Coadministered cannabidiol and clobazam : preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

Objective: Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syn-drome and Lennox‐Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first‐line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. Methods: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N‐desmethylclobazam (N‐CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharma-cokinetics of clobazam in mice. We then used the Scn1a+/− mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD‐clobazam combination therapy to monotherapy against thermally‐in-duced seizures, spontaneous seizures and mortality in Scn1a+/− mice. In addition, we used Xenopus oocytes expressing γ‐aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together. Results: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N‐CLB. Combination CBD‐clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/− mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub‐anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation