Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome

Abstract

Objective: To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome.

Methods: Patients aged 4-10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality.

Results: Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose-proportional (AUC_0-t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed.

Conclusions: Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated.

Classification of evidence: This study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.

Figure 1. Disposition of patients

There was a delay of ≥23 weeks between treatment completion and when the open-label extension trial was available for enrollment. All pharmacokinetic analyses were conducted using the safety analysis set. CBD = cannabidiol.

Figure 2. Plasma pharmacokinetics (PK) of cannabidiol (CBD) and metabolites

(A) Arithmetic mean plasma concentrations of CBD, 6-hydroxy-cannabidiol (6-OH-CBD), and 7-carboxy-cannabidiol (7-COOH-CBD) over time at baseline (day 1) and end of treatment (day 22). Note that the day 1 dose was 1.25 mg/kg for all 3 treatment groups. (B) Dose linearity for CBD, 6-OH-CBD, and 7-COOH-CBD exposures (based on area under the curve [AUC]_0–t) at end of treatment (day 22). Qualitative data generated for the 7-OH-CBD metabolite also showed a dose-proportional increase. R² values relate to geometric mean fitted regression lines.

Figure 3. Percentage change from baseline to end of treatment in plasma clobazam (CLB) and N-desmethylclobazam (N-CLB) concentrations

(A) By treatment group. Note that 2 patients in the 5 mg/kg/d cannabidiol (CBD) group reduced CLB dose during treatment, but no reason was listed. (B) By stiripentol use in all patients on CBD. Error bars: SEM.