Treatment of tuberous sclerosis with cannabidiol and everolimus

Abstract

The present invention relates to the use of cannabidiol (CBD) preparations for use in the treatment of seizures associated with tuberous sclerosis (TSC). [Solution] In particular, the present invention includes the step of administering everolimus in combination with a reduced dose of cannabidiol (CBD). In an alternative embodiment, the present invention relates to the treatment of seizures associated with tuberous sclerosis in everolimus-untreated patients currently treated with CBD. Preferably, the dose of everolimus is reduced by at least 10%.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of priority under U.S. Provisional Patent Application No. 62 / 982,506 filed February 27, 2020, and U.S. Provisional Patent Application No. 2002754.6 filed February 27, 2020, the contents of which are all incorporated herein by reference in whole for all purposes. [Background technology]

[0002] Tuberous sclerosis (TSC) is a genetic disorder characterized by the proliferation (hamartomas) and malformations (hamathiostomies) of specific benign tumors in multiple organ systems. The leading causes of morbidity and mortality in TSC patients are tumors of the central nervous system (CNS), followed by kidney disease. TSC patients may suffer from brain abnormalities, including seizures, intellectual disability, and developmental delay, as well as abnormalities of the skin, lungs, kidneys, and heart. The disorder affects 25,000 to 40,000 individuals in the United States and approximately 1 to 2 million individuals worldwide, with an estimated prevalence of 1 in 6,000 newborns.

[0003] The genetic deletions or de novo mutations associated with TSCs (Transcranial Steroid Cholesterols) occur in one of two genes, TSC1 and TSC2. A problem in only one of these genes can lead to the development of TSCs. The TSC1 gene, located on chromosome 9, produces a protein called hamartin. The TSC2 gene, discovered in 1993, is located on chromosome 16 and produces a protein called tuberine. Scientists believe these proteins act as growth inhibitors in a complex by inhibiting the activation of a major evolutionarily conserved kinase called mTOR. Loss of mTOR regulation occurs in cells lacking hamartin or tuberine, leading to abnormal differentiation and development, as seen in brain lesions of TSCs, and ultimately to the formation of giant cells.

[0004] One-quarter to one-half of all children with TSC develop autism spectrum disorder (ASD). Almost all TSC patients also develop epilepsy, and most experience multiple seizure types. Furthermore, most TSC patients suffer from refractory epilepsy and are therefore resistant to treatment with one or more antiepileptic drugs. On average, TSC patients are resistant to five types of automated external defibrillators (AEDs).

[0005] Currently, there is no single therapy that can treat all conditions and symptoms associated with TSC. To treat tumors and epileptic seizures, TSC patients are typically administered combinations of drugs, such as mTor inhibitors (e.g., everolimus) and antiepileptic drugs. In addition to the fact that TSC is generally refractory to multiple antiepileptic drugs, antiepileptic drugs may exhibit adverse drug interactions ("DDIs") with everolimus. Therefore, there is a need for safe and effective methods of treating patients with everolimus and antiepileptic drugs. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Patent Application Publication No. 2019 / 0231833 [Patent Document 2] International Publication No. 2019 / 020738 [Patent Document 3] International Publication No. 2004 / 016277 [Patent Document 4] U.S. Patent Application Publication No. 2019 / 0160393 [Patent Document 5] International Publication No. 2004 / 026802 [Patent Document 6] U.S. Patent Application Publication No. 2019 / 0031601 [Patent Document 7] U.S. Patent No. 9,447,019 [Patent Document 8] U.S. Patent Application Publication No. 2015 / 0320698 [Patent Document 9] European Patent Application Publication No. 2578561 [Patent Document 10] U.S. Patent Application Publication No. 2017 / 0008868 [Patent Document 11] U.S. Patent Application Publication No. 2016 / 0010126 [Patent Document 12] International Publication No. 2017 / 139496 [Patent Document 13] U.S. Patent No. 10,111,840 [Patent Document 14] U.S. Patent Application Publication No. 2016 / 0166514 [Non-patent literature]

