A Phase 1, Open‐Label, Parallel‐Group, Single‐Dose Trial of the Pharmacokinetics and Safety of Cannabidiol (CBD) in Subjects With Mild to Severe Hepatic Impairment

Abstract

The pharmacokinetics and safety of a single oral dose of 200‐mg plant‐derived pharmaceutical formulation of highly purified cannabidiol (CBD) in oral solution (Epidiolex in the United States; 100 mg/mL) were assessed in subjects with mild to severe hepatic impairment (n =  8 each for mild and moderate, n = 6 for severe) relative to matched subjects with normal hepatic function (n = 8). Blood samples were collected until 48 hours after dosing and evaluated by liquid chromatography and tandem mass spectrometry. Pharmacokinetic parameters (primarily maximum measured plasma concentration, area under the plasma concentration–time curve from time zero to time t, area under the concentration‐time curve from time zero to infinity, time to maximum plasma concentration, and terminal half‐life) of CBD and its major metabolites were derived using non‐compartmental analysis. CBD was rapidly absorbed in all groups independent of hepatic function (median time to maximum plasma concentration, 2‐2.8 hours). Exposure (area under the concentration–time curve from time zero to infinity) to total CBD slightly increased in subjects with mild hepatic impairment (geometric mean ratio [GMR], 1.48; 90% confidence interval [CI], 0.90‐2.41). However, there were clinically relevant increases in subjects with moderate (GMR, 2.45; 90%CI, 1.50‐4.01) and severe (GMR, 5.15; 90%CI, 2.94‐9.00) hepatic impairment, relative to subjects with normal hepatic function. Exposure to the CBD metabolites (6‐hydroxy‐CBD and 7‐hydroxy‐CBD) also increased in subjects with moderate and severe hepatic impairment, but to a lesser extent than the parent drug. The 7‐carboxy‐CBD metabolite exposure was lower in subjects with severe hepatic impairment when compared with subjects with normal liver function. These findings indicate that dose modification is necessary in patients with moderate and severe hepatic impairment, and a lower starting dose and slower titration are necessary based on benefit‐risk. CBD was well tolerated, and there were no serious adverse events reported during the trial.