Cannabidiol in Pharmacoresistant Epilepsy: Clinical Pharmacokinetic Data From an Expanded Access Program

Abstract

Background and Aim: Data on the clinical pharmacokinetics of cannabidiol (CBD) are scanty. We explored the effect of demographic and clinical variables on plasma concentrations of purified CBD in patients with Dravet (DS) and Lennox-Gastaut syndrome (LGS). Methods: The study design was an open, prospective, multicenter expanded access program (EAP). Venous blood samples were drawn from patients between 8 and 9 am, before the CBD morning dose, 12 h apart from the last evening dose, and then 2.5 h after their usual morning dose. Results: We collected 127 plasma samples (67-morning pre-dosing and 60 post-dosing) from 43 patients (24 females, 19 males), 27 with LGS and 16 with DS. Mean ± standard deviation age was 26 ± 15 years. Duration of CBD treatment averaged 4.2 ± 2.9 months at 13.2 ± 4.6 mg/kg/day. CBD median trough plasma concentration was 91 ng/ml; it doubled to 190 ng/ml 2.5 h post-dosing (p < 0.001). Cannabidiol trough plasma concentrations were linearly related to daily doses (r = 0.564, p < 0.001). Median trough CBD plasma concentration-to-weight-adjusted dose ratio (C/D) was 32% higher (p < 0.02) in plasma samples from subjects aged 18 and over than in those under 18. Sex and concomitant antiseizure medications (ASMs) were not associated with significant variations in CBD C/D, but caution is required due to the potential influence of confounders. Conclusion: These are the first data on CBD pharmacokinetics in children and adults with LGS or DS in a real-world setting. The most relevant finding was the higher CBD C/D in adults. In practice, reduced weight-normalized doses might be required with aging to achieve the same CBD plasma levels.

Keywords: Dravet syndrome; Lennox–Gastaut syndrome; antiseizure medication; cannabidiol; epilepsy; pharmacokinetics.

FIGURE 1

Correlation between cannabidiol trough plasma concentrations and related weight-adjusted daily doses (n = 67).

FIGURE 2

Intrasubject cannabidiol morning trough and 2.5 post-dosing plasma concentrations of cannabidiol (n = 60). Median values are represented by triangles.

FIGURE 3

Plasma concentration to weight-adjusted daily dose ratio of cannabidiol (C/D) from patients’ specimens (n) grouped by age (A) and sex (B). Box plots depict the range between the 25^th and 75^th percentiles of the data. The horizontal line marks the median value; capped bars indicate 10^th–90^th percentiles. Black circles represent outlying values. p, significance of comparison between age and sex groups by Mann-Whitney rank sum test; N.S., not significant (p ≥ 0.05).

FIGURE 4

Plasma concentration to weight-adjusted daily dose ratio of cannabidiol (C/D) from patients’ specimens (n) grouped by concomitant antiseizure medication (ASM): (A) patients not receiving strong inducers; (B) patients receiving strong inducers. Box plots depict the range between the 25^th and 75^th percentiles of the data. The horizontal line marks the median value; capped bars indicate 10^th–90^th percentiles. Black circles represent outlying values. p, significance of comparison between the two overall treatment groups by Mann-Whitney rank sum test; N.S., not significant (p ≥ 0.05). NotI/notInhib, not strong enzyme inducers/not inhibitors; I, strong enzyme inducers; Inhib, enzyme inhibitors.