Cannabidiol

Absorption

Cannabidiol demonstrated an increase in exposure that was less than dose-proportional over the range of 5 to 25 mg/kg/day in patients.
Absorption
Cannabidiol has a time to maximum plasma concentration (Tmax) of 2.5 to 5 hours at steady state (Css).
Effect of Food
Coadministration of EPIDIOLEX (750 or 1500 mg) with a high-fat/high-calorie meal increased Cmax by 5‑fold, AUC by 4‑fold, and reduced the total variability, compared with the fasted state in healthy subjects [see Dosage and Administration (2.4)]. Coadministration of EPIDIOLEX with a low-fat/low-calorie meal increased Cmax and AUC by 4‑fold and 3‑fold, respectively. Furthermore, coadministration of EPIDIOLEX with bovine milk increased exposure by approximately 3‑fold for Cmax and 2.5‑fold for AUC. Coadministration of EPIDIOLEX with alcohol also caused increased exposure to cannabidiol, with 93% increased Cmax and 63% greater AUC.
Distribution
The apparent volume of distribution in healthy subjects was 20963 L to 42849 L. Protein binding of the cannabidiol and its metabolites was >94% in vitro.
Elimination
The half-life of cannabidiol in plasma was 56 to 61 hours after twice-daily dosing for 7 days in healthy subjects. The plasma clearance of cannabidiol following a single EPIDIOLEX 1500 mg dose (approximately equal to the 20 mg/kg/day dosage) is 1111 L/h.
Metabolism
Cannabidiol is metabolized in the liver and the gut (primarily in the liver) by CYP2C19 and CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms.
After repeat dosing, the active metabolite of cannabidiol, 7-OH-CBD, has a 38% lower AUC than the parent drug. The 7-OH-CBD metabolite is converted to 7‑COOH-CBD, which has an approximately 40‑fold higher AUC than the parent drug. Based on two mouse models of acute seizure, the 7-OH-CBD metabolite is anticonvulsant in both models and 7-COOH-CBD is anticonvulsant in one model. The relevance of these findings to human epilepsy is unknown.
Excretion
EPIDIOLEX is excreted in feces, with minor renal clearance.
Specific Populations
Patients with Hepatic Impairment
No effects on the exposures of cannabidiol or metabolite exposures were observed following administration of a single dose of EPIDIOLEX 200 mg in patients with mild (Child-Pugh A) hepatic impairment. Patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment had an approximately 2.5 to 5.2-fold higher AUC, compared with healthy subjects with normal hepatic function [see Dosage and Administration (2.6), Warnings and Precautions (5.1), and Use in Specific Populations (8.6)].
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Drug Interaction Studies with AEDs
Clobazam and Valproate
The interaction potential with other AEDs (clobazam and valproate) was evaluated in dedicated clinical studies following coadministration of EPIDIOLEX (750 mg twice daily in healthy subjects and 20 mg/kg/day in patients).
Coadministration with clobazam in healthy subjects increased the cannabidiol active metabolite 7-OH-CBD mean Cmax by 73% and AUC by 47%; and increased the clobazam active metabolite, N-desmethylclobazam, a substrate of CYP2C19, Cmax and AUC by approximately 3-fold, with no effect on clobazam levels [see Drug Interactions (7.2)].
When EPIDIOLEX was coadministered with valproate in healthy subjects, there was no effect on the systemic exposure to valproate. In a separate study in epilepsy patients investigating the effect of EPIDIOLEX on valproate exposure, there were decreases in both the plasma Cmax and AUC of valproate, which were not clinically relevant (approximately 17% and 21%, respectively), and a decrease in exposure of the putative hepatotoxic metabolite of valproate, 2‑propyl‑4‑pentanoic acid (approximately 28% and 33%, respectively).
In healthy subjects, coadministration with valproate resulted in no clinically relevant changes in exposure to cannabidiol or its major metabolites (cannabidiol Cmax decreased by 26%; 7‑OH‑CB …