CBD showed no DDI with clobazam itself, but significantly increased the exposure of the metabolite N-desmethylclobazam by 2- to 2,6-fold.
Summary
Phase 2 RCT (n=20) on pharmacokinetic interaction of CBD (Epidiolex) with clobazam in epilepsy patients: no DDI between CBD and CLB (GMR Cmax=1,0; AUCtau=1,1; 90%CI 0,8–1,2 and 0,9–1,2 respectively), but significant DDI with N-desmethylclobazam (GMR Cmax=2,2, AUCtau=2,6; 90%CI 1,4–3,5 and 2,0–3,6 respectively). AEs predominantly mild to moderate; 1 serious AE (seizure cluster) led to CBD discontinuation.
P
PopulationPatients with uncontrolled epilepsy on stable clobazam therapy, n=20
OutcomeNo DDI between CBD and CLB (GMR C_max 1,0; 90% CI 0,8–1,2; AUC_tau 1,1; 90% CI 0,9–1,2); significant DDI between CBD and N-CLB (GMR C_max 2,2; 90% CI 1,4–3,5; AUC_tau 2,6; 90% CI 2,0–3,6)
Confidence in the evidence
Very lowLowModerateHigh
Moderate
The third of four GRADE levels, the effect estimate is probably reliable.
Downgraded for
Imprecision
Quality profile
Sample size★★★★★
BlindingDouble-blind
Effect sizeMixed
Citations / year★★★★★
Authors
VanLandingham KE, Crockett J, Taylor L, Morrison G.
<h4>Unlabelled</h4>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 C<sub>max</sub> and 1.1 (90%CI, 0.9-1.2) for AUC<sub>tau</sub> . 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 C<sub>max</sub> and 2.6 (90%CI, 2.0-3.6) for AUC<sub>tau</sub> . 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.