[0007] [Non-Patent Document 1] Cholongitas et al., “Systematic review: The model for end-stage liver disease--should it replace Child-Pugh's classification for assessing prognosis in cirrhosis?” Alimentary Pharmacology & Therapeutics, 22 (11-22): 1079–89 [Non-Patent Document 2] FDA-approved drug label for everolimus (AFINITOR® and AFINITOR DISPERZ®, updated January 2019) [Non-Patent Document 3] NCT02544750 [Non-Patent Document 4] GWEP17028 [Non-Patent Document 5] Clinical Drug Interaction Studies-Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry, FDA, January 2020 [Overview of the Initiative] [Means for solving the problem]

[0008] The applicant has discovered a safe and effective method for treating TSC patients with cannabidiol ("CBD") and everolimus.

[0009] In some embodiments, the present disclosure provides a method for treating TSC in a patient requiring treatment for TSC, comprising the step of administering everolimus in combination with a reduced dose of CBD.

[0010] In some embodiments, the patient is administered about 2 mg to about 10 mg of everolimus. In some embodiments, the patient is administered about 2.5 mg, about 5 mg, or about 10 mg of everolimus. In some embodiments, the patient is administered 2.5 mg or 5 mg of everolimus. In some embodiments, the patient is administered 2.5 mg of everolimus. In some embodiments, the patient is administered 5 mg of everolimus.

[0011] In some embodiments, the reduced dose of CBD is at least about 10% less than the dose of CBD the patient would normally receive in the absence of everolimus. In some embodiments, the reduced dose of CBD is 10% to 90% less than the dose of CBD the patient would normally receive in the absence of everolimus. In some embodiments, the reduced dose of CBD is in the range of about 5 mg / kg / day to about 20 mg / kg / day. In some embodiments, the reduced dose of CBD is about 5 mg / kg / day, about 7 mg / kg / day, about 9 mg / kg / day, about 10 mg / kg / day, about 12 mg / kg / day, about 14 mg / kg / day, about 15 mg / kg / day, about 16 mg / kg / day, about 18 mg / kg / day, or about 20 mg / kg / day. In some embodiments, the reduced dose of CBD is approximately 5 mg / kg / day, approximately 10 mg / kg / day, approximately 15 mg / kg / day, or approximately 20 mg / kg / day. In some embodiments, the reduced dose of CBD is approximately 5 mg / kg / day. In some embodiments, the reduced dose of CBD is approximately 10 mg / kg / day. In some embodiments, the reduced dose of CBD is approximately 15 mg / kg / day. In some embodiments, the reduced dose of CBD is approximately 20 mg / kg / day.

[0012] In some embodiments, the patient is administered 2.5 mg of everolimus and a reduced dose of CBD selected from the group consisting of approximately 5 mg / kg / day, approximately 10 mg / kg / day, approximately 15 mg / kg / day, and approximately 20 mg / kg / day. In some embodiments, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is selected from the group consisting of approximately 10 mg / kg / day, approximately 15 mg / kg / day, and approximately 20 mg / kg / day. In some embodiments, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is approximately 20 mg / kg / day. In some embodiments, the patient is administered 5 mg of everolimus and a reduced dose of CBD selected from the group consisting of approximately 5 mg / kg / day, approximately 10 mg / kg / day, approximately 15 mg / kg / day, and approximately 20 mg / kg / day. In some embodiments, the patient is administered 5 mg of everolimus and a reduced dose of CBD selected from the group consisting of approximately 10 mg / kg / day, approximately 15 mg / kg / day, and approximately 20 mg / kg / day. In some embodiments, the patient is administered 5 mg of everolimus and the reduced dose of CBD is approximately 20 mg / kg / day.

[0013] In some embodiments, CBD is present in highly purified plant-derived active pharmaceutical ingredients. In some embodiments, the CBD has a purity of at least 95 w / w%. In some embodiments, the CBD has a purity of at least 98 w / w%. In some embodiments, the CBD is synthetic CBD.

