A Phase 1 Open‐Label, Fixed‐Sequence Pharmacokinetic Drug Interaction Trial to Investigate the Effect of Cannabidiol on the CYP1A2 Probe Caffeine in Healthy Subjects. Issue 11 (5th May 2021)

• Record Type: Journal Article
• Authors: Thai, Ching; Tayo, Bola; Critchley, David
• Is Part Of: Clinical pharmacology in drug development. Volume 10:Issue 11(2021)
• Page Start: 1279
• Page End: 1289
• Publication Date: 2021-05-05
• Subjects: cannabinoid -- cannabidiol -- caffeine -- pharmacokinetics; Drugs -- Testing -- Periodicals; Drug development -- Periodicals; Clinical pharmacology -- Periodicals; 615.580724
• DOI: 10.1002/cpdd.950
• Languages: English
• ISSNs: 2160-7648

Abstract

Abstract: This pharmacokinetic (PK) drug‐interaction trial investigated the effects of repeated dosing of a plant‐derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the United States and Epidyolex in Europe; 100 mg/mL oral solution) on caffeine clearance via modulation of cytochrome P450 (CYP) 1A2 activity in healthy adults. In this phase 1 open‐label, fixed‐sequence trial, all subjects received a single 200 mg caffeine dose and placebo on day 1. Subjects then titrated CBD from 250 mg once daily to 750 mg twice daily between days 3 and 11 and took 750 mg CBD twice daily between days 12 and 27. On day 26, subjects received a single 200‐mg caffeine dose with their morning CBD dose. Plasma concentrations of caffeine and its CYP1A2‐mediated metabolite, paraxanthine, were determined on days 1 and 26 and PK parameters derived using noncompartmental analysis. Safety was monitored throughout. Sixteen subjects enrolled, and 9 completed treatment. When caffeine was administered with steady‐state CBD, caffeine exposure increased by 15% for Cmax and 95% for AUC0‐∞, tmax increased from 1.5 to 3.0 hours, and t1/2 increased from 5.4 to 10.9 hours compared with caffeine administered with placebo. Under the same conditions, paraxanthine exposure decreased by 22% for Cmax and increased by 18% for AUC0‐∞, tmax increased from 8.0 to 14.0 hours, and t1/2 increased from 7.2 to 13.7 hours. Overall, there were no unexpected adverse events; diarrhea was most common, and 6 subjects discontinued because of elevated liver transaminases. These data suggest that CBD is an inhibitor of CYP1A2.