A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects
Morrison et al.·Clinical Pharmacology in Drug Development
CBD markedly increased N-desmethylclobazam exposure (3,4-fold) and moderately affected stiripentol, while valproate and CBD showed no clinically relevant mutual interaction.
Summary
Phase 1 DDI study (healthy subjects): CBD (GW formulation, Epidiolex) inhibits CYP3A4/2C19 — N-desmethylclobazam exposure increased 3,4-fold with concomitant clobazam; stiripentol AUC increased 1,6-fold; no clinically relevant effect on valproate. Stiripentol decreased 7-OH-CBD exposure by 29%. No deaths, no serious adverse reactions; CBD moderately tolerable with all comedications.
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PopulationHealthy subjects in an open-label phase 1 drug interaction study, n not explicitly stated in the abstract
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InterventionHighly purified CBD (oral GW Pharmaceuticals preparation) in combination with clobazam, stiripentol or valproate
O
OutcomeCBD had little effect on clobazam exposure (Cmax/AUC 1,2-fold), increased N-desmethylclobazam (3,4-fold), stiripentol slightly (Cmax 1,3-fold, AUC 1,6-fold); no clinically relevant effect on valproate. Clobazam increased 7-OH-CBD (Cmax 1,7-fold, AUC 1,5-fold); stiripentol decreased 7-OH-CBD by 29%; valproate had no effect on CBD metabolites.
Confidence in the evidence
Very lowLowModerateHigh
Moderate
The third of four GRADE levels, the effect estimate is probably reliable.
GW Pharmaceuticals' formulation of highly purified cannabidiol oral solution is approved in the United States for seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure (maximum concentration [C<sub>max</sub> ] and area under the concentration-time curve [AUC], 1.2-fold), N-desmethylclobazam exposure increased (C<sub>max</sub> and AUC, 3.4-fold), stiripentol exposure increased slightly (C<sub>max</sub> , 1.3-fold; AUC, 1.6-fold), while no clinically relevant effect on valproate exposure was observed. Concomitant clobazam with cannabidiol increased 7-OH-CBD exposure (C<sub>max</sub> , 1.7-fold; AUC, 1.5-fold), without notable 7-COOH-CBD or cannabidiol increases. Stiripentol decreased 7-OH-CBD exposure by 29% and 7-COOH-CBD exposure by 13%. There was no effect of valproate on cannabidiol or its metabolites. Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate. There were no deaths, serious adverse events, pregnancies, or other clinically significant safety findings.