[0014] In some embodiments, the Disclosure provides a method for treating an everolimus-associated seizure in an everolimus-naive patient currently treated with CBD, comprising the steps of (a) administering everolimus to the patient, (b) monitoring the patient's everolimus plasma levels, and (c) reducing the dose of everolimus by at least 10% if the patient's everolimus plasma trough concentration exceeds 15 ng / mL. In some embodiments, the patient is treated with 25 mg / kg / day of CBD. In some embodiments, step (a) is 5 mg / m² 2The procedure includes the step of administering everolimus once daily. In some embodiments, step (a) is 5 mg / m² 2 The procedure includes administering an initial dose of everolimus once daily and adjusting the dose upward by 5 mg or less (e.g., 1, 2, 3, 4, or 5 mg). In some embodiments, the dose of everolimus is adjusted every 1-2 weeks until the patient's everolimus trough plasma concentration is in the range of 5-15 ng / mL. In some embodiments, monitoring in step (b) is performed for 1-2 weeks after the patient starts everolimus administration. In some embodiments, the dose of everolimus is reduced so that the everolimus trough plasma concentration is in the range of 5-15 ng / mL. In some embodiments, the dose of everolimus is C max The AUC is reduced to approximately 45 ng / mL, 40 ng / mL, 35 ng / mL, 30 ng / mL, 25 ng / mL, or 20 ng / mL or less (for example, by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%). In some embodiments, the dose of everolimus is reduced to AUC 0-24 The levels are reduced to approximately 490 h*ng / mL, approximately 450 h*ng / mL, approximately 400 h*ng / mL, approximately 350 h*ng / mL, approximately 300 h*ng / mL, approximately 250 h*ng / mL, or approximately 200 h*ng / mL or less.

[0015] In some embodiments, the present disclosure is a method for treating an everolimus-associated seizure in an everolimus-naive patient currently treated with CBD, comprising: (a) administering everolimus to the patient; (b) monitoring the patient's everolimus plasma levels; and (c) the patient's C max If the AUC exceeds 50 ng / mL, 0-last The present invention provides a method comprising the step of reducing the dose of everolimus by at least 10% if the CBD dose exceeds 500 hNg / mL. In some embodiments, the patient is treated with 25 mg / kg / day of CBD. In some embodiments, step (a) is 5 mg / m 2including the step of administering everolimus once a day. In some embodiments, step (a) is 5 mg / m 2 administering an initial dose of everolimus of once a day, and adjusting the dose of everolimus upward to 5 mg or less (e.g., 1, 2, 3, 4, or 5 mg). In some embodiments, the dose of everolimus is adjusted every 1-2 weeks until the trough concentration of everolimus in the patient's plasma is within the range of 5-15 ng / mL. In some embodiments, the monitoring in step (b) is performed 1-2 weeks after the start of everolimus administration to the patient. In some embodiments, the dose of everolimus is reduced so that the trough concentration of everolimus in the plasma is within the range of 5-15 ng / mL. In some embodiments, the dose of everolimus is reduced so that C max is about 45 ng / mL, about 40 ng / mL, about 35 ng / mL, about 30 ng / mL, about 25 ng / mL or about 20 ng / mL or less (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%). In some embodiments, the dose of everolimus is reduced so that the AUC 0-24 is about 490 h*ng / mL, about 450 h*ng / mL, about 400 h*ng / mL, about 350 h*ng / mL, about 300 h*ng / mL, about 250 h*ng / mL, or about 200 h*ng / mL or less.

[0016] In some embodiments, the seizures are focal seizures. In some embodiments, focal seizures are focal motor seizures without impaired consciousness or state of consciousness; focal seizures with impaired consciousness or state of consciousness; or focal seizures that develop into bilateral generalized seizures and generalized seizures. In some embodiments, generalized seizures are tonic-clonic, tonic, clonic, or atonic seizures. In some embodiments, the seizures are generalized seizures. In some embodiments, generalized seizures are tonic-clonic, tonic, clonic, or atonic seizures. In some embodiments, the total number of seizures is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline. In some embodiments, the total number of seizures is reduced by at least 50% compared to baseline. In some embodiments, the total number of focal seizures is reduced by at least 50% compared to baseline. In some embodiments, focal seizures are focal motor seizures without impaired consciousness or state of consciousness; focal seizures with impaired consciousness or state of consciousness; or focal seizures that develop into bilateral generalized seizures and generalized seizures. In some embodiments, the total number of tonic-clonic, tonic, clonic, atonic, or absence seizures is reduced by at least 50% compared to baseline.

