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      • Record: found
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      Is Open Access

      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome

      research-article
      Author(s): , MD , , MD, , MD, , MD, , MD, , MD, , PhD, , , MD, On behalf of the GWPCARE1 Part A Study Group
      Other contributor(s): (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab)
      Publication date PMC-release:
      Journal: Neurology
      Publisher: Lippincott Williams & Wilkins

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          Abstract

          Objective

          To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome.

          Methods

          Patients aged 4–10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality.

          Results

          Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose-proportional (AUC 0–t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed.

          Conclusions

          Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated.

          Classification of evidence

          This study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.

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          Most cited references9

          • Record: found
          • Abstract: not found
          • Article: not found

          Human cannabinoid pharmacokinetics.

          Marilyn A. Huestis (2007)
          Article 0 comments Cited 337 times – based on 0 reviews     Review now
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            Interactions between cannabidiol and commonly used antiepileptic drugs

            Tyler E. Gaston, E. Martina Bebin, Gary R Cutter … (2017)
            To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs.
            Article 0 comments Cited 122 times – based on 0 reviews     Review now
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              Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.

              Stephen M. Stout, Nina Cimino (2014)
              Exogenous cannabinoids are structurally and pharmacologically diverse compounds that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for these compounds to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clinical care and drug interactions. In vitro data were identified that characterize cytochrome P-450 (CYP-450) enzymes as potential significant contributors to the primary metabolism of several exogenous cannabinoids: tetrahydrocannabinol (THC; CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); cannabinol (CBN; CYPs 2C9, 3A4); JWH-018 (CYPs 1A2, 2C9); and AM2201 (CYPs 1A2, 2C9). CYP-450 enzymes may also contribute to the secondary metabolism of THC, and UDP-glucuronosyltransferases have been identified as capable of catalyzing both primary (CBD, CBN) and secondary (THC, JWH-018, JWH-073) cannabinoid metabolism. Clinical pharmacogenetic data further support CYP2C9 as a significant contributor to THC metabolism, and a pharmacokinetic interaction study using ketoconazole with oromucosal cannabis extract further supports CYP3A4 as a significant metabolic pathway for THC and CBD. However, the absence of interaction between CBD from oromucosal cannabis extract with omeprazole suggests a less significant role of CYP2C19 in CBD metabolism. Studies of THC, CBD, and CBN inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clinically significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb (marijuana) likely induces CYP1A2 mediated theophylline metabolism, although the role of cannabinoids specifically in eliciting this effect is questionable.
              Article 0 comments Cited 103 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Orrin Devinsky:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. Cognitive and Behavioral Neurology; Oxford University Press, 2002 Epilepsy: Patient and Family Guide, Demos Press, 2008 Alternative Therapies for Epilepsy, Demos Press, 2012 Epilepsy In Children, Demos Press, 2015

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other activities:

                1. Scientific Advisory Board for Pairnomix, Egg Rock, and Tilray. Principal Investigator, North American SUDEP Registry and Sudden Unexplained Childhood Death Registry and Research Collaborative

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. Ongoing Support NIH U01 NS090407 (PI: S. Lhatoo) 09/30/14 ? 7/31/2019 Center for SUDEP Research: Autonomic and Imaging Biomarkers of SUDEP The principal aim is to identify the central mechanisms and markers of autonomic and respiratory dysfunction that underlie the fatal scenario in SUDEP, and thus, provide insights into potential interventions. Role: Co-Investigator NIH U01 NS090415 (PIs: M. Thom, O. Devinsky) 9/30/14 ? 7/31/2019 Center for SUDEP Research: The Neuropathology of SUDEP: The central autonomic network, serotonin and adenosine The proposed studies will leverage the world?s largest collection of SUDEP brains to explore the role of specific histopathological and biomolecular abnormalities in the brain, focusing on critical brainstem regions and the neurotransmitters serotonin and adenosine. Role: PI National Center for Chronic Disease Prevention and Promotion U48 DP 005008-01S4 (PIs: T. Spruill, O. Devinsky) 9/1/2014 ? 8/31/2019 Managing Epilepsy Well: Adapting Project UPLIFT for Hispanic Adults with Epilepsy This project proposes to translate and culturally tailor Project UPLIFT for Hispanic patients, then test and disseminate the Spanish version. Project UPLIFT is an evidence-based intervention that incorporates cognitive behavioral and mindfulness techniques to reduce depression in adults with epilepsy. Role: Co-Investigator NIH R01 EB 018308 (PIs: K.T. Block, H. Chandarana) 9/1/2014 - 8/31/2019 Comprehensive Motion-Robust Pediatric MR Imaging Using Radial Acquisitions The proposed project aims to develop novel motion-robust magnetic resonance imaging techniques and evaluate them in clinical studies for imaging of pediatric patients with Tuberous Sclerosis. Role: Co-Investigator

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. Pairnomix - Stock Tilray - Stock Egg Rock - Stock Embrace - Stock Engage - Stock

