Drug-drug Interaction Studies with Coadministration of Cannabidiol (CBD) and Clobazam, Valproate, Stiripentol or Midazolam in Healthy Volunteers and Adults with Epilepsy

Jerzy Szaflarski; Philip Patsalos; Barry Gidal; Kevan VanLandingham; David Critchley; Gilmour Morrison

doi:10.1055/s-0039-1698213

Neuropediatrics, Table of Contents

Neuropediatrics 2019; 50(S 02): S1-S55
DOI: 10.1055/s-0039-1698213

Poster Presentations

Poster Area GNP Epilepsy 1

Georg Thieme Verlag KG Stuttgart · New York

Drug-drug Interaction Studies with Coadministration of Cannabidiol (CBD) and Clobazam, Valproate, Stiripentol or Midazolam in Healthy Volunteers and Adults with Epilepsy

Authors

Jerzy Szaflarski

¹Department of Neurology and University of Alabama at Birmingham Epilepsy Center, University of Alabama at Birmingham, Department of Neurology, Birmingham, AL, United States
Philip Patsalos

²Institute of Neurology, University College London, Queen Square, Clinical Pharmacology, London, United Kingdom
Barry Gidal

³School of Pharmacy, University of Wisconsin-Madison, School of Pharmacy, Wisconsin-Madison, WI, United States
Kevan VanLandingham

⁴Greenwich Biosciences, Inc., Neurology, Carlsbad, CA, United States
David Critchley

⁵GW Research Ltd, Neurology, Cambridge, United Kingdom
Gilmour Morrison

⁵GW Research Ltd, Neurology, Cambridge, United Kingdom

Abstract

Full Text

Research Question: Drug-drug interaction studies (DDIs) between CBD and commonly used antiepileptic drugs (AEDs) are of clinical interest since it is anticipated that CBD will be used concomitantly with other AEDs. We present current understanding of DDIs when CBD is coadministered with clobazam (CLB), valproate (VPA), stiripentol (STP), or a CYP3A4 substrate.

Materials and Methods: Effects of multiple-dose CBD on steady-state pharmacokinetics (PK) of CLB, N-desmethyl clobazam (N-CLB), VPA, 2-propyl-4-pentenoic acid (4-ene-VPA), and STP, and multiple-dose CLB, VPA, and STP on steady-state PK of CBD and metabolites were evaluated in healthy volunteers. 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 healthy volunteers using midazolam (MDZ; 2.5 mg) as a probe. In all studies, GW Pharmaceuticals’ formulation of plant-derived highly purified CBD in oral solution (100 mg/mL) was uptitrated over 10 days to 750 mg twice daily in healthy volunteers (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 mean exposure (AUC) to its active metabolite, N-CLB, in healthy volunteers (3.4-fold) and patients (2.6-fold). Conversely, concomitant CLB increased CBD (by 30%) but predominantly its active metabolite, 7-OH-CBD (by 47%). Concomitant CBD had no effect on VPA or 4-ene-VPA and increased STP exposure (by 55%). Concomitant VPA or STP did not alter exposure to CBD or its metabolites. CBD had no effect on MDZ clearance. CBD demonstrated a safety profile consistent with previous randomised placebo-controlled trials.

Discussion and Conclusion: 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 enzyme activity (MDZ). The slight increase in exposure to STP when coadministered with CBD is not expected to be clinically important.

Funding: GW Research Ltd, Cambridge, UK.