[0017] In some embodiments, the Disclosure provides a method for treating seizures associated with tuberous sclerosis in a patient requiring treatment for seizures associated with tuberous sclerosis, comprising the step of administering 2.5 to 10 mg of everolimus in combination with cannabidiol (CBD), wherein the CBD has a purity of at least 95 w / w%, and the CBD is administered in a dose ranging from about 10 mg / kg / day to about 20 mg / kg / day. In some embodiments, the patient is administered about 2.5 mg, about 5 mg, or about 10 mg of everolimus. In some embodiments, the patient is administered 2.5 mg or 5 mg of everolimus. In some embodiments, the dose of CBD is about 10 mg / kg / day, about 15 mg / kg / day, or about 20 mg / kg / day. In some embodiments, the dose of CBD is about 20 mg / kg / day. In some embodiments, the seizures are focal seizures. In some embodiments, a focal seizure is a focal motor seizure without impaired consciousness or state of consciousness; a focal seizure with impaired consciousness or state of consciousness; or a focal seizure that develops into a bilateral generalized seizure or generalized seizure. In some embodiments, a generalized seizure is a tonic-clonic, tonic, clonic, or atonic seizure. In some embodiments, a seizure is a generalized seizure. In some embodiments, a generalized seizure is a tonic-clonic, tonic, clonic, or atonic seizure. In some embodiments, the total number of seizures is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline. In some embodiments, the total number of seizures is reduced by at least 50% compared to baseline. In some embodiments, the total number of focal seizures is reduced by at least 50% compared to baseline. In some embodiments, a focal seizure is a focal motor seizure without impaired consciousness or state of consciousness; a focal seizure with impaired consciousness or state of consciousness; or a focal seizure that develops into a bilateral generalized seizure or generalized seizure. In some embodiments, the total number of tonic-clonic, tonic, clonic, atonic, or absence seizures is reduced by at least 50% compared to baseline. [Brief explanation of the drawing]

[0018] [Figure 1] This diagram schematically shows a prototype design for measuring the pharmacokinetic effects of everolimus (5 mg daily dose) on CBD (25 mg / kg / day). [Figure 2] This figure shows the everolimus blood concentration profiles (ng / mL) in patients who received everolimus alone and in patients who received both everolimus and CBD. [Figure 3] This figure shows the CBD blood concentration profiles (ng / mL) in patients who received CBD alone and in patients who received both everolimus and CBD. [Figure 4] This figure shows the 1-OH-CBD blood concentration profiles (ng / mL) in patients who received CBD alone and in patients who received both everolimus and CBD. [Figure 5] This figure shows the 1-COOH-CBD blood concentration profiles (ng / mL) in patients who received CBD alone and in patients who received both everolimus and CBD. [Modes for carrying out the invention]

[0019] definition In this specification, the term “about” refers to the degree of variation that is acceptable in the art. In some embodiments, “about” means ±10% of the referenced value, unless otherwise stated or a different interpretation is evident from the context, and unless such a range exceeds 100% of the possible value or falls below 0% of the possible value, for example, when the content of a certain component is less than 0% or the total content of the composition is greater than 100%.

[0020] The terms "a" or "an" refer to one or more entities. For example, "antiepileptic drug" (AED) refers to one or more AEDs or at least one AED. Therefore, the terms "a" (or "an"), "one or more," and "at least one" are used synonymously in this specification. Furthermore, a reference to an "element" with the indefinite article "a" or "an" does not rule out the possibility that there may be more than one element unless the context explicitly requires that there is one element and only one.

