Clinical implications of trials investigating drug‐drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs

Abstract

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/ Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

Time to onset of cannabidiol (CBD) treatment effect in Lennox–Gastaut syndrome: Analysis from two randomized controlled trials

“…Drug-drug interactions between CBD and other AEDs such as valproate and stiripentol are less notable and have been previously reviewed. 27 Although we could not investigate the effect of other AEDs on the onset of CBD treatment effect in this study, it is possible that interactions with other medications could affect the onset of both efficacy and AEs. In addition to the interactions with other AEDs, which may affect the timing of CBD treatment effect, there is an established food effect on CBD exposure, in which taking CBD with a high-fat meal leads to a four-to five-fold increase in exposure, with no notable effect on T max or terminal half-life.…”

Cannabidiol in Pharmacoresistant Epilepsy: Clinical Pharmacokinetic Data From an Expanded Access Program

“…CBD shows challenging pharmacokinetic characteristics, including very low and variable oral bioavailability and high drug-drug interaction potential ( Franco and Perucca, 2019 ; Landmark and Brandl, 2020 ; Lattanzi et al, 2020a ; Patsalos et al, 2020 ; Perucca and Bialer, 2020 ). Published data, mostly from healthy volunteers, show remarkable intersubject variability in CBD plasma concentrations after oral dosing ( Millar et al, 2019 ).…”

Selection of antiseizure medications for first add-on use: A consensus paper

“…Conversely, enzyme inhibition results in increased plasma concentration of the affected compound, potentially leading to manifestations of overdosage. Examples include the inhibition of lamotrigine metabolism by valproic acid [8], and the impairment of the clearance of norclobazam, the active metabolite of clobazam, by cannabidiol [24,25]. Clinically important ASM interactions can also occur at the site of action [10,26], examples being the synergistic therapeutic efficacy of the combination of valproic acid of lamotrigine [27], the loss of efficacy of brivaracetam added on to levetiracetam [28,29], and the enhanced risk of neurological adverse effects when using combinations of sodium channel blockers [30].…”