Use of cannabidiol in the treatment of epilepsy

Abstract

The present invention relates to the use of cannabidiol (CBD) in the treatment of patients with childhood-onset epilepsy who are concurrently consuming caffeine. Caution is advised when CBD is used in combination with caffeine. For example, it may be necessary to reduce the dose of either CBD and / or caffeine. Furthermore, patients may need to be monitored for adverse drug-drug interactions. The CBD used is preferably in the form of a highly purified extract of cannabis, in which CBD is present at greater than 95% of the total extract (w / w), and the other components of the extract have been characterized. Specifically, the cannabinoid tetrahydrocannabinol (THC) is substantially removed to levels of 0.15% (w / w) or less, and cannabidivarin (CBDV), a propyl analog of CBD, is present in amounts up to 1%. Alternatively, the CBD may be synthetically produced CBD.

Description

[Technical Field]

[0001] This invention relates to the use of cannabidiol (CBD) in the treatment of patients with childhood-onset epilepsy who are also taking caffeine.

[0002] Caution is necessary when CBD is used in combination with caffeine. For example, it may be necessary to reduce the dose of either CBD or / or caffeine. Furthermore, patients may need to be monitored for side effects of the drug interaction.

[0003] The CBD used is preferably in the form of a highly purified cannabis extract, such that CBD makes up more than 95% of the total extract (w / w) and the other components of the extract are characterized. Specifically, the cannabinoid tetrahydrocannabinol (THC) is substantially removed to a level of 0.15% (w / w) or less, and cannabidivarin (CBDV), a propyl analog of CBD, is present in amounts of up to 1%. Alternatively, the CBD may be synthetically produced CBD. [Background technology]

[0004] Cannabis sativa L. produces trichomes that synthesize many pharmacologically active compounds called phytocannabinoids. While THC and CBD are the most abundant of these phytocannabinoids, the amount and proportion of diverse phytocannabinoids in each plant vary from strain to strain and can be controlled through breeding.

[0005] Epidiolex is a highly purified CBD extract, a plant-derived liquid formulation developed for use in the treatment of a variety of orphan childhood epilepsy syndromes characterized by patients appearing resistant to one or more antiepileptic drugs (AEDs) (see WO2019 / 97238 and WO2016 / 203239). This drug is approved for the treatment of epileptic seizures associated with Dravet syndrome and Lennox-Gastaut syndrome. It is formulated from an extract prepared from the Cannabis sativa L. plant, which has a distinct chemical profile and contains consistent levels of CBD as the primary phytocannabinoid. Extracts from these plants are processed to obtain pure (>95~>98% w / w) CBD. The pure CBD is then dissolved in excipients to which sweeteners and flavorings are added.

[0006] As a result of the use of CBD in medicine outlined above, it has become necessary to understand the various interactions that CBD may have with other medicines or drugs. Drug-drug interactions (DDIs) are one of the leading causes of medication errors and can induce both adverse drug reactions and reduced clinical efficacy.

[0007] Caffeine is the most widely consumed psychotropic drug in the world. Caffeine is a methylxanthine class central nervous system stimulant. Caffeine is derived from the Arabica coffee plant (used in coffee), the tea plant (Thea sinensis) (used in tea), the cola tree (Cola acuminata) (used as a nut in tea or soft drinks including cola), theobroma cacao (used in cocoa and chocolate), and Paulinia cupana (used as guarana in snack bars and energy drinks). 1It is found in the seeds, nuts, and leaves of several different plants, including [mention specific plant species]. The effects of caffeine include feeling more alert and energetic, as well as feeling more restless and excitable. A 2010 Pediatrics journal study reported that a remarkably high percentage of children, 75%, consume caffeine on a daily basis. 2 Such high rates suggest a significant overlap between children consuming caffeine and young patients being administered prescribed CBD-based medications, highlighting the importance of understanding the effects of co-consumption of caffeine and CBD.

[0008] Previous case studies have suggested a synergistic effect between CBD and caffeine. Authors of these reports argue that the combination of CBD and caffeine may alleviate the jittery edge, anxiety, and nausea often associated with caffeine use (caffeine hit). 3、4 In fact, several companies, such as Green Roads CBD Coffee and Green Roads CBD Tea, have been selling them. 5 Also, Subduction Coffee + Hemp 6 CBD-infused coffees are being commercialized. However, these commercially available products and case reports use low doses of CBD (~30mg per serving), which is nowhere near the therapeutic dose used in Epidiolex, which is used to treat Dravet syndrome and Lennox-Gastaut syndrome. Epidiolex is prescribed for use at doses of 10-20mg / kg / day, and therefore a 40kg child may be taking up to 800mg / day. Clearly, heavier children or adolescents may take even higher doses, such as 1500mg / day.

[0009] The most common type of drug-mediated drug inhalant (DDI) involves a drug inhibiting or inducing one or more drug-metabolizing enzymes. When an inhibitor or inducer of a specific drug-metabolizing enzyme is administered concurrently with a drug metabolized by that enzyme, the pharmacokinetic parameters of one or both drugs are altered, resulting in increased or decreased drug exposure. Depending on the level of exposure, it is this alteration in exposure that can lead to adverse events, and dose adjustments may be necessary. Dosage reduction carries too great a risk of inadequate treatment for the patient, while overdose can increase exposure to potentially dangerous levels, making dose modifications unpredictable.

[0010] High levels of CBD are known to cause elevated aminotransferase levels, rash, somnolence, sedation, fatigue, diarrhea, fever, weight loss, nasopharyngitis, irritability, oropharyngeal pain, and loss of appetite. Elevated aminotransferase levels may result in unexplained nausea, vomiting, right upper abdominal pain, fatigue, loss of appetite, or liver dysfunction, including jaundice and / or dark urine. High exposure to caffeine is known to cause insomnia, nervousness and restlessness, stomach pain, nausea and vomiting, increased heart rate and increased respiration, and other side effects. This disclosure reduces the incidence of one or more of the above-mentioned side effects.

[0011] The pharmacological properties of CBD are not fully understood. As stated on the FDA approval label for EPIDIOLEX®, CBD is metabolized in the liver and intestines by the enzymes CYP2C19 and CYP3A4, as well as their isoforms UGT1A7, UGT1A9, and UGT2B7. CBD inhibits the uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes UGT1A9 and UGT2B7. CBD has been 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 unknown whether CBD is a strong, moderate, or weak inhibitor, or whether CBD-mediated inhibition of any of these enzymes actually has clinically significant consequences. Samanta (2019) 7 This further suggests that CBD may induce or inhibit CYP1A2 activity and that caffeine may be considered a substrate of CYP1A2, but it does not present any evidence regarding inhibition or induction. This invention discloses clinically important biochemical findings in some subjects during testing, namely elevated liver enzymes (ALT, AST, and GGT).

[0012] This invention describes data from healthy subjects who received a single dose of caffeine after repeated doses of CBD during an open-label Phase 1 clinical trial. It was found that CBD increased the levels of caffeine in the subjects' blood. Such interactions were unexpected, and therefore the concomitant use of these drugs should be accompanied by close monitoring of the patient.

[0013] Furthermore, in the same study, when CBD was administered to healthy adults at the dose generally administered to patients with DS and patients with LGS (approximately 20 mg / kg / day), it was observed that an increase in liver chemistries consistent with drug-induced liver injury (DILI) occurred. This finding was surprising, as such high elevations had not previously been observed in healthy volunteers. [Prior Art Document] [Patent Documents]

[0014] [Patent Document 1] WO2019 / 97238 [Patent Document 2] WO2016 / 203239 [Non-Patent Documents]

[0015] [Non-Patent Document 1] 2010, Pediatrics journal study [Summary of the Invention] [Means for Solving the Problems]

[0016] According to a first aspect of the present invention, there is provided cannabidiol (CBD) for use in the treatment of childhood-onset epilepsy in a patient concurrently ingesting caffeine, characterized by monitoring blood levels of caffeine and related markers to ensure that the levels do not become toxic.

[0017] In a further embodiment of the present invention, blood levels of liver enzymes are further monitored. These enzymes, ALT, AST and GGT, are markers associated with drug-induced liver injury (DILI). When CBD and caffeine are co-administered, higher than normal levels of liver enzymes may be present.

[0018] It is preferable to reduce the dose of CBD. Alternatively, it is preferable to reduce the dose of caffeine. It is even more preferable to reduce the doses of both CBD and caffeine.

[0019] The CBD is preferably in the form of a highly purified cannabis extract containing at least 95% (w / w) CBD, less than 0.15% THC, and up to 1% CBDV. Alternatively, the CBD may exist as a synthetic compound.

[0020] The reduced dose of CBD is preferably in the range of approximately 5 mg / kg / day to approximately 20 mg / kg / day. Alternatively, the caffeine dose can be reduced to up to 200 mg / day.

[0021] Since an average cup of coffee contains approximately 95 mg of caffeine, patients may unknowingly consume amounts of caffeine exceeding safe levels, and therefore blood levels should be monitored during treatment.

[0022] Childhood-onset epilepsy is preferably Lennox-Gastaut syndrome, Mykoloni's absence epilepsy, tuberous sclerosis, Dravet syndrome, Douse syndrome, Sievons syndrome, CDKL5, Dup15q, neuronal ceroid lipofuscinosis (NCL), and brain abnormalities.

[0023] A second aspect of the present invention provides a method for treating childhood-onset epilepsy in an individual in need, comprising administering a therapeutically effective amount of cannabidiol to the patient in parallel with the individual's intake of caffeine.

[0024] The aforementioned precaution preferably includes reducing the dose of cannabidiol, or it may include reducing the dose of caffeine.

[0025] The aforementioned precautions preferably include monitoring the individual for side effects.

[0026] The aforementioned precautions more preferably further include discontinuing cannabidiol if the aforementioned side effects are observed.

[0027] The aforementioned precautions more preferably include advising the individual on the side effects of the combination therapy.

[0028] Embodiments of the present invention will be further described below with reference to the accompanying drawings. [Brief explanation of the drawing]

[0029] [Figure 1] This graph shows the geometric mean plasma concentrations of caffeine on a uniform scale after administration of caffeine + placebo (day 1) and caffeine + CBD (day 26). [Figure 2] This graph shows the geometric mean plasma concentrations of paraxanthine on a uniform scale after administration of caffeine + placebo (day 1) and caffeine + CBD (day 26). [Figure 3] This figure shows the geometric mean and individual Cmax values ​​for caffeine and paraxanthine after administration of caffeine + placebo (day 1) and caffeine + CBD (day 26). [Figure 4] This figure shows the geometric mean and individual AUC0-∞ for caffeine and paraxanthine after administration of caffeine + placebo (day 1) and caffeine + CBD (day 26). [Figure 5] This figure shows the geometric LS mean ratio and 90% CI, indicating the steady-state effects of CBD upon exposure to caffeine and paraxanthine. [Figure 6] This figure shows a graph of continuous intrahepatic chemical levels for five participants with ALT ≥ 5 × ULN.

[0030] definition The definitions of some terms used to describe this invention are detailed below.

[0031] The cannabinoids described in this application are listed below, along with their common abbreviations.

[0032] [Table 1]

[0033] The table above is not exhaustive and merely provides a detailed list of the cannabinoids identified in this application for reference purposes. To date, more than 60 different cannabinoids have been identified, and these cannabinoids can be divided into the following distinct groups: phytocannabinoids, endocannabinoids, and synthetic cannabinoids (which may be novel cannabinoids, or synthetically produced phytocannabinoids or synthetically produced endocannabinoids).

[0034] Phytocannabinoids are naturally occurring cannabinoids that can be found in the cannabis plant. Phytocannabinoids can be isolated from plants to produce highly purified extracts, or they can be synthesized synthetically.

[0035] "Highly purified cannabinoid extract" is defined as cannabinoids extracted from the cannabis plant, from which other cannabinoids and non-cannabinoid components extracted together with the cannabinoids have been substantially removed, to the extent that the highly purified cannabinoids have a purity of 95% (w / w) or higher. Highly purified cannabinoid extract may be further purified to a purity of 98% (w / w) or higher of cannabinoids.

[0036] "Synthetic cannabinoids" are compounds that have a cannabinoid or cannabinoid-like structure and are produced using chemical means rather than by plants.

[0037] 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 results in decarboxylation of most of the carboxylic acid form to yield the neutral form.

[0038] "Childhood epilepsy" refers to many different conditions and genetic mutations that can cause epilepsy in childhood. Some examples of these are as follows: Dravet syndrome, myoclonic absence epilepsy, Lennox-Gastaut syndrome, idiopathic generalized epilepsy, CDKL5 mutations, Aicardi syndrome, tuberous sclerosis, bilateral polymicrogyria, Dup15q, SNAP25 and febrile infection-related epilepsy syndrome (FIRES), benign rolandic epilepsy, juvenile myoclonic epilepsy, infantile spasms (West syndrome), and Landau-Kleffner syndrome. The above list is not exhaustive since there exist many different types of childhood epilepsy.

