Abstracts

Rationale: Studies have shown that Cannabidiol (CBD) can reduce seizures in children with epilepsy; however, a lack of pharmacokinetic data of Cannabis Herbal Extracts (CHE) in the pediatric population prevents dosage recommendations. We present the preliminary data of six participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial in which participants receive a CHE preparation of 1:20 9-tetrahydrocannabinol (9-THC):CBD. In total, 28 children aged 1-10 years with refractory epileptic encephalopathy are recruited from four Canadian cities.The primary objectives are to determine the 1:20 CHE’s tolerability and efficacy on seizure burden. Secondary objectives are to determine the relation between CHE’s dose escalation and steady state trough levels of bioactive cannabinoids and CHE’s effect on steady-state levels of anticonvulsant medications. Upon enrollment, participants continue their current anticonvulsant regimen and receive their first dose of CHE. The dosage of CHE is escalated in monthly intervals with 2-3, 5-6, 8-9 and 10-12 mg/kg/day of CBD, after which the CHE is discontinued over three weeks. The participants then return for a final visit one week afterwards. Seizure frequency is monitored in daily logs. In subsequent visits, the participants undergo physical examination, EEG monitoring, and trough serum levels (CSS,Min) of cannabinoids and anticonvulsants. Caregivers complete modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating. CBD, ?9-THC, and cannabichromene (CBC) and selected metabolites are quantified using tandem liquid chromatography/mass spectroscopy. Results: All six participants tolerated the CHE up to 10-12 mg/kg/day without any major adverse events. All participants had improvements in seizure frequency, QOLCE and EEG rating scores- with three participants showing continued improvements in these measures after CHE was discontinued. C_SS,Min data for CBD, D⁹-THC, and CBC showed linear dose independent pharmacokinetics in all but one participant. In most participants, C_SS,Min levels of D⁹-THC remained lower than what would be expected to cause intoxication even at the maximum dose of CHE.  Conclusions: The preliminary data suggest an effective and well-tolerated CBD target dose of 8-9 mg/kg/day is safe when a 1:20 D⁹-THC:CBD CHE is used.  Serum concentration of CBD follows dose-independent linear pharmacokinetics for most participants, although non-linear pharmacokinetics might occur but requires confirmation. Continued improvement in seizure frequency and QOLCE following the discontinuation of CHE suggest a possible enduring anticonvulsant effect. Funding: Saskatchewan Health Research FoundationJim Pattison Children’s Hospital FoundationThe Durwood Seafoot EstateThe Savoy Foundation