Cargando…
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
BACKGROUND: A 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. OBJECTIVE: This trial assessed the s...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223703/ https://www.ncbi.nlm.nih.gov/pubmed/30374683 http://dx.doi.org/10.1007/s40263-018-0578-5 |
_version_ | 1783369448606924800 |
---|---|
author | Taylor, Lesley Gidal, Barry Blakey, Graham Tayo, Bola Morrison, Gilmour |
author_facet | Taylor, Lesley Gidal, Barry Blakey, Graham Tayo, Bola Morrison, Gilmour |
author_sort | Taylor, Lesley |
collection | PubMed |
description | BACKGROUND: A 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. OBJECTIVE: This 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. METHODS: The 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. RESULTS: CBD 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 (t(max)) 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 (C(max)) and area under the plasma concentration-time curve from time zero to time t (AUC(t))] increased in a less than dose-proportional manner (C(max) slope 0.73; AUC(t) 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 C(max) and area under the plasma concentration-time curve over a dosing interval (AUC(τ)), 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. C(max) was 541.2 ng/mL and AUC(τ) was 3236 ng·h/mL after 1500 mg CBD twice daily. A high-fat meal increased CBD plasma exposure (C(max) and AUC(t)) by 4.85- and 4.2-fold, respectively; there was no effect of food on t(max) or terminal half-life. CONCLUSION: CBD 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. |
format | Online Article Text |
id | pubmed-6223703 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-62237032018-11-18 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 Taylor, Lesley Gidal, Barry Blakey, Graham Tayo, Bola Morrison, Gilmour CNS Drugs Original Research Article BACKGROUND: A 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. OBJECTIVE: This 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. METHODS: The 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. RESULTS: CBD 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 (t(max)) 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 (C(max)) and area under the plasma concentration-time curve from time zero to time t (AUC(t))] increased in a less than dose-proportional manner (C(max) slope 0.73; AUC(t) 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 C(max) and area under the plasma concentration-time curve over a dosing interval (AUC(τ)), 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. C(max) was 541.2 ng/mL and AUC(τ) was 3236 ng·h/mL after 1500 mg CBD twice daily. A high-fat meal increased CBD plasma exposure (C(max) and AUC(t)) by 4.85- and 4.2-fold, respectively; there was no effect of food on t(max) or terminal half-life. CONCLUSION: CBD 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. Springer International Publishing 2018-10-30 2018 /pmc/articles/PMC6223703/ /pubmed/30374683 http://dx.doi.org/10.1007/s40263-018-0578-5 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Research Article Taylor, Lesley Gidal, Barry Blakey, Graham Tayo, Bola Morrison, Gilmour 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223703/ https://www.ncbi.nlm.nih.gov/pubmed/30374683 http://dx.doi.org/10.1007/s40263-018-0578-5 |
work_keys_str_mv | AT taylorlesley aphaseirandomizeddoubleblindplacebocontrolledsingleascendingdosemultipledoseandfoodeffecttrialofthesafetytolerabilityandpharmacokineticsofhighlypurifiedcannabidiolinhealthysubjects AT gidalbarry aphaseirandomizeddoubleblindplacebocontrolledsingleascendingdosemultipledoseandfoodeffecttrialofthesafetytolerabilityandpharmacokineticsofhighlypurifiedcannabidiolinhealthysubjects AT blakeygraham aphaseirandomizeddoubleblindplacebocontrolledsingleascendingdosemultipledoseandfoodeffecttrialofthesafetytolerabilityandpharmacokineticsofhighlypurifiedcannabidiolinhealthysubjects AT tayobola aphaseirandomizeddoubleblindplacebocontrolledsingleascendingdosemultipledoseandfoodeffecttrialofthesafetytolerabilityandpharmacokineticsofhighlypurifiedcannabidiolinhealthysubjects AT morrisongilmour aphaseirandomizeddoubleblindplacebocontrolledsingleascendingdosemultipledoseandfoodeffecttrialofthesafetytolerabilityandpharmacokineticsofhighlypurifiedcannabidiolinhealthysubjects AT taylorlesley phaseirandomizeddoubleblindplacebocontrolledsingleascendingdosemultipledoseandfoodeffecttrialofthesafetytolerabilityandpharmacokineticsofhighlypurifiedcannabidiolinhealthysubjects AT gidalbarry phaseirandomizeddoubleblindplacebocontrolledsingleascendingdosemultipledoseandfoodeffecttrialofthesafetytolerabilityandpharmacokineticsofhighlypurifiedcannabidiolinhealthysubjects AT blakeygraham phaseirandomizeddoubleblindplacebocontrolledsingleascendingdosemultipledoseandfoodeffecttrialofthesafetytolerabilityandpharmacokineticsofhighlypurifiedcannabidiolinhealthysubjects AT tayobola phaseirandomizeddoubleblindplacebocontrolledsingleascendingdosemultipledoseandfoodeffecttrialofthesafetytolerabilityandpharmacokineticsofhighlypurifiedcannabidiolinhealthysubjects AT morrisongilmour phaseirandomizeddoubleblindplacebocontrolledsingleascendingdosemultipledoseandfoodeffecttrialofthesafetytolerabilityandpharmacokineticsofhighlypurifiedcannabidiolinhealthysubjects |