[0039] C max is the maximum measured plasma concentration.

[0040] t max is the time to reach the maximum measured plasma concentration.

[0041] AUC 0-∞ is the area under the plasma concentration-time curve from time 0 to infinity, and AUC 0-∞ =AUC 0-t +C last / k el wherein C last is the estimated last plasma concentration, and k el is the terminal phase rate constant.

[0042] AUC 0-t is the area under the plasma concentration-time curve up to time t, wherein t is the last measurement point at a concentration above the lower limit of quantification (LLOQ).

[0043] For clinical laboratory measurements of liver damage and liver function, the upper limit of normal (ULN) values ​​used are 68 international units [IU] / L for ALT, 45 IU / L for aspartate aminotransferase (AST), 129 IU / L for alkaline hostafase (ALP), 29 μmol / L for total bilirubin (TBL), and 59 IU / L for gamma glutamyltransferase (GGT).

[0044] Drug-induced liver injury (DILI) is defined as serum ALT levels exceeding 5 × ULN. [Modes for carrying out the invention]

[0045] Preparation of highly purified CBD extract In the following examples, we will explain that the preparation of highly purified (>95~98% w / w) cannabidiol extracts having a certain known composition was used.

[0046] In summary, the active pharmaceutical ingredient used is a liquid carbon dioxide extract of a high-CBD-containing chemical species of Cannabis sativa L., further purified by solvent crystallization to obtain CBD. Specifically, the crystallization method removes other cannabinoids and plant components, resulting in a CBD content of over 98%. Although the CBD is highly purified, it is produced from the cannabis plant rather than synthetically, so small amounts of other cannabinoids are present that are produced and extracted together with the CBD. Details of these cannabinoids and the amounts of cannabinoids present in the drug are shown in Table 2 below.

[0047] [Table 2] [Examples]

[0048] A phase 1, open-label pharmacokinetic drug interaction study to investigate the effect of cannabidiol on the pharmacokinetics (PK) of caffeine. Primary objective: To investigate the effect of repeated CBD therapy on the pharmacokinetic (PK) of single-dose caffeine in healthy subjects.

[0049] Primary endpoint: The primary PK parameter is AUC for caffeine. 0-∞ AUC 0-t , C max and t max The PK parameter endpoints were obtained from the plasma concentration-time profile of caffeine administered with placebo on day 1, and from a single dose of caffeine in participants who were in a steady state of CBD after 13 days of CBD at 20 mg / kg twice daily (bid).

[0050] Secondary objective: To evaluate the safety and tolerability of CBD when administered in conjunction with a single dose of caffeine in healthy subjects.

[0051] Secondary endpoints for safety include the incidence and severity of adverse events (AEs), incidence of abnormal laboratory findings based on hematological, clinical chemistry, and urinalysis results, 12-lead electrocardiogram (ECG) parameters, vital signs measurements, physical examination, Columbia Suicide Severity Scale (C-SSRS) questionnaire scores, PK parameter endpoints derived from the plasma concentration-time profile of caffeine administered with placebo on day 1, and PK parameter endpoints derived from a single dose of caffeine in participants who were in a steady state after 13 days of CBD at 20 mg / kg twice daily (bid).

