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

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

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).

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / adverse effects*
  • Anticonvulsants / blood*
  • Cannabidiol / administration & dosage
  • Cannabidiol / adverse effects*
  • Cannabidiol / blood*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Drug Resistant Epilepsy / blood
  • Drug Resistant Epilepsy / drug therapy*
  • Drug Therapy, Combination
  • Humans
  • Infant
  • Treatment Outcome

Substances

  • Anticonvulsants
  • Cannabidiol

Associated data

  • ClinicalTrials.gov/NCT02324673