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Anup D. Patel:
                Comment :

                Scientific Advisory Boards:

                1. 1. UCB Pharma

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. Book and Associate Editor for the Journal of Child Neurology

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. Consulting for Greenwich Biosciences, LivaNova, and Supernus

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. Greenwich Biosciences Brain Sentinel Upsher Smith Pharmaceuticals LivaNova

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. Pediatric Epilepsy Research Foundation (PERF) American Academy of Neurology (AAN)

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Elizabeth A. Thiele:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. funding for travel to international tuberous sclerosis research conference (from TS Alliance), and for travel to give talks at Australia TS conference (from TS Australia), and travel to cannabinoid meetings (from GW Pharma), and for travel to serve as faculty at the Penry epilepsy courses and Neuroresident scholar program.

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. Tuberous sclerosis text book, Libby, co-editor

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. 1. GW Pharma 2. Esai Pharmaceuticals 3. Novartis Pharmaceuticals 4. Zogenix pharmaceuticals 5. Aquestive pharmaceuticals

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. research grant from GW Pharma

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. Lennox Gastaut foundation

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Matthew H. Wong:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. GW Pharmaceuticals provided research support during the conduct of this study.

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Richard Appleton:
                Comment :

                Scientific Advisory Boards:

                1. SHIRE: Non-profit entity (April 2014) NOVARTIS: Advisory Board Member (Expert Opinion): single meeting and single honorarium received (June 2016) GW DSMC member: from 2016 and on-going; fees for work carried out for this work

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. EISAI: Single honorarium for a presentation at a satelllite symposium in a scientific meeting (January 2014)

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. a) 'Management of Brain-injured Children'; second edition; Oxford University Press; 2006 b) 'Epilepsy: The Facts'; third edition; Oxford University Press; 2009 c) 'Childhood Epilepsy: Management from Diagnosis to Remission'; Cambridge University Press; 2011

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. I am listed as an External Professional Advisor for the British Government's All-Party Healthcare Ombudsman regarding complaints from the British public about NHS treatments. This involves providing expert Reports which are remunerated at a fixed fee

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Cynthia L. Harden:
                Comment :

                Scientific Advisory Boards:

                1. I served as chairperson of the data safety monitoring board for the GW cannabidiol studies.

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. Royalties from Wiley and Up-to-date.

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Sam Greenwood:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. (1) GW Research Ltd, Medical Writer, 4

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. (1) GW Research Ltd, 2016 & 2017

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Gilmour Morrison:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. GW pharmaceuticals, Head of Clinical Pharmacology 2 years

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Kenneth Sommerville:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. 1-Greenwich Biosciences (US affiliate of GW Pharmaceuticals) 2-Vice President of Clinical Sciences 3-Since April of 2014

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. 1-Greenwich Biosciences (GW Pharmaceuticals) stock options exercised in May, 2017. 2-Plan to exercise remaining Greenwich Biosciences options in 1H18.

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Journal
                Journal ID (nlm-ta): Neurology
                Journal ID (iso-abbrev): Neurology
                Journal ID (hwp): neurology
                Journal ID (publisher-id): neur
                Journal ID (pmc): neurology
                Journal ID (publisher-id): NEUROLOGY
                Title: Neurology
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Print): 0028-3878
                ISSN (Electronic): 1526-632X
                Publication date (Print): 03 April 2018
                Publication date PMC-release: 03 April 2018
                Volume: 90
                Issue: 14
                Pages: e1204-e1211
                Affiliations
                From the NYU Comprehensive Epilepsy Center (O.D.), New York, NY;Nationwide Children's Hospital and the Ohio State University College of Medicine (A.D.P.), Columbus; Massachusetts General Hospital (E.A.T.), Boston; Wake Forest School of Medicine (M.H.W.), Winston-Salem, NC; Alder Hey Children's Health Park (R.A.), Liverpool, UK; Mount Sinai Health System (C.L.H.), New York, NY; GW Research Ltd. (S.G., G.M.), Cambridge, UK; and Greenwich Biosciences (K.S.), Carlsbad, CA.
                Author notes
                Correspondence Dr. Devinsky Od4@ 123456nyu.edu

                Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

                The Article Processing Charge was funded by Greenwich Biosciences, Inc.

                Coinvestigators are listed at links.lww.com/WNL/A307.

                Article
                Publisher ID: NEUROLOGY2017824698
                DOI: 10.1212/WNL.0000000000005254
                PMC ID: 5890607
                PubMed ID: 29540584
                SO-VID: 3ebe27b1-d213-433b-8e4a-45bb5115a242
                Copyright © Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                Date received : 30 May 2017
                Date accepted : 03 January 2018
                Categories
                Subject: 19
                Subject: 60
                Subject: 61
                Subject: 227
                Subject: Article
                Custom metadata
                STATUS ONLINE-ONLY
                OPEN-ACCESS TRUE
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