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Abstract Details

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
Epilepsy/Clinical Neurophysiology (EEG)
S3 - Epilepsy/Clinical Neurophysiology (EEG) I (1:22 PM-1:33 PM)
003

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.

To summarise current understanding of DDIs when CBD is coadministered with CLB, VPA, STP or CYP3A4 substrate.

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.

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.

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.

Authors/Disclosures
Jerzy P. Szaflarski, MD, PhD, FAAN (University of Alabama At Birmingham)
PRESENTER
Dr. Szaflarski has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB Pharma. Dr. Szaflarski has received personal compensation in the range of $500-$4,999 for serving as a Consultant for LivaNova Inc. Dr. Szaflarski has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PureTech Health. Dr. Szaflarski has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Gidley, Sarli & Marusak, LLP. Dr. Szaflarski has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Szaflarski has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Law Firm. Dr. Szaflarski has stock in AdCel Biopharma, LLC. Dr. Szaflarski has stock in iFovea.
No disclosure on file
Barry E. Gidal, PhD Dr. Gidal has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eisai . Dr. Gidal has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Greenwich. Dr. Gidal has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for SK life sciences . Dr. Gidal has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Dr. Gidal has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for SK life science .
Kevan E. VanLandingham, MD, PhD, FAAN (US Food and Drug Administration) Dr. VanLandingham has received personal compensation for serving as an employee of Greenwich Biosciences. Dr. VanLandingham has received stock or an ownership interest from Greenwich Biosciences.
No disclosure on file
No disclosure on file