A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects

Abstract

BackgroundA formal single ascending and multiple dose pharmacokinetic (PK) trial of cannabidiol (CBD) oral solution was required to determine the safety and tolerability of CBD, the maximum tolerated dose, and to examine the effect of food on CBD PK parameters.ObjectiveThis trial assessed the safety, tolerability and PK of CBD oral solution in healthy adult volunteers, as well as the effect of food on CBD PK parameters.MethodsThe study consisted of three arms: single ascending dose (1500, 3000, 4500 or 6000 mg CBD [n = 6 per group]/placebo [n = 8; 2 per CBD dose group]), multiple dose (750 or 1500 mg CBD [n = 9 per group]/placebo [n = 6; 3 per CBD dose group] twice daily), and food effect (1500 mg CBD single dose [n = 12]). All subjects completed all trial arms and were analyzed as planned.ResultsCBD was generally well tolerated. Diarrhea, nausea, headache, and somnolence were the most common adverse events (AEs) across all trial arms, with an increased incidence of some gastrointestinal and nervous system disorder AEs (most notably diarrhea and headache) apparent in subjects taking CBD compared with placebo. All AEs were of mild or moderate severity; none were severe or serious. There were no deaths or discontinuations in the trial. After single oral doses, CBD appeared rapidly in plasma; time to maximum plasma concentration (tmax) was approximately 4–5 h. The major circulating metabolite was 7-carboxy-CBD, then parent CBD, 7-hydroxy-CBD (active metabolite), and 6-hydroxy-CBD (a relatively minor metabolite). Plasma exposure to CBD [maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to time t (AUCt)] increased in a less than dose-proportional manner (Cmax slope 0.73; AUCt slope 0.64). Oral clearance of CBD was high (1111–1909 L/h) and apparent volume of distribution was large (20,963–42,849 L). CBD reached steady state after approximately 2 days, with moderate accumulation (1.8- to 2.6-fold) after 750 and 1500 mg CBD twice daily. After 7 days, a twofold increase in CBD dose resulted in 1.6- and 1.9-fold increases in geometric mean Cmax and area under the plasma concentration-time curve over a dosing interval (AUCτ), respectively. CBD elimination was multiphasic; the terminal elimination half-life was approximately 60 h after 750 and 1500 mg CBD twice daily; and effective half-life estimates ranged from 10 to 17 h. Cmax was 541.2 ng/mL and AUCτ was 3236 ng·h/mL after 1500 mg CBD twice daily. A high-fat meal increased CBD plasma exposure (Cmax and AUCt) by 4.85- and 4.2-fold, respectively; there was no effect of food on tmax or terminal half-life.ConclusionCBD was generally well tolerated. Most AEs were mild in severity; none were severe or serious. The safety and PK profile support twice-daily administration of CBD.

A Phase 1, Open‐Label, Pharmacokinetic Trial to Investigate Possible Drug‐Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects

“…With the exception of the higher incidence of rashes, the AE profile when cannabidiol was administered in combination with clobazam, stiripentol, or valproate is highly consistent with another cannabidiol trial in healthy volunteers and in recent phase 3 trials . In this healthy volunteer DDI trial, most AEs were mild, with 8 subjects reporting moderate and 2 reporting severe AEs.…”

Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy

“…CBD is reported to have a high apparent volume of distribution after oral dosing ( V / F ) ranging from 250 to 450 L/kg and a highly variable plasma oral clearance (CL/ F ) ranging from 533 to 3783 L/h . CBD half‐life ( t 1/2 ) ranges from 18 to 60 hours …”

“…Evidence exists for a large food effect with lower doses (approximately 40 mg single dose) of tetrahydrocannabinol (THC) and CBD (1:1) delivered as an oromucosal spray, resulting in a threefold higher C max and fivefold higher area‐under‐the‐concentration‐time curve (AUC 0‐∞ ) for fed compared to fasting states . A similar food effect for the currently approved FDA liquid formulation (Epidiolex) has also been reported . Liquid formulations are associated with a higher possibility of inconsistent dosing, which complicates the characterization of drug pharmacokinetics .…”

Model‐Based Analysis of Cannabidiol Dose‐Exposure Relationship and Bioavailability

“…Few descriptive PK parameters of CBD, such as area under the concentration‐time curve (AUC), maximum concentration (Cmax), and time of Cmax (Tmax), have been reported, and a large variation in PK parameters was found among the study subjects . The large variability was partly explained by feeding status, as food intake has been shown to delay Tmax and increase AUC and Cmax . The various dosage forms also resulted in different PK profiles; for example, smoking or vaping CBD results in a shorter Tmax compared with other dosage forms .…”

“…The various dosage forms also resulted in different PK profiles; for example, smoking or vaping CBD results in a shorter Tmax compared with other dosage forms . Additionally, other studies reported a less than proportional dose‐exposure relationship . The feeding status, dosage form, and dose contributed to CBD PK variability; however, their contributions were not well quantified.…”