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.

A Phase 1, Randomised, Placebo-Controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Fed Healthy Volunteers

“…A limitation of this study is that it was performed in healthy volunteers rather than a patient cohort with the Table 5 Key pharmacokinetic parameters for the subjects Pharmacokinetic parameters were determined using Phoenix WinNonlin 8.0 AUC last area under the plasma concentration versus time curve from time zero to the last quantifiable concentration, AUC inf area under the plasma concentration versus time curve extrapolated to infinite time, C max maximum observed plasma concentration, CV coefficient of variance, GeoCV geometric mean coefficient of variance, GeoMean geometric mean, K el apparent terminal elimination rate constant, SD standard deviation, T 1/2 apparent terminal elimination half-life, T max time of maximum observed plasma concentration potential for drug-drug and drug-disease interactions. Two recent trials have documented clinically significant interactions with commonly prescribed antiepileptic drugs [15,30], while another study has reported that the metabolism of cannabidiol is significantly altered in patients with moderate or severe hepatic impairment [12]. Further limitations are that only plasma cannabidiol was measured, not its primary metabolites.…”

“…A limitation of this study is that it was performed in healthy volunteers rather than a patient cohort with the potential for drug–drug and drug–disease interactions. Two recent trials have documented clinically significant interactions with commonly prescribed antiepileptic drugs [ 15 , 30 ], while another study has reported that the metabolism of cannabidiol is significantly altered in patients with moderate or severe hepatic impairment [ 12 ]. Further limitations are that only plasma cannabidiol was measured, not its primary metabolites.…”

“…CBD 6α-hydroxylation is catalysed primarily by CYP3A4 and CYP2C19, while CBD 7-hydroxylation is catalysed mainly by CYP2C19 [13]. Other metabolic pathways include further CYP-mediated pathways (1A2, 2D6 and 2C914) and direct conjugations via uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes such as UGT1A7, UGT1A9 and UGT2B7 [12].…”

“…Cannabidiol is highly lipophilic (log P > 5) and subject to substantial first-pass metabolism; it has low bioavailability and around one-third of the dose is excreted unchanged in the faeces [ 12 ]. As is the case with most other cannabinoids, cannabidiol is metabolised in the liver, primarily by cytochrome P450.…”

Cannabidiol and Sports Performance: a Narrative Review of Relevant Evidence and Recommendations for Future Research

“…Cannabis has been prohibited in all sports during competition since the World Anti-Doping Agency first assumed the responsibility of establishing and maintaining the list of prohibited substances in sport 15 years ago [89]. In 2018, however, CBD was removed from the Prohibited List [199], presumably on the basis of mounting scientific evidence that the cannabinoid is safe and well-tolerated in humans [16,169], even at very high doses (e.g. 1500 mg•day −1 or as an acute dose of 6000 mg) [170].…”