Cannabidiol for treating drug‐resistant epilepsy in children: the New South Wales experience

Chen, Kerrie-Anne; Farrar, Michelle A.; Cardamone, Michael; Gill, Deepak; Smith, Robert L.; Cowell, Christopher T.; Truong, Linda; Lawson, John A.

doi:10.5694/mja18.00023

Cited by 35 publications

(43 citation statements)

References 12 publications

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“…[26][27][28] CBD has been shown to attenuate seizures in a mouse model of Dravet syndrome and reduce seizure frequency and severity in various acute seizure models. [12][13][14][15] In the present study we used various in vivo and in vitro approaches to explore pharmacodynamic and pharmacokinetic interactions between CBD and clobazam. Despite abundant evidence detailing the anticonvulsant efficacy of CBD, several commentators question CBD's intrinsic anticonvulsant activity and have attributed the positive trial outcomes to a pharmacokinetic interaction, where CBD simply increases the plasma levels and consequent efficacy of clobazam and its active metabolite, N-CLB.…”

Section: Discussionmentioning

confidence: 99%

“…Despite abundant evidence detailing the anticonvulsant efficacy of CBD, several commentators question CBD's intrinsic anticonvulsant activity and have attributed the positive trial outcomes to a pharmacokinetic interaction, where CBD simply increases the plasma levels and consequent efficacy of clobazam and its active metabolite, N-CLB. [12][13][14][15] In the present study we used various in vivo and in vitro approaches to explore pharmacodynamic and pharmacokinetic interactions between CBD and clobazam. We provide direct in vitro evidence that CBD potently inhibits the metabolism of clobazam and N-CLB mediated by human CYP3A4 and CYP2C19, respectively, and reproduce a robust pharmacokinetic interaction between CBD and clobazam in mice.…”

Section: Discussionmentioning

confidence: 99%

“…8 The adjunctive nature of CBD use in Dravet syndrome means that it is administered concomitantly with other AEDs. [12][13][14][15] The existing clinical studies were not specifically designed to test this hypothesis, which would require a group given CBD without any concomitant AEDs. 1 A drug-drug interaction between CBD and clobazam has been identified, where CBD increased plasma concentrations of both clobazam and its active metabolite, N-desmethylclobazam (N-CLB).…”

Section: Introductionmentioning

confidence: 99%

“…9,11 The pharmacokinetic interaction between CBD and clobazam has led to repeated suggestions that the anticonvulsant efficacy of CBD may be overstated and its efficacy is merely explained by CBD enhancing clobazam and N-CLB exposure. [12][13][14][15] The existing clinical studies were not specifically designed to test this hypothesis, which would require a group given CBD without any concomitant AEDs. Furthermore, the issue has not been solved by subgroup analyses of CBD efficacy in patients taking clobazam vs those who were not, as such analyses are confounded by a range of factors, including CBD having interactions with other AEDs that patients may have been administered.…”

Section: Introductionmentioning

confidence: 99%

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Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

et al. 2019

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Objective: Cannabidiol (CBD) has been approved by the US Food and DrugAdministration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. Methods: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a +/− mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a +/− mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA) A receptors to investigate the activity of GABA A receptors when treated with CBD and clobazam together. Results: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a +/− mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABA A receptor activation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

et al. 2019

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“…This issue of the MJA includes reports on the experiences of paediatric neurologists in New South Wales 3 and Victoria 4 who have trialled a 98% cannabidiol extract as an adjunct treatment for children with intractable epilepsy. Parents reported improvements in 12 of 20 children in Victoria and 12 of 40 in NSW; adverse events were also experienced by 16 and 15 children respectively, most frequently somnolence, nausea, and vomiting.…”

mentioning

confidence: 99%

The challenges in providing safe, effective, affordable cannabis‐based medicines for unapproved indications

Hall

Farrell

2018

Medical Journal of Australia

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Adverse Events of Cannabidiol Use in Patients With Epilepsy

et al. 2023

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ImportanceEpilepsy is one of the most common neurologic disorders globally. Cannabidiol (CBD) has been approved for the treatment of epilepsy, but its use has been associated with several different adverse events (AEs).ObjectiveTo investigate the frequency and risk of AEs developing in patients with epilepsy who are using CBD.Data SourcesPubMed, Scopus, Web of Science, and Google Scholar were searched for relevant studies published from database inception up to August 4, 2022. The search strategy included a combination of the following keywords: (cannabidiol OR epidiolex) AND (epilepsy OR seizures).Study SelectionThe review included all randomized clinical trials that investigated at least 1 AE from the use of CBD in patients with epilepsy.Data Extraction and SynthesisBasic information about each study was extracted. I2 statistics were calculated using Q statistics to assess the statistical heterogeneity among the included studies. A random-effects model was used in cases of substantial heterogeneity, and a fixed-effects model was used if the I2 statistic for the AEs was lower than 40%. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.Main Outcomes and MeasuresFrequency of each AE and risk of developing each AE in patients with epilepsy using CBD.ResultsNine studies were included. Overall incidences of 9.7% in the CBD group and 4.0% in the control group were found for any grade AEs. The overall risk ratios (RRs) for any grade and severe grade AEs were 1.12 (95% CI, 1.02-1.23) and 3.39 (95% CI, 1.42-8.09), respectively, for the CBD group compared with the control group. Compared with the control group, the CBD group had a greater risk for incidence of serious AEs (RR, 2.67; 95% CI, 1.83-3.88), AEs resulting in discontinuation (RR, 3.95; 95% CI, 1.86-8.37), and AEs resulting in dose reduction (RR, 9.87; 95% CI, 5.34-14.40). Because most of the included studies had some risk of bias (3 raised some concerns and 3 were at high risk of bias), these findings should be interpreted with some caution.Conclusions and RelevanceIn this systematic review and meta-analysis of clinical trials, the use of CBD to treat patients with epilepsy was associated with an increased risk of several AEs. Additional studies are needed to determine the safe and effective CBD dosage for treating epilepsy.

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Cannabidiol for treating drug‐resistant epilepsy in children: the New South Wales experience

Cited by 35 publications

References 12 publications

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

The challenges in providing safe, effective, affordable cannabis‐based medicines for unapproved indications

Adverse Events of Cannabidiol Use in Patients With Epilepsy

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