Cannabidiol in Pharmacoresistant Epilepsy: Clinical Pharmacokinetic Data From an Expanded Access Program

Contin, Manuela; Sinaa, Mohamed; Santucci, Margherita; Lodi, Monica; Russo, Emilio; Mecarelli, Oriano

doi:10.3389/fphar.2021.637801

Cited by 23 publications

(26 citation statements)

References 24 publications

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“…During the follow-up period, 68.5% of the patients with at least 1 month of treatment remained on CBD, relatively in line with the other EAPs at 12 months (~60%) ( 11 ) and studies with no TREs (63–81%) ( 16 ). Bearing in mind the limitation of the low number of patients treated, we found that the retention rate for adults was significantly higher than that for pediatric patients; this parameter is not accompanied by a significant difference on seizures, but it is worth noting that in our ancillary study on CBD plasma concentrations, we observed that concentration/dose ratio is significantly lower in patients younger than 18 years ( 17 ). Also in this latter case, no correlation was found between dose, plasma concentration, and efficacy, and further studies are warranted to understand whether this low trough CBD concentration is meaningfully linked to efficacy and safety.…”

Section: Discussionmentioning

confidence: 64%

Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox–Gastaut Syndrome

et al. 2021

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Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox–Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period.Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline.Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite.Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.

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Section: Discussionmentioning

confidence: 64%

Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox–Gastaut Syndrome

et al. 2021

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“…Several trials have proved its effectiveness in DS and LGS patients ( Devinsky et al, 2017 ; Lattanzi et al, 2019 ; Verrotti and Striano 2021 ). A highly purified plant-based form of oral CBD formulation was approved by the Food and Drug Administration (FDA) in 2018 and the European Medicines Agency (EMA) in 2019 for the treatment of seizures associated with DS and LGS ( Contin et al, 2021 ). Cenobamate, a novel tetrazole-derived carbamate compound, has been recently approved in the United States for the treatment of partial-onset seizures in adult patients [Keam 2020] ( Löscher et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Improving Therapy of Pharmacoresistant Epilepsies: The Role of Fenfluramine

et al. 2022

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Epilepsy is among the most common neurological chronic disorders, with a prevalence of 0.5–1%. Despite the introduction of new antiepileptic drugs during recent years, about one third of the epileptic population remain drug-resistant. Hence, especially in the pediatric population limited by different pharmacokinetics and pharmacodynamics and by ethical and regulatory issues it is needed to identify new therapeutic resources. New molecules initially used with other therapeutic indications, such as fenfluramine, are being considered for the treatment of pharmacoresistant epilepsies, including Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). Drug-refractory seizures are a hallmark of both these conditions and their treatment remains a major challenge. Fenfluramine is an amphetamine derivative that was previously approved as a weight loss drug and later withdrawn when major cardiac adverse events were reported. However, a new role of fenfluramine has emerged in recent years. Indeed, fenfluramine has proved to be a promising antiepileptic drug with a favorable risk–benefit profile for the treatment of DS, LGS and possibly other drug-resistant epileptic syndromes. The mechanism by which fenfluramine provide an antiepileptic action is not fully understood but it seems to go beyond its pro-serotoninergic activity. This review aims to provide a comprehensive analysis of the literature, including ongoing trials, regarding the efficacy and safety of fenfluramine as adjunctive treatment of pharmacoresistant epilepsies.

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“…In any case, these findings should be taken with caution due to the limited number of patients and the high intersubject variability in CB's plasma concentrations at a given dose, observed both with Sativex® and Bediol®. Many factors can contribute to this generally recognized variability, such as subject characteristics (i.e., age, body composition) ( 31 , 32 ), drug peculiar pharmacokinetics ( 15 , 24 ), pharmaceutical characteristics (i.e., poor CB's recovery in oils and variable stability over time) ( 33 , 34 ).…”

Section: Discussionmentioning

confidence: 99%

Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey

Sinaa

Lopane²,

Sabattini³

et al. 2022

Front. Neurol.

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Background and AimLimited data are available in clinical settings on the pharmacokinetics of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We investigated the use of cannabis-based products in neurological practice, monitoring patients' steady-state cannabinoids (CBs) plasma concentrations matched with different preparations.MethodsThis was a prospective, single-center, observational study. Patients underwent venous blood withdrawal before the CBs' morning dose and then 2.5 h post-dosing. Spasticity or pain were patient self-assessed by the Numeric Rating Scale (NRS) before the morning CB's administration and 2.5 h post-dosing.ResultsThirty-three patients were enrolled. Main indications for CBs were spasticity and chronic pain. Sixteen patients were treated with oromucosal spray formulation Sativex® and 17 with oil-based solutions. Both CBs trough plasma concentrations were ≤ limit of detection (0.1 ng/ml) in 45% of patients. Intrasubject CB's plasma levels significantly increased over baseline values in patients treated with Bediol® oil (p < 0.05) and Sativex® (p < 0.01). Post-dosing CB's bioavailability did not significantly differ between oral oil and oromucosal spray. NRS scores decreased (p < 0.01), matching the increase (p < 0.01) in CB's plasma concentrations.ConclusionThis is the first study investigating CB's plasma concentrations of oral and oromucosal preparations in real-world neurological practice. Findings of similar bioavailability for both CBD and THC after galenic oil compared with oromucosal spray dosing may be clinically relevant and deserve additional research in larger cohorts.

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Cannabidiol in Pharmacoresistant Epilepsy: Clinical Pharmacokinetic Data From an Expanded Access Program

Cited by 23 publications

References 24 publications

Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox–Gastaut Syndrome

Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox–Gastaut Syndrome

Improving Therapy of Pharmacoresistant Epilepsies: The Role of Fenfluramine

Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey

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