Doron Michaeli, Reem Smoum, Raphael Meschoulam, Haitham Amal
Cannabis-derived cannabinoids such as CBD and THC have various neuroactive properties. The CBD oral solution known as Epidiolex® in the US (Epidyolex® in EU) is a pharmaceutical grade product approved for the treatment of Lennox-Gastaut syndrome, Dravet syndrome, and seizures associated with tuberous sclerosis complex, all severe forms of childhood epilepsy (Epidiolex® product label). In human, CBD is metabolized by cytochrome P450 (CYP) 2C19 to its active metabolite 7-hydroxy-cannabidiol, which is further metabolized by CYP3A4 to its inactive metabolite 7-carboxy-cannabidiol. In vitro studies suggest that CBD may inhibit various CYP enzymes including CYP2C19. In vivo drug-drug interaction studies demonstrated no inhibitory effect of CBD on CYP3A4, however interactions with CBD as a perpetrator were seen with CYP1A2 and CYP2C19 (Epidiolex® product label).
Clobazam is a widely used as an anxiolytic and antiseizure medication for over 50 years, including children with Lennox-Gastaut syndrome. CLB is metabolized to over 20 metabolites in humans, including NCLB, its main metabolite. Based on animal and in vitro receptor-binding data, the relative potency of NCLB is estimated to be between one-fifth to equally as potent as. Conversion of CLB to NCLB is mediated by CYP3A, whereas NCLB is metabolized primarily via CYP2C19. In vivo drug interaction studies demonstrated that when CBD and CLB are administered concomitantly, a very mild increase in CLB plasma levels is seen. A significant increase of NCLB plasma levels is however evident, due to the inhibitory effect of CBD on CYP2C19.
Cannabis sativa has a long history of use for control of human seizures. Medical cannabis is also provided to adult DRE patients, and in both populations may be co-administered with CLB. It is however unknown whether the combination of cannabis extract at a 20:1 CBD:THC ratio interacts with CLB. The purpose of this study is to test whether a pharmacokinetic interaction is present when cannabis extract and CLB are co-administered to adult DRE patients.
