A Phase 2, Double-Blind, Placebo-Controlled Trial to Investigate Potential Drug-Drug Interactions Between Cannabidiol and Clobazam

Abstract

We investigated the effects of cannabidiol (CBD; 21-day maintenance dose) on the pharmacokinetics (PK) of clobazam (CLB) and monitored the safety of CBD (or placebo) plus CLB in 20 patients with uncontrolled epilepsy on stable doses of CLB. Blood samples collected until 24 hours postdose were evaluated by liquid chromatography tandem mass spectrometry. PK parameters of CLB and major metabolite N-desmethylclobazam (N-CLB), valproic acid, stiripentol, levetiracetam, topiramate, plant-derived highly purified CBD (Epidiolex in the United States; 100 mg/mL oral solution) and its major metabolites were derived using noncompartmental analysis. There was no evidence of a drug-drug interaction (DDI) between CBD and CLB: geometric mean ratio (GMR) of day 33:day 1 CLB was 1.0 (90%CI, 0.8-1.2) for Cmax and 1.1 (90%CI, 0.9-1.2) for AUCtau . There was a significant DDI between CBD and N-CLB: the GMR of day 33:day 1 N-CLB was 2.2 (90%CI, 1.4-3.5) for Cmax and 2.6 (90%CI, 2.0-3.6) for AUCtau . Placebo had no effect on CLB or N-CLB; CBD had no effect on levetiracetam. Data were insufficient regarding DDIs with other antiepileptic drugs. The safety profile of CBD (20 mg/kg/day) with CLB was acceptable; all but 1 adverse events (AEs) were mild or moderate. One serious AE (seizure cluster) led to CBD discontinuation. One patient withdrew after intolerable AEs. Although there was no evidence of a CBD and CLB DDI, there was a significant DDI between CBD and N-CLB. The safety profile of GW Pharmaceuticals' CBD formulation with CLB was consistent with other GW-sponsored trials.

Trial registration: ClinicalTrials.gov NCT02565108.

Keywords: cannabidiol; cannabinoid; clobazam; drug; epilepsy; interaction.

Conflict of interest statement

K.V.L. is an employee of Greenwich Biosciences Inc. and owns share options in the company. J.C. and G.M. are employees of GW Research Ltd. and own share options in the company. L.T. was an employee of GW Research Ltd. when the trial was conducted.

© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

CONSORT flow chart of patient disposition. *Included all patients who received ≥1 dose of study drug and provided sufficient PK data to derive PK parameters at Day 1 or 2 and at Day 33 or 34. Six CBD patients and 1 placebo patient were excluded owing to: CBD and CLB dose modifications (2 CBD patients), CLB dose modification (1 CBD patient), discontinued trial before the last visit (1 CBD patient), CBD dosed at 10 mg/kg/day instead of 20 mg/kg/day (1 CBD patient), stopped taking CBD before the last visit (1 CBD patient), and study drug taken after predose sampling (1 placebo patient). AE, adverse event; bid., twice daily; CBD, cannabidiol; CLB, clobazam; PK, pharmacokinetics.

Figure 2

Mean (SD) (A) clobazam (CLB) and (B) N‐desmethylclobazam (N‐CLB) plasma concentrations versus time on Day 1 and Day 33 (linear scale; log‐linear scale values are shown in the insets) in the absence and presence of placebo or cannabidiol (CBD) coadministration; pharmacokinetics (PK) analysis set.