Jon Beck BS Pharm D Coordinator Investigational Pharmacy Disclosure I have no relevant financial relationships with a Commercial Provider Nebraska Medicine Omaha, NE Investigational Pharmacy Cannabidiol treatment in Epilepsy EPILEPSY: a central nervous system disorder (neurological disorder) in which nerve cell activity in the brain becomes disrupted SEIZURES: a chronic hyper-excitability disease stemming from various defects in neuronal networks HISTORY Cannabis used medicinally for thousands of years Medicinal preparations of cannabis have been used in China since around 2700 BC Islamic physicians used cannabis in medieval times Treatment of epilepsy around 1800 in Sumeria Also reported success from Victorian-era neurologists Available OTC in the US until 1941 The Controlled Substance Act of 1970 classified cannabis as a Schedule I 23 states and DC have allowed for use as a therapeutic agent 4 states have legalized recreational use Cannabis 3 distinct species Sativa Indica ruderalis >545 distinct compounds Cannabinoids 21 carbon structures 1940 cannabidiol isolated 1964 THC or tetrahydrocannabinol isolated phytocannabinoids 1
Cannabis 1988 identification of cannabinoid receptors CB1 - located in the CNS as well as periphery such as muscle, liver and fat CB2 located mainly in the immune system 1992 discovery of ligands or endocannabinoids Anandamide (AEA) 2-arachidonoyl glycerol (2-AG) modulators of neuronal excitability and therefore may affect the initiation, propagation and spread of seizures Phytocannabinoids (researchgate.net) negative regulation of CB1 receptor 1) Release of neurotransmitters across synapse. 2) release of endocannabinoid post-synaptically where it binds 3) pre-synaptically to CB1 inhibiting further release of neurotransmitters. 4) Phytocannabinoids are able to mimic or augment the actions of the endocannibinoids. 2) 414all.org Cannabidiol Mode of Action 1.Cannabinoid receptors 2.Adenosine (A1 and A2) receptors 3.Glycine receptors 4.Serotonin receptors 5. Nicotinic Acetylcholine receptors 6. G-protein-coupled receptor 55 7.Voltage gated calcium channels Cannabidiol Kinetics Routes and bioavailability 1. Smoking variable 2. Aerosol or vapor 31% 3. Patches accumulation in skin 4. Capsule 6% 5. Oil based liquid Cannabidiol Kinetics Distribution Highly lipophilic, high VD around 32 L/kg Rapidly distributed into brain, adipose tissue Highly protein bound Metabolism Hepatic via CYP3A and CYP2C Inducers such as carbamazepine, topiramateand phenytoin can decrease CBD levels Inhibitors like valproate can elevate CBD CBD shown to elevate the active metabolite of clobazam(onfi) causing sedative effects Half-Life 18-32 Hours 2
GWEP 1332 Dravet Syndrome (DS) A double-blind, placebo-controlled, two-part study to investigate the doseranging safety and pharmacokinetics, followed by the efficacy and safety of cannabidiol in children and young adults with Dravet Syndrome. Summary GWEP 1332 Part A Exposure to CBD and its metabolites increased in a dose-proportional manner; CBD resulted in more adverse events than placebo, but it was generally well tolerated at all doses examined. 20 mg/kg/day was approved by the Data Safety Monitoring Committee for further investigation in Part B GWEP 1332 Part B -120 Subjects titrated to 20 mg/kg/day for a total of 14 weeks vs. placebo - Eligible patients were aged 2 18 years, with a clinical diagnosis of DS inadequately controlled by 1 current AED(s), and were experiencing 4 convulsive seizures during the 28-day baseline period. % change in total seizures in DS No significant difference in patients with Non-convulsive seizures. Non-convulsive refers to alterations of consciousness without jerking movements. Convulsive means that there are muscle movements like jerking or stiffening. GWEP 1423 Lennox- Gastaut (LGS) METHODS 2 55 years with a clinical diagnosis of LGS inadequately controlled by 1 current AED(s) with at least 2 drop seizures per week 171 subjects randomized (1:1) to 20 mg/kg/day of CBD (100 mg/ml) or matched placebo, administered b.i.d. starting at 2.5 mg/kg/day and titrated up to 20 mg/kg/day over a 2-week period, followed by a 12-week dose-maintenance period. GWEP 1423 Lennox-Gastaut (LGS) Non-drop seizures was also significant 3
GWEP 1423 Summary The trial met its primary endpoint, demonstrating that CBD (20 mg/kg/day), as an add-on to standard of care, produced significantly greater reductions in drop seizures vs. placebo in patients with Lennox- Gastaut Syndrome (LGS). CBD resulted in significantly greater reductions in total seizure and non-drop seizure frequency vs. placebo. CBD resulted in more adverse events than placebo, but it was generally well tolerated. GWEP 1414 Lennox- Gastaut 1:1:1 randomized, double-blind, 14-week comparison of two Dose Levels of CBD versus placebo over a two-week titration period followed by a 12-week maintenance period. evaluate the safety and efficacy of 10 mg/kg/day and 20 mg/kg/day CBD added to existing AED treatment compared with placebo randomize 225 patients. The primary efficacy endpoint was the comparison between CBD and placebo in the reduction in monthly drop seizures GWEP 1414 RESULTS 20 mg/kg/day CBD group the median drop seizure frequency reduction was 42% compared with 17% in the placebo group (p=0.0047). 10 mg/kg/day CBD group the median drop seizure frequency reduction was 37%, compared with 17% in the placebo group (p=0.0016). Adverse Events reported in >10% patients GWEP1423 CBD (n=86) Placebo (n=85) 1. Diarrhea 18.6% 8.2% 2. Somnolence 15.1% 9.4% 3. Pyrexia 12.8% 8.2% 4. Decreased appetite 12.8% 2.4% 5. Vomiting 10.5% 16.5% 1. LB390 2. DEA 3. Social Media Hurdles Questions? 4
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