Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic
Encephalopathy : Preliminary Results of the CARE-E Study

Richard J. Huntsman, Richard Tang-Wai, Jane Alcorn, Stephanie Vuong, Bryan Acton1,5, Scott Corley, Robert Laprairie, Andrew W. Lyon, Simona Meier, Darrell D. Mousseau, Doris Newmeyer, Erin Prosser-Loose, Blair Seifert, Jose Tellez-Zenteno, Linda Huh, Edward Leung and Philippe Major

Frontiers in  Neurology, 2019, 10:716.

doi: 10.3389/fneur.2019.00716

 

Purpose : There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study.

Methods : The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 delta-9-tetrahydrocannabinol (THC): CBD up to 10–12mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css, Min) of selected cannabinoids were quantified.

Results : All seven participants tolerated the CHE up to 10–12mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS,Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS,Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS,Min levels of THC remained lower than what would be expected to cause intoxication.

Conclusion : The preliminary data suggest an initial CBD target dose of 5–6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.

Keywords : cannabidiol, delta-9-tetrahydrocannabinol, cannabis, epileptic encephalopathy, cannabinoid plasma levels

 

INTRODUCTION

Recent trials with pharmaceutical grade cannabidiol (CBD) or CBD-enriched Cannabis Herbal Extract (CHE) support CBD’s ability to reduce seizure frequency in children with intractable epilepsy, including those with epileptic encephalopathy (1– 5). Yet, there are significant knowledge gaps regarding the use of CBD and other cannabinoids in children, including the pharmacokinetics (PK), pharmacogenetics, and doseconcentration- effect relationships for these compounds (6).

The resultant inability to provide evidence-based dosing and therapeutic monitoring of Cannabis-based products in children, combined with concerns regarding potential intoxicant effects of 19 tetrahydro-cannabinol (THC), leads to a reluctance by many physicians to authorize CHE to these patients. The age related developmental changes that influence drug PK and pharmacodynamics (PD) complicate the development of appropriate dosing regimens for pediatric age groups (6). Without an understanding of dose concentration-effect relationship, a dosing regimen is largely empirical and/or anecdotal, and fraught with potential safety concerns. CARE-E is a multi-center, phase 1, open-label, dosage escalation study using a Health Canada approved and Good

Manufacturing Practices certified 1:20 THC:CBDCHE as adjunct therapy to treat children with epileptic encephalopathy. The primary objectives were to assess the safety and efficacy of CBD-enriched CHE, whereas secondary objectives included an analysis of trough steady state (CSS,Min) levels of CBD, THC, and cannabichromene (CBC); as well as an assessment of the correlation between cannabinoid levels and therapeutic effect. CBC levels were measured as the CHE used in this study contained 4% CBC by volume. We present results for seven CARE-E participants recruited at the University of Saskatchewan site.

METHODS

Trial Design
The study is a phase 1, open-label, dosage-escalation clinical trial in which participants receive a 1:20 THC:CBD CHE in twice daily dosing. Upon enrollment (Visit 1) participants continue their current anticonvulsant regimen and baseline seizure frequency is determined for 1 month. At Visit 2 CHE dosing is initiated with a CBD dose of 2–3 mg/kg/day. At Visits 3–5 the CHE is increased at 1-month intervals with CBD doses of 5–6mg/kg/day at Visit 3, 8–9 mg/kg/day at Visit 4, and 10–12 mg/kg/day at Visit 5. At Visit 6 the CHE is weaned over a 1-month period after which the participants have their end of study visit (Visit 7). Care-givers monitor and record seizure frequencies in daily seizure logs. The complete study design and methodology have been described previously (7).