[0021] In some embodiments, the composition contains cannabidiol ("CBD"). Herein, CBD refers to synthetic CBD or a cannabis extract containing 95 w / w% to 100 w / w% CBD. In some embodiments, the CBD extract may contain about 95 w / w%, about 96 w / w%, about 97 w / w%, about 98 w / w%, about 99 w / w%, or about 100 w / w% CBD. In some embodiments, the CBD extract contains 98 w / w% CBD. Such a cannabis extract containing at least 95 w / w% CBD may be referred to as a high-purity plant-based active pharmaceutical ingredient. In some embodiments, the CBD extract contains about 99 w / w% CBD. Unless otherwise noted, references to CBD in this disclosure should be understood as references to the decarboxylated version of CBD and not to acidic CBDA.

[0022] In this specification, when modifying CBD, “purity” and “pure” refer to the mass of CBD in the active pharmaceutical ingredient (API) relative to the total mass of all cannabinoids in the API. Additional cannabinoids that may be present in the API include, but are not limited to, CBDV, Δ9THC, and CBD-C4, and combinations thereof. To avoid doubt, API is different from pharmaceutical. Pharmaceutical refers to a pharmaceutical composition containing API. Therefore, when this disclosure refers to administering CBD having a purity of at least 95 w / w% (or similar expression), purity refers to CBD in the API, not CBD in the pharmaceutical.

[0023] As defined herein, a “reduced dose” of CBD is lower than the dose that an otherwise identical TSC patient would receive if everolimus were not co-administered. In other words, a reduced dose of CBD administered to a TSC patient in combination with everolimus is lower than the dose of CBD administered to the same (or similar) TSC patient in the absence of everolimus. The dose of CBD that a patient would normally receive in the absence of everolimus (i.e., if the patient were not co-administered with everolimus) is sometimes referred to as the “reference dose” or “recommended dose” of CBD. The terms “reference dose” and “recommended dose” may be used synonymously. Furthermore, “reference dose” and “recommended dose” are different from the “initial dose.” The “initial dose” is the dose administered to the patient to initiate treatment. The “initial dose” is a lower dose than the “reference dose,” and after being administered for a period of time (e.g., over a one-week course), the patient increases the dose to the “reference dose.”

[0024] In some embodiments, the “reference dose” or “recommended dose” of CBD is in the range of approximately 10 mg / kg / day to approximately 50 mg / kg / day. In some embodiments, the “reference dose” of CBD is the dose approved (e.g., by the FDA or EMA) to treat seizures in a particular patient. For virtually all FDA-approved drugs, the “recommended” dose (or dose) of the drug is determined based on the plasma level (or range of plasma levels) of the drug required to produce the desired clinical effect and / or to avoid undesirable side effects. The recommended dose of a particular drug is the dose recognized as appropriate for treating patients with (or within a range of) certain physical characteristics in the art, and is therefore the dose listed in the drug’s package insert. There may be multiple recommended doses for a particular condition. For example, there are two recommended doses of EPIDIOLEX® for treating seizures associated with Lennox-Gastaut or Dravet syndrome: (1) a maintenance dose of 10 mg / kg / day and (2) a maximum recommended maintenance dose of 20 mg / kg / day (revised 11 / 2018; 7 / 2020). To avoid ambiguity, both doses (i.e., (1) and (2)) are considered “recommended doses” as defined herein. Therefore, in various embodiments, the methods of this disclosure concern adjustments or modifications to the administration of CBD to the FDA “recommended” doses, for example, as described in the CBD package insert, which are suitable for treating TSC patients with specific physical characteristics. Patients with moderate or severe hepatic impairment may receive different recommended doses of CBD as described herein and in accordance with the EPIDIOLEX® drug labeling (revised 11 / 2018; 7 / 2020), so hepatic impairment can be cited as a specific characteristic. Therefore, in this specification, the “reference dose” or “recommended dose” of CBD may differ from the dose that may be disclosed by a specific physician for a specific patient. Depending on the specific pharmacokinetics and pharmacokinetics of the drug, the recommended dose may vary depending on one or more physical and physiological characteristics of the patient, such as age, sex, weight, body mass index, hepatic metabolic enzyme status (e.g., low or high metabolic rate), medical condition, etc.

