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

@article{Patsalos2020ClinicalIO,
  title={Clinical implications of trials investigating drug‐drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs},
  author={Philip N Patsalos and Jerzy P. Szaflarski and Barry E. Gidal and Kevan E. VanLandingham and David J.P. Critchley and Gilmour Morrison},
  journal={Epilepsia},
  year={2020},
  volume={61},
  pages={1854 - 1868}
}
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… 

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References

SHOWING 1-10 OF 55 REFERENCES

A Phase 2, Double‐Blind, Placebo‐Controlled Trial to Investigate Potential Drug‐Drug Interactions Between Cannabidiol and Clobazam

The safety profile of GW Pharmaceuticals’ CBD formulation with CLB was acceptable; all but 1 adverse events (AEs) were mild or moderate; one serious AE (seizure cluster) led to CBD discontinuation.

Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs.

  • G. ZaccaraE. Perucca
  • Biology, Medicine
    Epileptic disorders : international epilepsy journal with videotape
  • 2014
These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects,such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.

A Phase 1, Open‐Label, Pharmacokinetic Trial to Investigate Possible Drug‐Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects

Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate, and when co Administered with each antiepileptic drug.

Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy subjects: results from two clinical trials

Co-administration of CYP3A4/CYP2C19 inhibitors will likely increase exposure to selumetinib, while CYP 3A4 inducers will likely reduce its exposure.

Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy

Current knowledge on the pharmacokinetics and metabolic fate of CBD in humans is summarized, studies on the biological activity of CBD metabolites either in vitro or in vivo are reviewed, and relevant drug–drug interactions are discussed.

Cytochrome P450 Structure, Function and Clinical Significance: A Review.

This review is a comprehensive compilation of cytochrome P450 structure, function, pharmacogenetics, pharmacoepigenetics and clinical significance that may be used by clinicians to determine therapeutic strategy, and treatment doses for drugs that are metabolized by CYP gene products.

Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19.

Results indicate that CBD caused potent CYP2C19 inhibition, in which one free phenolic hydroxyl group and the pentyl side chain of CBD may play important roles.

Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy

Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children, and it is predicted a drug–drug interaction.

A Phase II Randomized Trial to Explore the Potential for Pharmacokinetic Drug–Drug Interactions with Stiripentol or Valproate when Combined with Cannabidiol in Patients with Epilepsy

Coadministration of cannabidiol did not affect the pharmacokinetics of valproate or its metabolite, 4-ene-VPA, in adult patients with epilepsy, and safety results were consistent with the known safety profile of cannABidiol at a dose of 20 mg/kg/day.
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