Abstracts

Rationale: Cannabidiol (CBD) has demonstrated a potential benefit in reducing seizures in patients with treatment-resistant epilepsy.1-3 The primary objective of this study was to characterize the pharmacokinetics (PK) and short-term tolerability of CBD oral solution in pediatric patients with treatment-resistant seizures. Methods: This was a phase 1/2, open-label, multiple-ascending dose study designed to assess the PK and tolerability of pharmaceutical-grade synthetic CBD oral solution in pediatric patients aged 1 to 17 years with treatment-resistant epilepsy. After screening, each patient completed a 10-day treatment period, and a 7-day follow-up period. CBD oral solution was sequentially examined in 3-dose cohorts (10, 20, and 40 mg/kg/d). The PK profile was assessed by blood sampling for the measurement of CBD and 7-hydroxy (7-OH) CBD concentrations collected at prespecified timepoints. Safety monitoring was performed throughout the study and consisted of collection of adverse events (AEs), clinical laboratory values, ECG, vital signs, physical and neurological examinations, and qualitative assessments. Results: A total of 61 patients were enrolled, completed the study, and were included in the PK and safety analyses. Mean age was 7.6 years, 54.1% were male, and 82% and 88.5% were white and non-Hispanic, respectively. The PK results are shown in Table 1. Clobazam and cannabidiol showed a reciprocal drug-drug interaction leading to the increased mean exposures of both cannabidiol (~2.5-fold) and clobazam, as well as norclobazam (~3-fold) at the highest dose. The most common (≥5%) treatment-emergent adverse events (TEAEs) are shown in Table 2. Three serious TEAEs were reported. Of these, only one, a skin rash, was judged to be probably related to the study drug. This serious AE occurred on Day 10, the last study day. Conclusions: A thorough PK study was performed with pharmaceutical-grade synthetic CBD oral solution 10, 20, and 40 mg/kg/d. CBD levels on Day 10 increased proportionally with weight-based dosing across the cohorts. Steady-state level was reached within 2 to 6 days of repeat dosing with moderate accumulation in CBD exposures. Single and repeat administrations of CBD oral solution showed interindividual variability in systemic exposures. Doses up to 40 mg/kg/d were generally safe and well tolerated for the duration of the study.  In addition, concomitant use of clobazam and cannabidiol led to increased mean exposures of cannabidiol, clobazam, and norclobazam at the highest dose.References1. Cunha JM et al. Pharmacol. 1980;21:175-85.2. Devinsky O et al. Lancet Neurol. 2016;15:270-8.3. Devinsky O, et al. N Engl J Med. 2017;376:2011-20. Funding: This study was supported by INSYS Development Company, Inc.