[0052] Study Plan: This was a phase 1, open-label, single-center trial to investigate the effect of multiple doses of CBD on the pharmacokinetic effects of caffeine in healthy subjects. The trial duration was approximately 10 weeks, including a screening period (up to 4 weeks), a treatment period (4 weeks), and a safety follow-up period (2 weeks). After signing an Informed Consent Form (ICF), participants entered the screening period (day -28 to day -1). On day -1, the day before day 1, the first day of IMP (caffeine + placebo) administration, participants who continued to meet the eligibility criteria were admitted to the Clinical Research Unit (CRU). Subjects remained in the CRU for two periods. On day 1, 30 minutes after the initiation of a standardized breakfast, subjects received a concurrent dose of 7.5 mL of oral placebo solution and 200 mg of caffeine. On day 3, subjects were discharged upon completion of the evaluation. On the morning of day 3, the subject received their first dose of CBD at the CRU, and on this day, they were supplied with an escalating dose of CBD for home use from day 4 to day 12. After being discharged on day 3, the subject returned to the CRU for outpatient visits on days 12, 18, and 23. During these outpatient visits, the subject was supplied with a maintenance dose of CBD for home use from day 13 to day 25 (the evening dose on day 25 was administered at the CRU). The subject was readmitted to the CRU on the afternoon of day 25. On days 26 and 27, the subject received CBD via bid, and on day 26, a single oral dose of caffeine was administered in parallel with the morning dose of CBD. On day 28, the subject was discharged after the completion of the evaluation. The subject underwent follow-up visits 14 to 16 days after the last IMP administration. In addition to scheduled follow-up visits, some subjects returned to the CRU on day 28 for unscheduled visits for additional blood tests for liver enzymes outside the normal reference range. CBD and caffeine were administered as shown in Table 3.

[0053] [Table 3]

[0054] Administration format, dosage, and regimen: The CBD preparation is a clear, colorless to yellow oral liquid (100 mg / mL of CBD in anhydrous ethanol and sesame oil with added sweetener (sucralose) and strawberry flavoring). The oral liquid is administered by syringe. The CBD preparation is taken as a bid 30 minutes after the start of a standardized breakfast. In this study, considering the therapeutic dose in epilepsy patients, a bid of 750 mg of maximum CBD was selected.

[0055] The placebo is an oral solution (sesame oil and anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The oral solution is administered using a syringe.

[0056] Caffeine is provided as a 50mg tablet.

[0057] On days 1 and 26, IMP (caffeine and placebo on day 1, and caffeine and CBD on day 26) was administered between 08:00 and 09:00. From days 3 to 27, a morning dose of CBD was administered at approximately 08:00, followed 12 hours later by an evening dose (not applicable on day 3). Administration to each individual subject was scheduled for approximately the same time (±1 hour) on each administration day. The time of the morning dose on day 26 coincided with the time of the morning dose on day 1 (±5 minute error).

[0058] The use of all prescribed medications and all over-the-counter medications, vitamins and other nutritional supplements, or herbal medicines was prohibited from the initial admission to the CRU until follow-up visits. The use of methylxanthine-containing beverages or foods (coffee, [cold] tea, cola, chocolate [milk], mocha beverages / confectionery, energy drinks) was not permitted from the initial admission to the CRU until discharge on day 28. Foods and beverages containing grapefruit, Seville oranges, pomelos, star fruit, cranberries, or cruciferous vegetables were not permitted from the initial admission to the CRU until discharge on day 28. Alcoholic beverages were not permitted from 48 hours prior to each admission to the CRU, throughout the hospital stay, and from 48 hours prior to safety follow-up visits. Strenuous exercise was not permitted from 7 days prior to the initial admission to the CRU until follow-up visits. Subjects were not allowed to consume any foods containing poppy seeds within 72 hours (3 days) prior to each admission to the CRU, as this could potentially cause false-positive drug screening results. The use of tobacco-containing or nicotine-containing products was not permitted from the initial admission to the CRU until follow-up appointments.

[0059] Pharmacokinetic evaluation: Plasma concentrations of caffeine and its metabolite, paraxanthine, were determined on days 1, 2, 3, 26, 27, and 28. Plasma concentrations of CBD were determined on days 23, 25, and 26. These were determined using liquid chromatography and tandem mass spectrometry.

[0060] The following evaluations were performed: demographics, medical history, physical examination, C-SSRS, vital signs, weight, height, 12-lead ECG, adverse events (AEs), recorded prior medications, and recorded concomitant medications. Laboratory samples included chemistry, hematology, serology, urinalysis, and alcohol testing.

[0061] The study included 16 healthy men and women aged 18 to 60 years. All 16 participants received at least one dose of the investigational drug, and 9 (56%) completed treatment as planned, receiving the planned total dose of 400 mg of caffeine and 31.25 g of cannabidiol.

[0062] result Figures 1 and 2 show the plasma concentrations of caffeine and paraxanthine after administration of caffeine + placebo and caffeine + CBD.

[0063] Trough plasma samples of CBD were collected on days 23, 25, and 26. The trough levels of CBD were used to confirm that CBD had reached a steady state before the simultaneous administration of caffeine and CBD on day 26.

