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

Published on Apr 3, 2018in Neurology8.69
· DOI :10.1212/WNL.0000000000005254
Orrin Devinsky81
Estimated H-index: 81
,
Anup D. Patel12
Estimated H-index: 12
+ 6 AuthorsKenneth W. Sommerville8
Estimated H-index: 8
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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.
  • References (12)
  • Citations (41)
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References12
Newest
Published on Sep 1, 2017in Epilepsia5.56
Tyler E. Gaston6
Estimated H-index: 6
(UAB: University of Alabama at Birmingham),
E. Martina Bebin14
Estimated H-index: 14
(UAB: University of Alabama at Birmingham)
+ 2 AuthorsJerzy P. Szaflarski49
Estimated H-index: 49
(UAB: University of Alabama at Birmingham)
SummaryObjective 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. Methods In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to...
Published on May 25, 2017in The New England Journal of Medicine70.67
Orrin Devinsky81
Estimated H-index: 81
(NYU: New York University),
Jh Cross45
Estimated H-index: 45
(UCL: University College London)
+ 6 AuthorsStephen Wright7
Estimated H-index: 7
(GW Pharmaceuticals)
BackgroundThe Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or p...
Published on May 1, 2017in Epilepsy & Behavior2.38
Brooke K. O'Connell1
Estimated H-index: 1
,
David Gloss1
Estimated H-index: 1
,
Orrin Devinsky81
Estimated H-index: 81
Abstract Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD a...
Published on Jan 1, 2017in Journal of Child Neurology2.09
Jacqueline S. Gofshteyn4
Estimated H-index: 4
(Children's Hospital of Philadelphia),
Angus A. Wilfong19
Estimated H-index: 19
(Boston Children's Hospital)
+ 5 AuthorsEric D. Marsh24
Estimated H-index: 24
(UPenn: University of Pennsylvania)
Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy affecting normal children after a febrile illness. FIRES presents with an acute phase with super-refractory status epilepticus and all patients progress to a chronic phase with persistent refractory epilepsy. The typical outcome is severe encephalopathy or death. The authors present 7 children from 5 centers with FIRES who had not responded to antiepileptic drugs or other therapies who were given cannabadiol (Epidiolex...
Published on Oct 1, 2016in Epilepsia5.56
Evan J. Hess1
Estimated H-index: 1
(Harvard University),
Kirsten A. Moody1
Estimated H-index: 1
(Harvard University)
+ 5 AuthorsElizabeth A. Thiele47
Estimated H-index: 47
(Harvard University)
SummaryObjective Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seiz...
Published on Mar 1, 2016in Lancet Neurology28.75
Orrin Devinsky81
Estimated H-index: 81
(NYU: New York University),
Eric D. Marsh24
Estimated H-index: 24
(UPenn: University of Pennsylvania)
+ 19 AuthorsFrancis Filloux28
Estimated H-index: 28
(Primary Children's Hospital)
Summary Background Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods In this open-label trial, patients ...
Published on Sep 10, 2015in The New England Journal of Medicine70.67
Daniel Freidman25
Estimated H-index: 25
,
Orrin Devinsky81
Estimated H-index: 81
The pharmacologic and biochemical features of cannabinoids make them candidates for antiseizure medications. At this time, anecdotes have outstripped controlled clinical trials as sources of support for their clinical value.
Published on Aug 1, 2015in Epilepsia5.56
Alexandra L. Geffrey5
Estimated H-index: 5
(Harvard University),
Sarah F. Pollack5
Estimated H-index: 5
(Harvard University)
+ 1 AuthorsElizabeth A. Thiele47
Estimated H-index: 47
(Harvard University)
SummaryObjective Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug–drug interaction, which we evaluate in this article. Methods Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD unde...
Published on Jan 1, 2015in European Journal of Clinical Pharmacology2.77
Sachiyo Hashi7
Estimated H-index: 7
(Kyoto University),
Ikuko Yano16
Estimated H-index: 16
(Kyoto University)
+ 6 AuthorsKazuo Matsubara25
Estimated H-index: 25
(Kyoto University)
Purpose Clobazam (CLB) is metabolized by cytochrome P450 (CYP) 3A4 to yield N-desmethylclobazam (N-CLB), which is further inactivated by CYP2C19. The aim of this study was to retrospectively evaluate the relationship between CYP2C19 polymorphisms and the efficacy of low-dose, add-on CLB therapy in Japanese patients with epilepsy.
Published on Feb 1, 2014in Drug Metabolism Reviews4.70
Stephen M. Stout1
Estimated H-index: 1
,
Nina M. Cimino3
Estimated H-index: 3
(UMB: University of Maryland, Baltimore)
AbstractExogenous 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 potent...
