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

James W. Wheless, · Dennis Dlugos, · Ian Miller, · D. Alexander Oh, · Neha Parikh, · Steven Phillips, ·
J. Ben Renfroe, · Colin M. Roberts, · Isra Saeed, · Steven P. Sparagana, · Jin Yu, · Maria Roberta Cilio, on behalf of the INS011-14-029 Study Investigators

CNS Drugs, 2019

https://doi.org/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).

 

Key Points

Data on the pharmacokinetics of cannabidiol in pediatric patients are lacking, and the proper dose for titration and optimization of safety is unclear.

Pharmaceutical-grade synthetic cannabidiol oral solution was generally safe and well tolerated; common adverse events were somnolence, anemia, and diarrhea. The study showed that systemic cannabidiol exposure generally increased linearly with increases in dose.

Close monitoring of plasma concentrations of antiepileptic drugs and their clinical effects may be needed in pediatric patients receiving clobazam concomitantly with cannabidiol, particularly at higher doses, as drug–drug interactions have been observed with increased exposure to cannabidiol, clobazam, and norclobazam.

1 Introduction

In the USA, the prevalence of epilepsy and seizure disorders in children has been estimated at 1% [1]. Currently, several non-pharmacologic interventions, such as resective surgery, dietary intervention (e.g., ketogenic diet), neurostimulation (e.g., vagus nerve stimulation or responsive neurostimulation), and pharmacologic therapies, are used to treat children with epilepsy [2, 3]. Despite the availability of several treatment options, a prospective observational study of 470 previously untreated children, adolescents, and adults with epilepsy showed that only 47% of patients had a response to initial monotherapy and only an additional 13% responded to a second monotherapy [4]. Of the 70 patients who received combination therapy, only 23% of patients who received two drugs were seizure free; further, no patients who received three drugs were free of seizures [4]. Therefore, there remains an unmet need for novel treatments.

Cannabidiol is a novel compound with central nervous system activity and, unlike other cannabinoids (e.g., tetrahydrocannabinol), produces no euphoria. Cannabidiol has a low affinity for the endogenous cannabinoid receptors and may modulate neuronal hyperexcitability through other mechanisms [5]. The possible mechanisms of anticonvulsive action include an anti-inflammatory effect on the nervous system, inverse agonism (or antagonism) at the cannabinoid receptors, modulation of neuronal channels, and enhancement of anandamide action [6–11]. Given these attributes, cannabidiol is being evaluated as a potential therapeutic option for several disorders, including seizures, chemotherapy – induced nausea and vomiting, spasticity, tics, posttraumatic stress disorder, and neuropathic pain, with seizures being, by far, the most frequently investigated condition [12, 13]. Indeed, previous studies have shown potential benefit of pure cannabidiol in decreasing the number of seizures in patients with treatment-resistant epilepsy associated with different forms of epilepsy, including Dravet syndrome and Lennox–Gastaut syndrome [14–19].

A highly purified plant-based form of oral cannabidiol formulation was approved by the US Food and Drug Administration in 2018 for the treatment of Dravet and Lennox Gastaut syndromes in patients aged ≥ 2 years [20]. Two randomized, phase III clinical trials in children, adolescents, and adults with Lennox–Gastaut syndrome demonstrated that plant-based cannabidiol decreased the monthly frequency of seizures [17, 19]. A clinical trial on the safety and pharmacokinetic (PK) parameters of cannabidiol (5- to 20-mg/kg/day doses) for the treatment of seizures in 34 children (aged 4–10 years) with Dravet syndrome reported common adverse events (AEs) of pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior in three or more patients at all doses tested [21]. Additional open-label studies have shown that cannabidiol was efficacious in decreasing median monthly seizure frequency in treatment-resistant epilepsies of multiple etiologies [18, 22].

Currently, there are still limited published data on the PK parameters and drug interactions related to cannabidiol use in the pediatric epilepsy population. The objective of this study was to characterize the PK parameters and short-term tolerability of pharmaceutical-grade synthetic cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy. The current study is the first to examine the synthetic cannabidiol formulation in humans.

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