[0064] After administering 200 mg of caffeine and a placebo on day 1, and after simultaneously administering 200 mg of caffeine and 750 mg of CBD on day 26, caffeine and its metabolite, paraxanthine, were quantifiable in the majority of subjects at the time of initial sample collection, i.e., 0.5 hours later.

[0065] On day 1, after administration of 200 mg of caffeine and placebo, the peak geometric mean plasma concentration after administration was reached in 1.5 hours for caffeine and in 6.0 hours for paraxanthine. On day 26, after simultaneous administration of 200 mg of caffeine and 750 mg of CBD, the peak geometric mean plasma concentration after administration was reached in 3 hours for caffeine and in 14.0 hours for paraxanthine.

[0066] As is evident from the individual and geometric mean profiles, after the co-administration of 200 mg of caffeine and 750 mg of CBD on day 26, the elimination phase of caffeine and paraxanthine was multiphasic, with higher caffeine concentrations and lower paraxanthine concentrations compared to the administration of 200 mg of caffeine and placebo on day 1.

[0067] The PK parameters for caffeine and paraxanthine are shown in Table 4. Figure 3(C) shows the difference between the geometric mean PK parameters for caffeine and paraxanthine and the PK parameters for individual subjects after administration of caffeine + placebo (day 1) and after administration of caffeine + CBD (day 26). max ) and Figure 4 (AUC 0-∞ The results are shown in ( ), and the statistical analysis of the differences in PK parameters is shown in Table 5.

[0068] [Table 4]

[0069] [Table 5]

[0070] Regarding caffeine, as shown by the estimated therapeutic ratio (primary analysis) in Table 5, when compared to caffeine and placebo (day 1), simultaneous administration of caffeine and CBD (day 26) resulted in C max A slight increase in (1.15, 90% CI:[1.04, 1.26]) indicates an increase in AUC. 0-t (1.88, 90%CI:[1.56,2.27]) and AUC 0-∞ A significant increase was observed at (1.95, 90% CI: [1.62, 2.35]). Caffeine t max The response time was slower after administration of caffeine and CBD (day 26) compared with administration of caffeine and placebo (day 1) (Hodges-Lehman estimate difference: 0.58, 90% CI: [0.01, 1.50]).

[0071] Regarding paraxanthine, as shown by the estimated therapeutic ratio (primary analysis), simultaneous administration of caffeine and CBD (day 26) compared to caffeine and placebo (day 1) resulted in C maxA decrease was observed in (0.78, 90% CI:[0.72, 0.86]) and AUC. 0-t (1.10, 90%CI:[0.96,1.26]) and AUC 0-∞ A slight increase was observed at (1.18, 90% CI: [1.03, 1.35]). Paraxanthine t max The response tended to be slower after administration of caffeine and CBD (day 26) compared with administration of caffeine and placebo (day 1) (Hodges-Lehman estimate difference: 3.49, 90% CI: [0.48, 6.00]).

[0072] Similar results were observed in both the primary and sensitivity analyses.

[0073] Therefore, compared to administering caffeine with a placebo, when caffeine is administered with steady-state CBD, caffeine exposure is C max For 15% and AUC 0-∞ Therefore, it was increased by 95%.

[0074] C max A 22% decrease and AUC 0-∞ As evidenced by the 18% increase in [specific data point], exposure to paraxanthine, a CYP1A2-mediated caffeine metabolite, was affected by co-administration of CBD. When caffeine was co-administered with CBD, the t of paraxanthine was affected. max This is delayed, which may reflect the slow formation of metabolites.

[0075] Figure 5 provides a visual summary of the results for the primary PK endpoint of this study, showing estimated geometric mean ratios and 90% confidence intervals for caffeine and paraxanthine exposure when subjects were administered caffeine in the presence of steady-state CBD, compared to administration of caffeine and placebo.

[0076] Simultaneous administration of caffeine and CBD resulted in altered exposure to caffeine and paraxanthine (AUC). 0-t AUC 0-∞and C max (Based on) AUC compared to administration of caffeine and placebo. 0-t The AUC increased by 88% and 10% for caffeine and paraxanthine, respectively. 0-∞ Caffeine and paraxanthine increased by 95% and 18%, respectively. max CBD increased by 15% and decreased by 22% for caffeine and paraxanthine, respectively. Overall, CBD affects exposure to caffeine and its metabolite, paraxanthine.

