Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003)

Objective: To summarise current understanding of DDIs when CBD is coadministered with CLB, VPA, STP or CYP3A4 substrate. Background: DDIs between CBD and commonly used antiepileptic drugs (AEDs) is of clinical interest since it is anticipated that CBD will be used concomitantly with other AEDs. Design/Methods: Effects of multiple-dose CBD on steady-state pharmacokinetics (PK) of CLB, N-desmethyl clobazam (N-CLB), VPA, 4-ene-VPA, and STP, and multiple-dose CLB, VPA, and STP on steady-state PK of CBD and metabolites were evaluated in HVTs. Effects of multiple-dose CBD on steady-state PK of CLB, N-CLB, VPA, and 4-ene-VPA were evaluated in patients with epilepsy. The effect of CBD on CYP3A4 activity was evaluated in HVTs using MDZ as a probe. In all studies, a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (Epidiolex®; 100 mg/mL) was uptitrated over 10 days to 750 mg twice daily in HVTs (20 mg/kg/day for a 75 kg subject) or 20 mg/kg/day in patients. Results: Concomitant CBD had no relevant effect on CLB exposure but increased exposure to its active metabolite, N-CLB, in HVTs (3.4 fold) and patients (2.6 fold). Conversely, concomitant CLB increased CBD (by 30%) and its active metabolite, 7-OH-CBD (by 47%). Concomitant CBD had no effect on VPA, or 4-ene-VPA, and slightly increased exposure to STP (by 55%). Concomitant VPA or STP did not alter CBD or its metabolites. CBD had no effect on MDZ clearance. CBD demonstrated a safety profile consistent with previous randomised placebo-controlled trials. Conclusions: Combination of CBD with CLB resulted in a bidirectional DDI that increased levels of active metabolites of both compounds. There was no evidence of DDI between CBD and VPA, or any effect of CBD on CYP3A4 activity (MDZ). The slight increase of exposure to STP when coadministered with CBD is not expected to result in a clinically important DDI. Disclosure: Dr. Szaflarski has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SAGE Therapeutics Inc., GW Pharmaceuticals Inc., NeuroPace, Inc., Upsher-Smith Laboratories, Inc., Medical Association of the State of AL, SK LifeSciences Inc., Serina Therapeutics Inc., LivaNova Inc., Lundbeck, and Elite Medical Experts LLC. Dr. Szaflarski has received personal compensation in an editorial capacity Epilepsy \u0026 Behavior, Journal of Epileptology, Restorative Neurology and Neuroscience, Journal of Medical Science, Epilepsy Currents, and Folia Medica Copernicana. Dr. Szaflarski has received research support from NIH, NSF, Shor Foundation for Epilepsy Research, Department of Defense, UCB Biosciences, NeuroPace Inc., SAGE Therapeutics Inc., Serina Therapeutics Inc., Greenwich Biosciences Inc., State of AL, Biogen Inc., and Eisai Inc. Dr. Patsalos has received personal compensation in an editorial capacity for Epilepsia and Therapeutic Drug Monitoring. Dr. Gidal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai, Sunovion, UCB Pharma, and Lundbeck, Upsher-Smith and GW Pharmaceuticals. Dr. VanLandingham has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Greenwich Biosciences Inc. Dr. Critchley has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Research Ltd. Dr. Morrison has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Research Ltd.