Pharmacokinetic variability and use of therapeutic drug monitoring of cannabidiol in patients with refractory epilepsy.

Objective

Cannabidiol (CBD) (Epidyolex) is a new antiseizure medication (ASM) for rare and severe epileptic syndromes. We aimed to investigate the pharmacokinetic variability of CBD to elucidate relationships between doses, serum concentrations, metabolites, and biochemical markers of toxicity by using therapeutic drug monitoring (TDM) data.

Methods

Data on serum concentrations of all ASMs, CBD, and the active metabolite 7-hydroxy-cannabidiol (7-OH-CBD) were collected (January 2022 to June 2023) at the Section for Clinical Pharmacology, National Centre for Epilepsy, Oslo University Hospital.

Results

Data from 52 patients were included: 122 serum concentration measurements (1-7 per patient); 48% female, mean age 23 (range 3-55) years. At maintenance (n = 34), the mean daily dose was 535 (SD 224) mg, that is, 10.03 (standard deviation [SD] .49) mg/kg/day, serum concentration .26 (SD .14) for CBD and .13 (SD .10) μmol/L for 7-OH-CBD. Reference ranges of .15-.50 μmol/L for CBD and .04-.25 μmol/L for 7-OH-CBD are proposed, which included 80% of measurements. There was a linear correlation between CBD dose to concentration and CBD to CBD-7-OH concentrations (r2 = .39 and .38) (p < .05). The hepatic marker alanine aminotransferase (ALT) increased on average 37%, demonstrating a moderate effect on liver function. Intra-individual coefficients of variation (CVs) were 32% (SD 17) for CBD and 48% (SD 24) for 7-OH-CBD (n = 15, ≥3 measurements). Twenty different ASMs were used: clobazam (n = 24), valproate (n = 17), and stiripentol (n = 8) were most common. The mean concentration ratio of desmethyl-clobazam/clobazam increased by 140% (7.29-17.5; p < .05) but was variable, pointing to enzyme inhibition by CBD.

Significance

This observational study with TDM data revealed extensive pharmacokinetic variability of CBD in patients with refractory epilepsy. The results demonstrate the need for close follow-up and use of TDM, including biochemical markers of toxicity, for individualized treatment with CBD.

© 2025 International League Against Epilepsy.