[0077] conclusion These findings represent a significant concern for epilepsy patients and for the broader community where marijuana legalization continues to grow. This drug interaction could have implications for epilepsy patients who are not adequately monitored during treatment.

[0078] Patients taking caffeine-containing drugs or products should be carefully monitored during treatment with CBD to ensure that no toxicity from long-term caffeine exposure occurs. [Examples]

[0079] Liver safety In the Phase 1 trial outlined above, abnormal hepatic chemical levels were found in the subjects. This was unexpected, as the subjects were healthy adults receiving a therapeutic equivalent dose (1500 mg / day) of CBD used to treat Dravet syndrome and Lennox-Gastaut syndrome.

[0080] Measurements were taken during screening and follow-up on days -1, 12, 18, 23, and 27 of the study.

[0081] result The most prominent biochemical abnormalities were elevated serum ALT, the related enzyme AST, and GGT. In 7 participants (44%), peak serum ALT levels were >ULN, in 6 participants (38%), >2, and in 5 participants (31%), peak ALT levels were >5×ULN, which is the international consensus criteria for DILI (Table 6). Sequential intrahepatic chemical values ​​observed in the 5 participants with peak ALT levels >5×ULN are shown in Figure 6.

[0082] All elevations occurred between 18 and 27 days after exposure to cannabidiol, 2 to 4 weeks prior. Among the six participants who discontinued the protocol due to elevated ALT levels, some presented with symptoms consistent with hepatitis, fever, or eosinophilia.

[0083] [Table 6]

[0084] conclusion Therapeutic doses of cannabidiol administered to healthy adults may result in elevated serum alanine aminotransferase levels consistent with drug-induced liver injury. Physicians should be vigilant about this potential effect of cannabidiol and be aware of its potential association with clinically significant liver damage.

[0085] Furthermore, abnormal liver chemical levels in healthy volunteers administered CBD at the doses used in this study were not previously observed at the high rate (44%) seen in this trial. Therefore, the DDI observed between CBD and caffeine may be influencing the DILI experienced by these patients.

[0086] Therefore, in patients receiving CBD who are also taking caffeine as a medication or for recreational purposes, it is essential to measure levels of CBD, caffeine, and liver enzymes (ALT, AST, and GGT). Care must be taken in these patients to ensure that DILI does not occur. To ensure that the patient's hepatic chemical levels are safe, it may be necessary to reduce the dose of CBD, caffeine, or both. (References) TIFF0007918101000007.tif165166

Claims

1. A pharmaceutical composition containing cannabidiol (CBD) for use in the treatment of childhood-onset epilepsy in patients concurrently taking caffeine, characterized in that the dose of cannabidiol (CBD) is in the range of 5 mg / kg / day to 20 mg / kg / day and the dose of caffeine is less than 200 mg / day.

2. The pharmaceutical composition according to claim 1, which monitors the blood levels of liver enzymes in a patient to ensure that they are not toxic.

3. The pharmaceutical composition according to claim 1 or 2, wherein the CBD is in the form of a cannabis extract containing at least 95% (w / w) CBD.

4. The pharmaceutical composition according to claim 1, wherein CBD is present as a synthetic compound.

5. The pharmaceutical composition according to claim 3, wherein the extract contains less than 0.15% THC.

6. The pharmaceutical composition according to claim 3, wherein the extract further comprises up to 1% CBDV.

7. A pharmaceutical composition according to any one of claims 1 to 6, wherein childhood-onset epilepsy is a condition selected from Douse syndrome, Siebons syndrome, and neuronal ceroid lipofuscinosis (NCL), or is caused by a gene mutation.

8. A pharmaceutical composition according to any one of claims 1 to 6, wherein childhood-onset epilepsy is a condition selected from Dravet syndrome, myquoronie's absence epilepsy, Lennox-Gastaut syndrome, generalized epilepsy of unknown cause, CDKL5 mutation, Aicardi syndrome, tuberous sclerosis, bilateral polymicrogyria, Dup15q, SNAP25, febrile infection-associated epilepsy syndrome (FIRES), benign Rolandic epilepsy, juvenile myoclonic epilepsy, infantile spasms (West syndrome), and Landau-Kleffner syndrome, or is caused by a gene mutation.

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