Cited By41
Newest
Published on 2019in Neuropharmacology4.37
Katarzyna Socała10
Estimated H-index: 10
(UMCS: Maria Curie-Skłodowska University),
Elżbieta Wyska11
Estimated H-index: 11
(Jagiellonian University Medical College)
+ 2 AuthorsPiotr Wlaź22
Estimated H-index: 22
(UMCS: Maria Curie-Skłodowska University)
Abstract Cannabidiol and cannabidiol-enriched products have recently attracted much attention as an add-on therapy for epilepsy, especially drug-resistant seizures. It should be, however, remembered that concomitant use of cannabidiol and antiepileptic drugs may pose a risk of interactions between them. For this reason, the aim of our study was to assess the effect of cannabidiol on the activity of selected new antiepileptic drugs in the electrically-induced seizure models in mice. We studied th...
Joel Ehrenkranz1
Estimated H-index: 1
(University of Colorado Denver),
Michael Levine91
Estimated H-index: 91
(Children's Hospital of Philadelphia)
Published on May 1, 2019in Pharmacology & Therapeutics9.40
Yi Wang , Zhong Chen1
Estimated H-index: 1
(ZJU: Zhejiang University),
Zhong Chen
Abstract Epilepsy involves neuronal dysfunction at molecular, cellular, and circuit levels. The understanding of the mechanism of the epilepsies has advanced greatly in the last three decades, especially in terms of their cellular and molecular basis. However, despite the availability of ~30 anti-epileptic drugs (AEDs) with diverse molecular targets, there are still many challenges (e.g. drug resistance, side effects) in pharmacological treatment of epilepsies today. Because molecular mechanisms...
Published on Sep 1, 2019in Epilepsy & Behavior2.38
Pavel Klein16
Estimated H-index: 16
,
Dwain Tolbert6
Estimated H-index: 6
(Lundbeck),
Barry E. Gidal36
Estimated H-index: 36
(UW: University of Wisconsin-Madison)
Abstract Objective The goal of this study was to characterize the drug–drug interactions between clobazam and 2 antiseizure drugs, cannabidiol and stiripentol, for treatment of refractory seizures through the use of pharmacokinetic modeling. Methods A population pharmacokinetic/pharmacodynamic model was developed to characterize the combined effect of clobazam and its active metabolite, N-desmethylclobazam (i.e., N-clobazam), on seizure protection in patients with Lennox–Gastaut syndrome using d...
Published on 2019in Epilepsy & Behavior2.38
Tyler E. Gaston6
Estimated H-index: 6
(UAB: University of Alabama at Birmingham),
E. Martina Bebin14
Estimated H-index: 14
(UAB: University of Alabama at Birmingham)
+ 4 AuthorsJerzy P. Szaflarski49
Estimated H-index: 49
(UAB: University of Alabama at Birmingham)
Abstract Objective We have previously shown that cannabidiol (CBD; Epidiolex®) significantly affects levels of clobazam/N-desmethylclobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine. In the present study, we tested whether the presence of concomitant clobazam affected seizure frequency and severity (treatment response) 12 weeks after initiation of therapy with CBD in patients with treatment-resistant epilepsy (TRE). The secondary questions were whether the presence of any of the o...
Published on 2019in Drugs4.99
Valentina Franco12
Estimated H-index: 12
(UNIPV: University of Pavia),
Emilio Perucca79
Estimated H-index: 79
(UNIPV: University of Pavia)
Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome...
Published on May 1, 2019in Environmental Toxicology and Pharmacology3.06
Chen Xu (CAU: China Agricultural University), Tanran Chang + 3 AuthorsXiangdong Li
Abstract Cannabidiol (CBD) exhibits significant efficacy in mental and inflammatory diseases. Several studies have recently reported on the rapid antidepressant-like effects of CBD, suggesting that CBD is a potential anti-depressant or anti-stress drug. However, CBD is mainly administered orally or by inhalation with poor bioavailability, resulting in high costs. We aim to explore the efficacy of long-term periodic administration of CBD in chronic mild stress (CMS) via two routes and its pharmac...
Published on Jun 3, 2019in Expert Review of Clinical Pharmacology2.78
Peter Cogan1
Estimated H-index: 1
(Regis University),
Peter S. Cogan4
Estimated H-index: 4
(Regis University)
ABSTRACTIntroduction: In recent decades, federal legislation in the U.S. has recognized a new paradigm of pharmacotherapy in which ideology and popular demand, as opposed to sound clinical evidence, drives the marketing of ostensible herbal therapeutics as ‘dietary supplements’. This vogue of democratizing medicine has more recently manifested in the ongoing legalization of cannabis products at the state level, where an arbitrary variety of definitions, restrictions, and assumed therapeutic uses...