[0025] At the time of this disclosure, the applicant intends that the approved CBD dosage for TSC (in the absence of everolimus) is in the range of 5 mg / kg / day to 25 mg / kg / day (for example, for patients with normal liver function or mild hepatic impairment). The applicant intends that a TSC patient would receive a starting dose of 5 mg / kg / day of CBD, and that the starting dose could be increased to achieve and / or maintain efficacy. Typically, the effective dose may be 10 mg / kg / day, about 15 mg / kg / day, about 20 mg / kg / day, or about 25 mg / kg / day when administered in the absence of everolimus, but the exact effective dose will depend on the specific patient and the patient's physical and physiological characteristics. Therefore, in some embodiments, the “reference dose” of CBD is about 10 mg / kg / day, about 15 mg / kg / day, about 20 mg / kg / day, or about 25 mg / kg / day. In July 2020 (after the priority date of this application), the FDA approved CBD for the treatment of seizures associated with TSC. According to the EPIDIOLEX® drug labeling (revised 7 / 2020), the recommended dose for treating seizures associated with TSC is 25 mg / kg / day (for example, for patients with normal liver function or mild hepatic impairment). Therefore, in some embodiments, the reduced dose is lower than the reference dose of EPIDIOLEX® approved for treating seizures associated with TSC, 25 mg / kg / day, in accordance with the EPIDIOLEX® drug labeling (revised 7 / 2020).

[0026] In some embodiments, the methods of the present disclosure provide a reduction in the dose of CBD that a patient would normally receive in the absence of everolimus. For example, if a TSC patient is administered CBD at 10 mg / kg / day in the absence of everolimus, when everolimus is co-administered, the TSC patient receives a reduced dose of less than 10 mg / kg / day (e.g., about 1 mg / kg / day, about 2 mg / kg / day, about 3 mg / kg / day, about 4 mg / kg / day, about 5 mg / kg / day, about 6 mg / kg / day, about 7 mg / kg / day, about 8 mg / kg / day, or about 9 mg / kg / day). For example, if a TSC patient is administered CBD at 15 mg / kg / day in the absence of everolimus, when everolimus is co-administered, the TSC patient will receive a reduced dose of less than 15 mg / kg / day (e.g., approximately 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, 9 mg / kg / day, 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, or 14 mg / kg / day). As another example, if a TSC patient is administered CBD at 20 mg / kg / day in the absence of everolimus, when everolimus is co-administered, the TSC patient will receive a reduced dose of less than 20 mg / kg / day (e.g., approximately 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, 9 mg / kg / day, 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, 14 mg / kg / day, 15 mg / kg / day, 16 mg / kg / day, 17 mg / kg / day, 18 mg / kg / day, 19 mg / kg / day).As yet another example, when a TSC patient is administered CBD at 25 mg / kg / day in the absence of everolimus, when everolimus is co-administered, the TSC patient should be given a reduced dose of less than 25 mg / kg / day (for example, approximately 1 mg / kg / day, approximately 2 mg / kg / day, approximately 3 mg / kg / day, approximately 4 mg / kg / day, approximately 5 mg / kg / day, approximately 6 mg / kg / day, approximately 7 mg / kg / day, approximately 8 mg / kg / day, approximately 9 mg / kg / day). The dose received is approximately 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, 14 mg / kg / day, 15 mg / kg / day, 16 mg / kg / day, 17 mg / kg / day, 18 mg / kg / day, 19 mg / kg / day, 20 mg / kg / day, 21 mg / kg / day, 22 mg / kg / day, 23 mg / kg / day, or 24 mg / kg / day). In this specification, the amount of CBD (unit: mg / kg / day or mg / kg) refers to the amount of active pharmaceutical ingredient (i.e., CBD) administered, regardless of the purity of CBD in the active pharmaceutical ingredient.

