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In children with Dravet syndrome, short-term exposure to purified cannabidiol (CBD) is safe and well tolerated overall, despite being associated with a greater number of adverse effects than placebo, according to a randomized trial published in Neurology.
Investigators randomly assigned pediatric patients (age 4-10 years) to receive either twice-daily 5, 10, or 20 mg/kg/day CBD (n=27) or placebo (n=7). The double-blind phase of the study consisted of a 4-week baseline period, 3-week treatment period, 10-day taper, and 4-week follow-up. The 32 patients who completed treatment were invited to continue in the open-label extension study.
On the first day of dosing and at the end of treatment, investigators obtained pharmacokinetic blood samples to measure CBD levels as well as levels of antiepileptic drugs. Investigators also assessed safety outcomes using clinical laboratory tests, physical examinations, vital signs, and electrocardiograms.
Exposure to both CBD and its metabolites (ie, 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD) was found to be dose proportional (area under the curve0-t). The most prevalent circulating metabolite when concentrations of 6-OH-CBD were <10% of CBD was 7-COOH-CBD. There was no significant effect of CBD on concomitant antiepileptic drug levels, despite there being an increase in N-desmethylclobazam.
The placebo group and all CBD dosing groups reported treatment-emergent adverse events (placebo [86%], CBD 5 mg/kg/day [80%], 10 mg/kg/ day [63%], 20 mg/kg/day [78%]). According to the pooled analysis of all CBD dosing groups, the most common adverse events occurring in ≥3 patients included abnormal behavior, ataxia, decreased appetite, pyrexia, sedation, somnolence, and vomiting.
Because of the small size of the study sample, the findings may be limited to this patient population and may be hard to generalize across all pediatric patients with Dravet syndrome.
The findings that CBD and its metabolites showed no interaction with antiepileptic drugs except for the N-desmethylclobazam elevation possibly reflects “prior saturation and inhibition of the CYP2C19 isoenzyme” in these patients.
Reference
Devinsky O, Patel AD, Thiele EA; for the GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome [published online April 3, 2018]. Neurology. doi: 10.1212/WNL.0000000000005254
