A Phase 2, Double-Blind, Placebo-Controlled Trial to Investigate Potential Drug-Drug Interactions Between Cannabidiol and
Kevan E. Van Landingham, MD, PhD1, Julie Crockett, PhD2, Lesley Taylor, PhD2*, and Gilmour Morrison, HND2
The Journal of Clinical Pharmacology, 2020, 0, (0), 1–10
Doi : 10.1002/jcph.1634
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.
Keywords : cannabinoid, cannabidiol, clobazam, drug, interaction, epilepsy
Highly purified cannabidiol (CBD) oral solution is approved for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome (DS) in patients ≥2 years of age1-6 and is available in the United States as Epidiolex and in Europe as Epidyolex, where it is used in conjunction with clobazam (CLB). Data from nonclinical studies and the scientific literature support at least 3 targets for the mechanism of anticonvulsant action of CBD: modulation of intracellular Ca2+ by antagonism of G-protein-coupled receptor 55 and desensitization of transient receptor potential vanilloid type 1 channels, and inhibition of adenosine reuptake via inhibition of the equilibrative nucleoside transporter 1.7-9 Importantly, CBD lacks detectable euphoric effects associated with a propensity for abuse because of limited or no interaction with the cannabinoid receptors, CB1 and CB2.10 CBD is extensively metabolized in the liver by cytochrome P450 (CYP) enzymes, mainly CYP2C19 and, to a lesser extent, CYP3A4.11,12 These CYP enzymes are induced by several antiepileptic drugs (AEDs) (eg, carbamazepine, topiramate, and phenytoin) and inhibited by others (eg, valproic acid [VPA]). CBD may also inhibit the CYP2C family of isozymes.12,13 In vivo data show that coadministration of CBD increases plasma concentrations of CYP2C19 substrates and may increase the risk of adverse reactions with these substrates.4 CLB is also extensively metabolized in the liver, mainly by CYP3A, with minor contributions from CYP2B6 and CYP2C19, resulting in formation of its active metabolite, N-desmethylclobazam (N-CLB). NCLB is then further metabolized by CYP2C19.14,15
Based on animal and in vitro receptor-binding data, the relative potency of N-CLB is estimated to be between one-fifth to equally as potent as CLB, and moderate-tostrong inhibitors of CYP2C19 may result in increased exposure to N-CLB.16 Indeed, several uncontrolled studies found that levels of N-CLB are increased by
CBD.17-19 As such, a formal assessment of any drugdrug interaction (DDI) between CBD and CLB (and N-CLB) in patients with epilepsy is important and of clinical interest.