[0027] In this specification, “to treat” or “to treat” means one or more of the relief, reduction, delay, decrease, improvement, improvement, or management of at least one symptom of a condition in the subject. Such symptoms may include, but are not limited to, the onset, frequency, or duration of one or more types of seizures. Seizures associated with TSC may include, but are not limited to, infantile seizures, focal seizures (with or without impaired consciousness or state of consciousness; bilateral generalized seizures and focal seizures that develop into generalized seizures), tonic seizures, clonic seizures, tonic-clonic seizures, atonic seizures, myoclonic seizures, and absence seizures. The term “to treat” may also mean one or more of the onset (i.e., the period prior to the clinical manifestation of the condition) or the risk of developing or worsening the condition.

[0028] In this specification, the terms “otherwise identical patients” or “otherwise identical patients not co-administered with everolimus” refer to patients whose physical characteristics related to drug (e.g., CBD) administration are expected to be substantially the same as those of patients treated with reduced doses of CBD according to the methods of this disclosure, except that the patients are not concurrently administered everolimus. In some embodiments, otherwise identical patients are substantially the same age, sex, and weight. In some embodiments, substantially identical patients also have substantially the same liver function and drug metabolism.

[0029] In this specification, the term "co-administered" means that one or more drugs are administered on the same day. In some embodiments, one or more drugs (e.g., cannabidiol and everolimus) are administered sequentially. In some embodiments, one or more drugs (e.g., cannabidiol and everolimus) are administered simultaneously.

[0030] In this specification, “hepatic impairment” means a decrease in the execution and metabolic function of the liver compared to a normally functioning, otherwise healthy liver. The liver is involved in the clearance of many drugs through various oxidative and conjugation metabolic pathways and / or by biliary excretion of unchanged drugs or metabolites. Modifications of these execution and metabolic activities due to hepatic impairment can lead to drug accumulation or, less frequently, failure of active metabolite formation. In some embodiments, hepatic impairment can be determined using the Child-Pugh score. The Child-Pugh score is described in Cholongitas et al., “Systematic review: The model for end-stage liver disease--should it replace Child-Pugh’s classification for assessing prognosis in cirrhosis?”, Alimentary Pharmacology & Therapeutics, 22 (11-22):1079-89, which is incorporated herein by reference in its entirety.

[0031] The Child-Pugh score employs five clinical measures of liver disease. Each measure takes a score from 1 to 3, with 3 indicating the most severe impairment. The Child-Pugh score should be calculated using either the prothrombin time method or INR, but not both.

[0032] [Table 1]

[0033] Chronic liver disease is classified into Child-Pugh classes A to C using a score system that adds up from the top.

[0034] [Table 2]

[0035] In some embodiments, patients with "mild hepatic impairment" have a Child-Pugh score of A. In some embodiments, patients with "moderate hepatic impairment" have a Child-Pugh score of B. In some embodiments, patients with "severe hepatic impairment" have a Child-Pugh score of C.

[0036] In some embodiments, “mild hepatic impairment” is defined as bilirubin ≤ 1 × upper limit of the normal range ("ULN") and aspartate aminotransferase ("AST") > 1 × ULN, or bilirubin > 1.0–1.5 × ULN with any amount of AST exceeding ULN. In some embodiments, “moderate hepatic impairment” is defined as bilirubin > 1.5–3.033 × ULN with any amount of AST exceeding ULN. In some embodiments, “severe hepatic impairment” is defined as bilirubin ≥ 3.0 × ULN with any amount of AST exceeding ULN. In some embodiments, serum transaminase (ALT and AST) and total bilirubin levels are obtained before initiating treatment.

[0037] A method for treating TSC using CBD and everolimus. Patients with TSC have treatment-resistant epilepsy. This form of epilepsy involves several seizure types, including, but is not limited to, infantile seizures, focal seizures (with or without impaired consciousness or state of consciousness; bilateral generalized seizures and focal seizures that develop into generalized seizures), tonic seizures, clonic seizures, tonic-clonic seizures, atonic seizures, myoclonic seizures, and absence seizures. Patients with TSC also exhibit non-cancerous growths in many parts of the body, including the brain, skin, kidneys, and other organs. This disclosure provides a method for managing seizures in a patient diagnosed with TSC, comprising the step of administering everolimus in combination with a reduced dose of CBD.

