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Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs.

ABSTRACT: Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

SUBMITTER: Patsalos PN

PROVIDER: S-EPMC7693203 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs.

Patsalos Philip N PN Szaflarski Jerzy P JP Gidal Barry B VanLandingham Kevan K Critchley David D Morrison Gilmour G

Epilepsia 20200912 9

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved ...[more]

PMID: 32918835

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Project description:PurposeTo show the impact of drug-drug interactions (DDIs) associated with co-administration of enzyme-inducing (EI) antiseizure medications and oral contraceptives (OCs) on the annual number of unintended pregnancies, their outcomes, and their associated costs in the United States (US).MethodsA Microsoft Excel pregnancy-outcomes model was developed to determine the impact of DDIs in women who take an OC as well as an EI antiseizure medication known to lower the effectiveness of the OC in preventing pregnancy. The model compared the number of unintended pregnancies, the expected pregnancy outcomes, and associated costs in women taking an OC and an EI medication with a matched cohort of women who took an OC and an enzyme-neutral (EN) antiseizure medication that is known not to interact with OCs. The model perspectives were patients and third-party payers in the US. Unintended pregnancy rates, pregnancy outcomes, and cost inputs for the model were taken from published studies.ResultsThe results of the analysis showed an estimated increase in the annual number of unintended pregnancies in the US of 503 (a change from 1151 to 1654), an increase of 44.7%, for the estimated 71,922 women currently taking an OC plus an EI medication in the US when compared with a matched cohort taking an OC plus an EN medication. This resulted in an estimated annual healthcare cost increase of $3 million, which is an increase of 5.5% in the annual costs for contraception and pregnancy care. A scenario analysis showed that the annual number of unintended pregnancies could be lower (575 vs 1654) for a matched cohort of women taking EI medications and using a copper intrauterine device, a highly effective and nonhormonal form of contraception, rather than an OC.ConclusionsPhysicians treating women of reproductive age for epilepsy who wish to avoid pregnancy should consider the potential for DDIs that might result in unintended pregnancies. Thus, physicians should alert women using EI medications for epilepsy control to the increased potential for unintended pregnancies if they use OCs for contraception.

Project description:Drug-resistant epilepsy occurs in 25-30% of patients. Furthermore, treatment with a first-generation antiseizure drug (ASD) fails in 30-40% of individuals because of their intolerable adverse effects. Over the past three decades, 20 newer- (second- and third-)generation ASDs with unique mechanisms of action and pharmacokinetic profiles have been introduced into clinical practice. This advent has expanded the therapeutic armamentarium of epilepsy and broadens the choices of ASDs to match the individual patient's characteristics. In recent years, research has been focused on defining the ASD of choice for different seizure types. In 2017, the International League Against Epilepsy published a new classification for seizure types and epilepsy syndrome. This classification has been of paramount importance to accurately classify the patient's seizure type(s) and prescribe the ASD that is appropriate. A year later, the American Academy of Neurology published a new guideline for ASD selection in adult and pediatric patients with new-onset and treatment-resistant epilepsy. The guideline primarily relied on studies that compare the first-generation and second-generation ASDs, with limited data for the efficacy of third-generation drugs. While researchers have been called for investigating those drugs in future research, epilepsy specialists may wish to share their personal experiences to support the treatment guidelines. Given the rapid advances in the development of ASDs in recent years and the continuous updates in definitions, classifications, and treatment guidelines for seizure types and epilepsy syndromes, this review aims to present a complete overview of the current state of the literature about the efficacy and tolerability of ASDs and provide guidance to clinicians about selecting appropriate ASDs for initial treatment of epilepsy according to different seizure types and epilepsy syndromes based on the current literature and recent US and UK practical guidelines.

Project description:Drug repositioning or repurposing, i.e. identifying new indications for existing drugs, has gained increasing attention in the recent years. This approach enables the scientists to discover "new targets" for known drugs in a cost and time efficient manner. Glycation, the non-enzymatic reaction of sugars with proteins or nucleic acids to form early glycation (Amadori or fructosamine) products, is a key molecular basis of diabetic complications. Inhibiting the process of non-enzymatic protein glycation is one of the key strategies to prevent glycation-mediated diabetic complications. The present study focuses on the anti-glycation activity of 18 drugs, commonly used for the treatment of gastrointestinal, central nervous system, inflammatory diseases, bacterial infections, and gout. This study was carried out by using two in-vitro protein anti-glycation assay models. Results revealed that nimesulide (3), a non-steroidal anti-inflammatory drug, possesses a good anti-glycation activity in in-vitro BSA-MG and BSA-glucose glycation models with IC50 values of 330.56 ± 2.90, and 145.46 ± 16.35 μM, respectively. Phloroglucinol dihydrate (11), a drug used for the treatment of gastrointestinal diseases, showed a weak activity in BSA-MG glycation model (IC50 = 654.89 ± 2.50 μM), while it showed a good activity in BSA-glucose assay (IC50 = 148.23 ± 0.15 μM). Trimethylphloroglucinol (9), a drug used for the treatment of pain related to functional disorders of the digestive and biliary tracts, also showed a good antiglycation activity in BSA-MG model (IC50 = 321.15 ± 1.26 μM), while it was found to be inactive in in-vitro BSA-glucose assay (IC50 = 12.95% inhibition). These activities of drugs were compared with the anti-glycation activity of the standard, rutin (IC50 = 294.5 ± 1.50 μM in BSA-MG glycation model, and IC50 = 86.94 ± 0.24 μM in BSA- glucose model). Rest of the drugs exhibited a relatively weak antiglycation activity. This study identifies nimesulide (3), and phloroglucinol dihydrate (11) as new inhibitors of in-vitro protein glycation for further investigations as potential anti-diabetic agents.

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Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs.

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Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs.

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