of data on its utility in the broad population with common forms of epilepsy, the distinct differences between it and tetrahydrocannabinol (THC), its potential side effects despite being a “natural” plant-based compound, and even the practical and legal issues surrounding its availability in our particular part of the world (3, 4). A growing body of evidence, however, suggests that part of our answer should include educating patients about the potential for interactions between CBD and commonly used AEDs.
In the article by Gaston et al., the authors report on an open-label safety study conducted at their institution as part of a compassionate-use program for patients with medically refractory epilepsy. A total of 39 adults and 42 children received CBD (in the Epidiolex formulation from GW Pharmaceuticals) in gradually increasing doses, and had serum AED levels checked at baseline before starting CBD and on multiple subsequent occasions over the course of a year. AED doses could be adjusted by the treating clinician at any time in a naturalistic study design. Results were analyzed using a mixed linear model to identify statistically significant changes in the serum levels of AEDs with increasing CBD doses.
The main findings were that most AEDs did not demonstrate significantly different serum levels in the presence of increasing CBD doses. The several that did demonstrate such changes were topiramate, zonisamide, eslicarbazepine, rufinamide, and clobazam (with its active metabolite N-desmethylclobazam), all of which demonstrated higher serum levels with concomitant CBD use, either in adults or in both adults and children. A more useful analysis looking at the clinical meaningfulness and “effect sizes” of some of these elevations found that clobazam/N-desmethylclobazam had the largest degree of change between baseline and the first two serum level measurements while on CBD. The changes in eslicarbazepine levels were also notable, though the sample for that drug was only four adult patients, while the changes in topiramate, zonisamide, and rufinamide levels appeared to be much smaller in nature. Clinically, sedation was associated with higher clobazam metabolite levels and often necessitated clobazam dosage reductions, while transaminase elevations were associated with concomitant valproate usage, even though actual serum valproate levels were not significantly altered.
This is important work that provides additional data on which to base those conversations we ought to be having with patients about potential drug–drug interactions while taking CBD. The interaction with clobazam and its metabolite has previously been identified, including in a case series of 13 children (5); perhaps not surprisingly, in a large open-label study, patients had both increased toxicity (sedation) and increased efficacy (fewer motor seizures) if they were taking CBD and clobazam together, presumably as a result of this interaction (2). The potential hepatotoxicity from taking CBD and valproate together has also been previously noted in the two published large trials (1, 2). The presence or absence of interactions with the other commonly used AEDs are newly described here.
The authors detail the likely biological explanation behind some of these interactions, namely the inhibitory effect of CBD on CYP enzymes that are responsible for metabolizing multiple AEDs. For eslicarbazepine and rufinamide, which are metabolized differently, the mechanism of the interaction is less clear, however, and although the study was conducted quite rigorously, there remain other potential explanations for some of these findings, including increased adherence to the conventional AEDs once CBD was started, for example.
In this age of personalized medicine, it may be important in future studies to explore the individualized, possibly genetic factors that may affect patients’ susceptibility to certain drug metabolism-based interactions. More work that focuses on this interindividual variability and any relevant predictive factors would allow us to better counsel patients on their risk of clinically meaningful drug–drug interactions. In the meantime, as additional studies like the one by Gaston et al. add to our understanding of CBD in epilepsy, our standard spiel in response to patients’ questions may just have to get a little bit longer.