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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

• the present invention relates to the use of cannabidiol (CBD) in the treatment of patients with childhood-onset epilepsy who are concurrently taking caffeine.
• CBD cannabidiol
• CBD is used in combination with caffeine
• the dose of either the CBD and / or caffeine may be required to be reduced.
• the patient may need to be monitored for side effects of said drug-drug interaction.
• the CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 95% of the total extract (w/w) and the other components of the extract are characterised.
• the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% (w/w) and the propyl analogue of CBD, cannabidivarin, (CBDV) is present in amounts of up to 1%.
• the CBD may be a synthetically produced CBD.
• the cannabis plant ( Cannabis sativa L.) produces trichomes that synthesize a large number of pharmacologically active compounds called phytocannabinoids.
• Epidiolex is a liquid formulation of botanically derived, highly purified CBD extract that has been developed for use as a treatment for various orphan paediatric epilepsy syndromes, characterised in that the patients are deemed to be treatment-resistant on one or more anti epileptic drugs (AEDs) (see WO 2019/97238 and WO 2016/203239).
• the drug has been approved for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome. It is formulated from extracts prepared from Cannabis sativa L. plants that have a defined chemical profile and contain consistent levels of CBD as the principal phytocannabinoid. Extracts from these plants are processed to yield pure (> 95 to >98% w/w) CBD. The pure CBD is subsequently dissolved in excipients with added sweetener and flavouring.
• DAIs Drug-drug interactions
• Caffeine is the world's most widely consumed psychoactive drug. It is a central nervous system stimulant of the methylxanthine class. It is found in the seeds, nuts and leaves of a number of different plants, including: Coffea Arabica (used for coffee), Thea sinensis (used for tea), Cola acuminata (used as a nut, tea or in soft drinks including cola), Theobroma cacao (used in cocoa and chocolate) and Paulinia cupana (used as guarana in snack bars and energy drinks) 1 . Effects of caffeine include feeling more alert and active, as well as being more restless and excitable.
• Epidiolex is prescribed for use at doses of 10-20 mg/kg/day, therefore a 40kg child may be taking doses of up to 800mg/day. Clearly in a heavier child or adolescent even higher doses such as 1500 mg/day could be taken.
• DDIs The most common types of DDIs involve the inhibition or induction of one or more drug-metabolizing enzymes by a drug.
• inhibitors or inducers of a particular drug- metabolizing enzyme are coadministered with a drug that is metabolized by that enzyme, the pharmacokinetic parameters of one or both drugs change, leading to increased or decreased drug exposures. It is this change in exposure that may result in adverse events, depending on the level of exposure, and doses may have to be changed. Dosing modifications are unpredictable because reducing a dose too much risks undertreating the patients, but over dosing can increase exposure to potentially dangerous levels.
• Elevated levels of CBD are known to cause transaminase elevation, rash, somnolence, sedation, lethargy, diarrhoea, pyrexia, weight decrease, nasopharyngitis, irritability, oropharyngeal pain, and decreased appetite.
• Transaminase elevations can lead to hepatic dysfunction, including unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.
• Elevated exposure of caffeine exposure is known to cause insomnia, nervousness and restlessness, stomach irritation, nausea and vomiting, increased heart rate and respiration, and other side effects. The present disclosure reduces the incidence of one or more of the above side effects.
• CBD is metabolized in the liver and the gut by CYP2C19 and CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms.
• CBD inhibits uridine 5'- diphospho-glucuronosyltransferase (UGT) enzymes UGT1A9 and UGT2B7.
• UGT uridine 5'- diphospho-glucuronosyltransferase
• CBD is reported to be an inhibitor of CYP2B6, CYP2C8, CYP2C9, and CYP2C19. Data also suggest that CBD inhibits CYP3A4.
• CBD may induce or inhibit CYP1A2 and CYP2B6 at clinically relevant concentrations. However, it is not known if CBD is a strong, moderate, or weak inhibitor, or indeed if CBD-mediated inhibition of any of these enzymes produces a clinically significant result. Samanta (2019) 7 further suggests CBD may induce or inhibit CYP1A2 activity, identifying caffeine as a substrate of CYP1A2, but does not present any evidence towards inhibition or induction.
• the present invention discloses clinically significant biochemical findings in several subjects during the trial: elevations in liver enzymes (ALT, AST, and GGT).
• the present invention describes data from healthy subjects who received a single dose of caffeine after having taken repeated doses of CBD during an open-label, Phase 1 clinical trial. It was found that CBD increased the levels of caffeine in the subject’s blood. Such an interaction is unexpected and as such the use of these drugs in combination should be done with close monitoring of the patient.
• CBD drug induced liver injury
• CBD cannabidiol
• liver enzymes are additionally monitored. These enzymes ALT, AST, and GGT are markers associated with drug induced liver injury (DILI). Higher than normal levels of liver enzymes may be present when CBD and caffeine are coadministered.
• DILI drug induced liver injury
• the dose of CBD is lowered.
