Abstracts

Rationale: Epidiolex is a recently approved formulation of cannabidiol (CBD) that is indicated for the treatment of seizures associated with Lennox-Gastaut and Dravet syndrome. CBD has a complex biotransformation and pharmacokinetic profile. In vitro data suggest that CBD may perpetrate inhibitory pharmacokinetic (PK) interactions with drugs that are substrates of several CYP450 isozymes including 1A2, 2B6, 2C19, 2C9 and possibly 3A4/5. During clinical development of Epidiolex several interactions were noted, with the most commonly recognized being inhibition of N-desmethylclobazam via CYP2C19. In addition to potential CYP interactions, it has also been suggested that CBD might also inhibit isoforms of UDP-glucuronyltransferase (UGT) including UGT1A9 and UGT2B7. To date, there is a paucity of clinical data examining potential inhibition of this particular enzyme family.Lamotrigine (LTG) is metabolized primarily by UGT1A4, but UGT1A1, 1A3, 1A6, 1A7 and 2B7 also contribute. Current product information for Epidiolex suggests clinicians consider a dosage reduction for UGT substrate drugs such as LTG, however no specific guidance or data is provided. Given that inhibition of LTG may pose the risk of hypersensitivity reactions (e.g. VPA+LTG), we sought to preliminarily evaluate whether comedication with LTG and Epidiolex resulted in a signal of likely PK interaction.  Methods: A retrospective chart review was conducted in patients receiving stable LTG treatment and subsequent addition of Epidiolex. Baseline and post-Epidiolex plasma LTG concentrations were assessed, as well as subsequent changes in LTG dose (based on clinical impression of response). Epidiolex dose and dose titration were also noted. Plasma samples were obtained as part of routine clinical monitoring. Laboratory assessment of CBD plasma concentrations were not conducted.  Results: N=5 patients were evaluated.   All patients carry a diagnosis of Lennox-Gastaut syndrome.  Data on Epidiolex and LTG doses and plasma concentrations and patient characteristics are listed in table 1. A very slight LTG concentration increase was noted in patient #1, which correlates with an expected increase with the dose increase.  Similarly, the increased LTG plasma concentration noted in patient #5 would be consistent with the LTG dose increase noted. A LTG concentration decrease was seen for patient #3 which could be considered to be clinically meaningful.  However, this patient’s baseline LTG level was drawn 19 months prior to starting Epidiolex. It is unclear as to why this reduction was seen, however it obviously would not be consistent with CBD-mediated inhibition of UGT.  Conclusions: Overall, our observations from this clinic-derived sample do not suggest an interaction between these medications, at least within the labeled dosages of Epidiolex. While encouraging, clearly, a larger patient cohort needs to be evaluated before clinicians can be assured that a PK interaction does not however exist.  Funding: No funding