Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy

Abstract

Background: Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population.

Objective: The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy.

Methods: In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years).

Results: Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2-6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%).

Conclusions: Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated.

Trial registration: ClinicalTrials.gov (NCT02324673).

Conflict of interest statement

James W. Wheless reports that his institution received research funding from Acadia Pharmaceuticals Inc., GW Pharmaceuticals, plc., INSYS Development Company, Inc., LivaNova, Mallinckrodt, National Institutes of Health, Neurelis, Inc., NeuroPace, Inc., Shainberg Foundation, Upsher-Smith Laboratories, LLC, and Zogenix, Inc.; and has been a consultant and/or on speaker’s bureaus for CombiMatrix, Eisai Co., Ltd., GW Pharmaceuticals, plc., LivaNova, Lundbeck, Mallinckrodt, NeuroPace, Sun Pharmaceutical Industries, Ltd., Supernus Pharmaceuticals, Inc., and Upsher-Smith Laboratories, LLC. Dennis Dlugos reports that he received salary support from the National Institutes of Health, the Commonwealth of Pennsylvania Department of Health, and the Epilepsy Study Consortium, and he also received research program support for pre-study protocol development agreements with Bio-Pharm Solutions Inc., INSYS Development Company, Inc., and UCB, Inc. His institution received research support for clinical trials from INSYS Development Company, Inc. Ian Miller received honoraria and travel support from INSYS Development Company, Inc. and reports that his institution received study funding from INSYS Development Company, Inc. D. Alexander Oh was an employee of INSYS Development Company, Inc. and owns stock options for INSYS Development Company, Inc. Neha Parikh is an employee of INSYS Development Company, Inc. and owns stock options for INSYS Development Company, Inc. Steven Phillips reports that his institution received study funding from INSYS Development Company, Inc. J. Ben Renfroe reports that his institution received study funding from INSYS Development Company, Inc. Colin M. Roberts reports that his institution received study funding from INSYS Development Company, Inc. Isra Saeed reports that her institution received funding from INSYS Development Company, Inc. Steven P. Sparagana reports that his institution received study funding from INSYS Development Company, Inc. Jin Yu is an employee of INSYS Development Company, Inc. and owns stock options for INSYS Development Company, Inc. Maria Roberta Cilio reports that her institution received research support for clinical trials from INSYS Development Company, Inc; she also has been a consultant for BioMarin Pharmaceutical Inc., GW Pharmaceuticals plc., and Xenon Pharmaceuticals; and she received administrative support paid to her institution and drugs free of charge from GW Pharmaceuticals for previous studies.

Figures

Fig. 1

Study design. After screening period, patients were randomly assigned to three dosing cohorts of cannabidiol oral solution (cohort 1:10 mg/kg/day; cohort 2: 20 mg/kg/day; and cohort 3: 40 mg/kg/day). Patients received a single dose (5 mg/kg, 10 mg/kg, or 20 mg/kg, respectively) on day 1, and no drug was given on days 2 and 3. Patients received 5 mg/kg, 10 mg/kg, or 20 mg/kg twice daily (10 mg/kg/day, 20 mg/kg/day or 40 mg/kg/day, respectively) from day 4 to day 10

Fig. 2

Mean overall plasma cannabidiol concentration–time profile (semi-log scale) on day 10. Data shown are geometric means; error bars represent standard deviations

Fig. 3

Mean plasma cannabidiol concentration–time profile on multiple-dose on day 10 in a infants, b childrena, and c adolescents. Data shown are geometric means; error bars represent standard deviations. aFor cohort 2 (20 mg/kg/day), two children missed one or more doses between the evening of day 8 and assessment at day 9 and were not included in the analysis for this cohort