• the dose of caffeine is lowered. More preferably the dose of CBD and caffeine are lowered.
• the CBD is in the form of a highly purified extract of cannabis which comprises at least 95% (w/w) CBD, which comprises less than 0.15% THC and up to 1% CBDV.
• the CBD is present as a synthetic compound.
• the lowered dose of CBD ranges from about 5 mg/kg/day to about 20 mg/kg/day.
• the dose of caffeine is lowered to below 200 mg/day.
• An average cup of coffee comprises approximately 95mg of caffeine and therefore a patient may inadvertently consume doses of caffeine which exceed safe levels without realizing and as such blood levels should be monitored during treatment.
• the childhood-onset epilepsy is: Lennox-Gastaut Syndrome; Myoclonic Absence Epilepsy; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Jeong Syndrome; CDKL5; Dup15q; Neuronal ceroid lipofuscinoses (NCL) and brain abnormalities.
• a method of treating childhood-onset epilepsy in an individual in need thereof comprising administering to the patient a therapeutically effective amount of cannabidiol with caution, wherein the individual is taking caffeine concurrently.
• the said caution comprises lowering the dose of cannabidiol.
• the said caution comprises lowering the dose of caffeine.
• the said caution comprises monitoring said individual for side effects.
• the said caution further comprises discontinuing cannabidiol if said side effects are observed.
• the said caution comprises advising said individual of side effects from said concurrent therapy.
• Figure 1 shows Geometric Mean Plasma Concentrations of Caffeine Following Administration of Caffeine + Placebo (Day 1) and of Caffeine + CBD (Day 26) on a linear scale.
• Figure 2 shows Geometric Mean Plasma Concentrations of Paraxanthine Following Administration of Caffeine + Placebo (Day 1) and of Caffeine + CBD (Day 26) on a linear scale.
• Figure 3 shows Geometric Mean and Individual Subject Cmaxfor Caffeine and Paraxanthine Following Administration of Caffeine + Placebo (Day 1) and of Caffeine + CBD (Day 26).
• Figure 4 shows Geometric Mean and Individual Subject AUC0- for Caffeine and Paraxanthine Following Administration of Caffeine + Placebo (Day 1) and of Caffeine + CBD (Day 26).
• Figure 5 shows Geometric LS Mean Ratio and 90% Cl Showing the Effect of Steady-state CBD on Exposure to Caffeine and Paraxanthine.
• Figure 6 shows a Graph of serial liver chemistries for the 5 participants with ALT 35x ULN.
• phytocannabinoids are cannabinoids that originate from nature and can be found in the cannabis plant.
• the phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.
• “Highly purified cannabinoid extracts” are defined as cannabinoids that have been extracted from the cannabis plant and purified to the extent that other cannabinoids and non- cannabinoid components that are co-extracted with the cannabinoids have been substantially removed, such that the highly purified cannabinoid is greater than or equal to 95% (w/w) pure.
• the highly purified cannabinoid extract may be purified further such that the cannabinoid content is greater than or equal to 98 % (w/w) pure.
• Synthetic cannabinoids are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than by the plant.
• Phytocannabinoids can be obtained as either the neutral (decarboxylated form) or the carboxylic acid form depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate into the neutral form.
• “Childhood epilepsy” refers to the many different syndromes and genetic mutations that can occur to cause epilepsy in childhood. Examples of some of these are as follows: Dravet Syndrome; Myoclonic-Absence Epilepsy; Lennox-Gastaut syndrome; Generalized Epilepsy of unknown origin; CDKL5 mutation; Aicardi syndrome; tuberous sclerosis complex; bilateral polymicrogyria; Dup15q; SNAP25; and febrile infection related epilepsy syndrome (FIRES); benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasm (West syndrome); and Landau- Kleffner syndrome. The list above is non-exhaustive as many different childhood epilepsies exist.
• C max is the maximum observed plasma concentration.
• t max is the time to attain maximum observed plasma concentration.
• AUC 0-t is the area under the plasma concentration-time curve up to time t, where t is the last point with a concentration above the lower limit of quantification (LLOQ).
• DILI Drug induced liver injury
• the drug substance used is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD.
• the crystallisation process specifically removes other cannabinoids and plant components to yield greater than 98% CBD.
• CBD is highly purified because it is produced from a cannabis plant rather than synthetically there is a small number of other cannabinoids which are co-produced and co-extracted with the CBD. Details of these cannabinoids and the quantities in which they are present in the medication are as described in Table 2 below.
• EXAMPLE 1 A Phase 1, Open-label, Pharmacokinetic Drug-Drug Interaction Trial to Investigate the Effect of Cannabidiol on the Pharmacokinetics (PK) of Caffeine [0024] Primary Objectives: To investigate the effect of CBD treatment following repeated dosing on the PK of a single dose of caffeine in healthy subjects.
• the primary PK parameters were: AUC 0- ⁇ , AUC 0-t , C max , and t max for caffeine.
