Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy

Abstract

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil‐based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3‐19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9‐6.2), 49.6 ng/mL (14.4‐302.0), and 226.3 ng ⋅ h/mL (70.5‐861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine‐CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.

Cannabidiol Impairs Brain Mitochondrial Metabolism and Neuronal Integrity

“… 49 Another study examined the pharmacokinetics of CBD in children with refractory epileptic encephalopathy. 50 Patients receiving 5.3–19.4 mg/kg/day had a mean (range) peak plasma concentration of 49.6 (14.4–302) ng/mL or 0.16 (0.04–0.96) μM.…”

Adverse Events of Cannabidiol Use in Patients With Epilepsy

“…After the removal of 1350 duplicate records, the remaining 1930 publications were screened, and 61 studies were selected for full-text review (Figure 1). Following the evaluation of these studies for eligibility, 52 were excluded for the following reasons: 48 studies were not RCTs, 2 did not report AEs, and 2 were reanalyses of previously published articles . Finally, a total of 9 articles met the eligibility criteria and were included in the qualitative and quantitative synthesis …”

Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

“…Endocannabinoids (eCBs) have also been shown capable of directly modifying Kv7 channel properties to regulate cell excitability ( Incontro et al., 2021 ; Larsson et al., 2020b ). Previous studies have established that CBD administered to subjects at 5–40 mg/kg/day produced peak plasma concentrations in the range of 0.29–1 μM ( Cáceres Guido et al., 2021 ; Hwang et al., 2021 ), while a 120 mg/kg oral dose in rats could reach 12.6 μg/mL brain (40 μM) concentration ( Deiana et al., 2012 ). We thus tested the effects of acute application of 1 μM CBD on the combination of Kv7.2mut + Kv7.2 wt + Kv7.3 subunits expressed in tsA-201 cells in the presence or absence of the combined CB1 blocker AM-251 (0.5 μM) and CB2 blocker SR 144528 (0.5 μM).…”