Cannabidiol Elevates Mechanistic Target of Rapamycin Inhibitor Levels in Patients With Tuberous Sclerosis Complex

Ebrahimi‐Fakhari, Daniel; Agricola, Karen; Tudor, Cynthia; Krueger, Darcy A.; Franz, David Neal

doi:10.1016/j.pediatrneurol.2019.11.017

Cited by 49 publications

(38 citation statements)

References 15 publications

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“…Reports of pharmacokinetic interactions were identified between CBD and brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide (Table 1). Of these pharmacokinetic interactions, clobazam, its active metabolite (N-desmethylclobazam, N-CLB), brivaracetam and sirolimus/everolimus have been found to have their serum concentrations altered beyond the therapeutic range [12][13][14][15][16]. Furthermore, Gaston et al, 2019 questioned whether any interactions with rufinamide, eslicarbazepine, zonisamide or topiramate affect treatment response [17].…”

Section: Resultsmentioning

confidence: 99%

Interaction of cannabidiol with other antiseizure medications: A narrative review

Gilmartin

Dowd

Parker

et al. 2021

Seizure

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Cannabidiol is efficacious as an adjunctive treatment in children with epilepsy associated with Dravet and Lennox-Gastaut syndromes. As its role is currently adjunctive, we reviewed the interactions of cannabidiol with other antiseizure medications (ASMs). Methods: A search of Cochrane, Pubmed and Embase databases from January 2015 to April 2020 was performed. All original research papers discussing interactions between cannabidiol and ASMs were included. Bibliographies of review articles were searched to identify further papers. Adverse events and side effects were excluded. Results: Cannabidiol interacts with ASMs through both pharmacokinetic and pharmacodynamic mechanisms. Thirty studies were identified (eighteen observational cohort studies, two randomised-control trials, three case reports/series, three animal studies, two briefing reports, an analysis of cohort data and a clinical trial simulation). There is potential for pharmacokinetic interactions between CBD and brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide. Pharmacodynamic interactions were identified for clobazam, valproate and levetiracetam. An animal study identified that the brain concentration of ASMs may be altered while the serum concentration remains the same. Conclusion: Pharmacokinetic and pharmacodynamic interactions exist between cannabidiol and ASMs. The cytochrome p450 system in particular has been implicated in pharmacokinetic interactions, although not exclusively. The existing literature is limited for some ASMs by studies having relatively small cohorts. As increasing numbers of patients use cannabidiol, specialists need to monitor closely for interactions clinically and with blood levels when required.

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Section: Resultsmentioning

confidence: 99%

Interaction of cannabidiol with other antiseizure medications: A narrative review

Gilmartin

Dowd

Parker

et al. 2021

Seizure

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“…1). The included studies were randomized placebo-controlled trials [13,43,47], open-label interventional studies and their subgroup analyses [14, 15, 17, 18, 20-24, 26-30, 32, 34-38, 41, 42, 48-52], retrospective chart reviews [39,44,46], clinical series [19,40,53], and case reports [16,25,31,33,45,54]. The participants of the studies included patients of pediatric age [14-17, 19, 28, 30, 31, 40, 41, 45, 46, 50, 52, 53], adult age [25,32,33,36,47,48,51,54], and both pediatric and adult age [13, 18, 20-24, 26, 27, 29, 34, 35, 37-39, 42-44, 49].…”

Section: Resultsmentioning

confidence: 99%

“…Most studies aimed to assess the efficacy and safety of CBD treatment, and study endpoints included seizure frequency reduction, seizure response rate, seizure freedom, change in seizure severity, treatment discontinuation, and occurrence of adverse events. Eight studies were primarily aimed to describe pharmacokinetic analyses or drug-drug interactions between CBD and antiseizure or non-antiseizure medications [17,23,25,33,39,43,47,54]. Seven studies included cognitive and/or quality-of-life measures [20-22, 32, 36, 50, 51], and three mainly focused on functional brain imaging assessment [35,49,51].…”

Section: Resultsmentioning

confidence: 99%

Highly Purified Cannabidiol for Epilepsy Treatment: A Systematic Review of Epileptic Conditions Beyond Dravet Syndrome and Lennox–Gastaut Syndrome

et al. 2021

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Background Cannabidiol (CBD), which is one major constituent of the Cannabis sativa plant, has anti-seizure properties and does not produce euphoric or intrusive side effects. A plant-derived, highly purified CBD formulation with a known and constant composition has been approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. In the European Union, the drug has been authorized by the European Medicines Agency for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome, in conjunction with clobazam, and is under regulatory review for the treatment of seizures in patients with tuberous sclerosis complex. Objectives This systematic review aimed to summarize the currently available body of knowledge about the use of this US Food and Drug Administration/European Medicines Agency-approved oral formulation of pharmaceutical-grade CBD in patients with epileptic conditions, especially developmental and epileptic encephalopathies other than Dravet syndrome and Lennox-Gastaut syndrome. Methods The relevant studies were identified through MEDLINE and the US National Institutes of Health Clinical Trials Registry in October 2020. There were no date limitations or language restrictions. The following types of studies were included: clinical trials, cohorts, case-control, cross-sectional, clinical series, and case reports. Participants had to meet the following criteria: any sex, any ethnicity, any age, diagnosis of epilepsy, receiving plant-derived, highly purified (> 98% w/w) CBD in a sesame oil-based oral solution for the treatment of seizures. Data extracted from selected records included efficacy, tolerability, and safety outcomes. Results Five hundred and seventy records were identified by database and trial register searching. Fifty-seven studies were retrieved for detailed assessment, of which 42 were eventually included for the review. The participants of the studies included patients of both pediatric and adult age. Across the trials, purified CBD was administered at dosages up to 50 mg/ kg/day. In a randomized double-blind controlled trial in patients with tuberous sclerosis complex, CBD was associated with a significantly greater percent reduction in seizure frequency than placebo over the treatment period. Open-label studies suggested the effectiveness of CBD in the treatment of children and adults presenting with other epilepsy syndromes than those addressed by regulatory trials, including CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences. The most common adverse events observed during treatment with CBD included somnolence, decreased appetite, diarrhea, and increased serum aminotransferases. Conclusions The currently available data suggest that response to treatment with a highly purified, plant-derived CBD oilbased solution can be seen in patients across a broad range of epilepsy disorders and et...

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“…Metformin has the advantage of not interacting with the cytochrome p450 system and therefore it is unlikely to interfere with the metabolism of other mTOR inhibitors. For the same reason, and in contrast to the other mTOR inhibitors everolimus and rapamycin, the metabolism of metformin will not be disturbed by antiepileptic drugs such as cannabidiol or carbamazepine that many TSC patients may be taking [39].…”

Section: Discussionmentioning

confidence: 99%

The metformin in tuberous sclerosis (MiTS) study: A randomised double-blind placebo-controlled trial

et al. 2021

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Cannabidiol Elevates Mechanistic Target of Rapamycin Inhibitor Levels in Patients With Tuberous Sclerosis Complex

Cited by 49 publications

References 15 publications

Interaction of cannabidiol with other antiseizure medications: A narrative review

Interaction of cannabidiol with other antiseizure medications: A narrative review

Highly Purified Cannabidiol for Epilepsy Treatment: A Systematic Review of Epileptic Conditions Beyond Dravet Syndrome and Lennox–Gastaut Syndrome

The metformin in tuberous sclerosis (MiTS) study: A randomised double-blind placebo-controlled trial

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