Abstracts

Rationale: CBD is being investigated for the treatment of severe epilepsy syndromes. While previous trials have not suggested an effect of oral CBD on cardiac repolarization, a formal assessment into CBD single therapeutic and supratherapeutic doses was conducted to elucidate whether CBD affects QTc. Methods: A randomized, double-blind, placebo (PBO)- and positive-controlled 4-way crossover study was conducted in healthy adults. Treatments were oral moxifloxacin 400 mg (MOX, positive control); CBD 750 mg (CBD750; therapeutic) or 4500 mg (CBD4500; supratherapeutic); or CBD-matched PBO during 4 successive treatment periods (washout of ≥10 d between periods). Subjects were randomized to 1 of 12 treatment sequences. Triplicate ECGs were from the continuous, 12-lead digital recording at -0.75, -0.5 and -0.25 hours (h) predose for construction of a baseline, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18 and 23 h postdose. Pharmacokinetic (PK) and pharmacodynamic (PD) analyses included plasma concentrations of CBD and its metabolites. Plasma PK parameters were estimated using noncompartmental analysis; PK-PD analyses used a linear mixed-effects modeling approach. Four timepoints (1, 2, 3, and 4 h) were prespecified for demonstration of assay sensitivity. The primary objective was to assess the effect of single therapeutic and supratherapeutic CBD doses on the QT interval corrected for HR using the Fridericia method (QTcF). Results: Fifty subjects (22 male; mean age 33 y) were enrolled. All received PBO and MOX; 98% CBD750; and 96% CBD4500. All completed Period 1; 98% Period 2; 96% Periods 3 and 4. Two withdrew. The trial was validated by expected change in QTc duration observed in the MOX group; for MOX, the lower limit of the 2-sided 90% CI for PBO-corrected change from baseline (CFB) in the primary endpoint, QTcF (??QTcF), was >5 ms at the 4 prespecified timepoints (Table 1). Neither CBD dose had an effect on cardiac repolarization; the upper bound of the 90% CI for ??QTcF for CBD was below 10 ms at all timepoints. CBD had no effect on cardiac repolarization based on other ECG parameters. Slopes for ??QTcF vs plasma concentrations of CBD and its major metabolites were flat, and the overall predicted PBO- and baseline-corrected value at Cmax for CBD4500 was −0.12 ms (1-sided 95% upper CI, 1.37 ms), suggesting no effect of CBD on cardiac repolarization. The time-averaged CFB was within 3.5 ms for QTcF in the PBO group, demonstrating good control of background variability. There was no effect on HR, or on either atrioventricular conduction or cardiac depolarization as measured by PR and QRS interval durations, respectively. Overall, 92% of patients reported an adverse event, all mild/moderate in severity. Diarrhea, headache, and nausea were most common; no deaths occurred. Conclusions: These results show that administration of single therapeutic and supratherapeutic doses of CBD had no effect on QTc or other ECG parameters and support existing data that CBD is generally well tolerated. Funding: GW Research Ltd