• the PK parameter endpoints derived from the plasma concentration-time profiles of caffeine on Day 1 administered with placebo and the PK parameter endpoints derived from a single dose of caffeine in participants at steady state CBD following 13 days of CBD, 20 mg/kg twice daily (b.i.d).
• Safety includes: incidence and severity of adverse events (AEs), incidence of laboratory abnormalities based on hematology, clinical chemistry, and urinalysis test results; 12-lead electrocardiogram (ECG) parameters, vital sign measurements, physical examinations, Columbia-Suicide Severity Rating Scale (C-SSRS) questionnaire scores; the PK parameter endpoints, derived from the plasma concentration-time profiles of caffeine on Day 1 administered with placebo and the PK parameter endpoints derived from a single dose of caffeine in participants at steady state CBD following 13 days of CBD, 20 mg/kg twice daily (b.i.d).
• AEs adverse events
• ECG electrocardiogram
• C-SSRS Columbia-Suicide Severity Rating Scale
• Subjects were administered a concurrent dose of 7.5 ml_ of placebo oral solution and 200 mg caffeine on Day 1, 30 minutes after starting a standardized breakfast. They were discharged on Day 3 after completion of the assessments.
• the first dose of CBD was taken in the morning in the CRU, and on this day, the escalating doses of CBD were dispensed to subjects to be taken at home from Day 4 to Day 12.
• the subjects returned to the CRU for ambulatory visits on Days 12, 18, and 23.
• the maintenance doses of CBD were dispensed to subjects to be taken at home from Day 13 to Day 25 (the evening dose of Day 25 was taken in the CRU). The subjects were admitted again to the CRU in the afternoon of Day 25.
• the CBD formulation is an oral liquid formulation that is clear and colourless to yellow in appearance (100 mg/ml_ CBD in sesame oil with anhydrous ethanol, added sweetener (sucralose), and strawberry flavouring.
• the oral liquid formulation is administered with a syringe.
• the CBD formulation is taken b.i.d. 30 minutes after starting a standard meal. In this trial, a maximum dose of 750 mg CBD b.i.d was selected, considered a therapeutic dose in epilepsy patients.
• the placebo is an oral liquid formulation (sesame oil and anhydrous ethanol with added sweetener [sucralose], and strawberry flavouring).
• the oral liquid formulation was administered with a syringe.
• the caffeine is provided as a 50 mg tablet.
• the IMP caffeine and placebo on Day 1, and caffeine and CBD on Day 26
• the morning dose of CBD was taken approximately at 08:00 h and the evening dose (not applicable on Day 3) was taken 12 hours later.
• Dosing for each individual subject was to be at around the same time ( ⁇ 1 hour) on each dosing day.
• the time of the morning dose on Day 26 matched the time of the morning dose on Day 1 (with a margin of ⁇ 5 minutes).
• Strenuous exercise was not allowed from 7 days prior to first admission to the CRU until the follow-up visit. Subjects were not to consume any foods containing poppy seeds within 72 hours (3 days) prior to each admission to the CRU as this could cause a false positive drug screen result. The use of tobacco- or nicotine- containing products was not allowed from first admission to the CRU until the follow-up visit.
• Plasma concentrations of caffeine and its metabolite paraxanthine were determined on the following days: 1, 2, 3, 26, 27 and 28.
• Plasma concentration of CBD determined on the following days: 23, 25, and 26. These were determined using liquid chromatography and tandem mass spectrometry.
• Trial subjects were sixteen healthy male and female subjects aged between 18 and 60. All 16 participants took at least 1 dose of trial drug; 9 (56%) completed treatment as planned and received the expected total dose of 400 mg caffeine and 31.25 g cannabidiol.
• Trough plasma samples for CBD were taken on Days 23, 25, and 26. Trough levels of CBD confirmed that CBD had reached steady state before caffeine and CBD were coadministered on Day 26.
• caffeine and its metabolite paraxanthine were quantifiable in the majority of subjects at the first sampling time point, i.e. , 0.5 hours.
• caffeine and its metabolite paraxanthine were quantifiable in the majority of subjects at the first sampling time point, i.e. , 0.5 hours.
• maximum postdose geometric mean plasma concentrations were reached at 1.5 hours for caffeine and 6.0 hours for paraxanthine.
• maximum postdose geometric mean plasma concentrations were reached at 3.0 hours for caffeine and 14.0 hours for paraxanthine.
• Table 4 Summary of the Pharmacokinetic Parameters (Geometric Mean [Geometric CV%]) of Caffeine and Paraxanthine Following Administration of Caffeine + Placebo (Day
• Figure 5 provides a visual summary of the results of the primary PK endpoint for the trial, illustrating the point estimates for the ratio of the geometric LS means and the 90% Cl for exposure to caffeine and paraxanthine when subjects were administered caffeine in the presence of steady-state CBD compared with administration of caffeine and placebo.
• Therapeutic doses of cannabidiol administered to healthy adults can result in elevations in serum alanine aminotransferase consistent with drug-induced liver injury. Physicians should be alert to this potential effect from cannabidiol and be on the lookout for association with clinically important liver injury.

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