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CNS Drugs. 2019 Jun;33(6):593-604. doi: 10.1007/s40263-019-00624-4.

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

Author information

1
University of Tennessee Health Science Center, Le Bonheur Children's Hospital, Memphis, TN, USA.
2
Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
3
Nicklaus Children's Hospital, Miami, FL, USA.
4
INSYS Development Company, Inc., Chandler, AZ, USA.
5
Arena Pharmaceuticals, San Diego, CA, USA.
6
Mary Bridge Children's Neurology Clinic, Tacoma, WA, USA.
7
Child Neurology Center of Northwest Florida, Gulf Breeze, FL, USA.
8
Doernbecher Childhood Epilepsy Program, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.
9
UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.
10
Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
11
UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA. Roberta.Cilio@ucsf.edu.
12
Saint-Luc University Hospital, University of Louvain, Brussels, Belgium. Roberta.Cilio@ucsf.edu.

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).

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