[0038] CBD (brand name EPIDIOLEX®) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome at doses ranging from 5 mg / kg / day to 20 mg / kg / day. Everolimus is approved by the FDA at 4.5 mg / m² for the treatment of TSC patients with subependymal giant cell astrocytoma (SEGA). 2 10 mg once daily for the treatment of TSC-associated renal angiomyolipoma, 5 mg / m² once daily orally as adjunctive treatment for TSC-associated partial-origin seizures. 2 It is approved for once-daily administration.

[0039] Since TSC patients also experience the seizures described herein, the applicant has found that CBD can be used in combination with everolimus to treat TSC patients. In fact, in July 2020, after the priority date of this application, the FDA approved CBD for the treatment of seizures associated with TSC. According to the EPIDIOLEX® drug labeling (revised 7 / 2020), the recommended dose for treating seizures associated with TSC is 25 mg / kg / day (for example, in patients with normal liver function or mild hepatic impairment). However, the applicant has discovered a potentially serious and harmful drug interaction ("DDI") between CBD and everolimus. The applicant has found that reducing the dose of everolimus (for example, as prescribed in the everolimus package insert or drug labeling) is insufficient to address the DDI between CBD and everolimus. In some embodiments, the applicant has found, surprisingly and unexpectedly, that the reference dose of CBD must be reduced to safely treat TSC patients concurrently treated with everolimus, and that this reduced dose is also effective. In some embodiments, the applicant has found, surprisingly and unexpectedly, that reducing the doses of both CBD and everolimus is critically important for safely and effectively co-administering CBD and everolimus to treat TSC.

[0040] The most common type of drug-mediated drug injector (DDI) involves the inhibition or induction of one or more drug-metabolizing enzymes by a drug. When an inhibitor or inducer of a specific drug-metabolizing enzyme is co-administered with a drug metabolized by that enzyme (called a substrate of that enzyme), the pharmacokinetic parameters of one or both drugs change, leading to an increase or decrease in drug exposure. It is this change in exposure that can result in adverse events. However, an increase in pharmacokinetic parameters alone does not necessarily cause adverse events or necessitate dose modification. Dose modification is only necessary if the increase in pharmacokinetic parameters poses a risk to the patient. However, dose modification is unpredictable. Reducing the dose too much risks inadequate treatment of the patient, while overdosing (e.g., not reducing the dose or not reducing the dose sufficiently) may increase exposure to potentially dangerous levels.

[0041] The target drug is classified as a weak, moderate, or strong CYP3A inhibitor based on its effect on the plasma area under the curve (AUC) of the prototype CYP3A4 / CYP3A5 substrate midazolam. If the target drug increases the AUC of midazolam by ≥5 times, it is a strong CYP3A inhibitor. If the target drug increases the AUC of midazolam by >2.0 to 4.9 times, it is a moderate CYP3A inhibitor. If the target drug increases the AUC of midazolam by ≤2 times, it is a weak CYP3A inhibitor.

[0042] According to the FDA-approved drug labeling (sometimes called prescribing information) for everolimus (AFINITOR® and AFINITOR DISPERZ®, updated January 2019, the entire label is incorporated herein by reference), everolimus is a substrate of P-gp and CYP3A4. Everolimus has also been reported to be a substrate of CYP3A5 and CYP2C8.

[0043] The combination of P-pg and CYP3A4 inhibitors is known to increase everolimus exposure. For example, P-gp and ketoconazole, a strong CYP3A4 inhibitor, are known to increase everolimus C max It increases the AUC by 3.9 times and 15 times, respectively. Erythromycin, a P-gp and moderate CYP3A4 inhibitor, increases the C of everolimus. max It increases the AUC by 2.0 and 4.4 times, respectively. Verapamil, a P-gp and moderate CYP3A4 inhibitor, is a C25 of everolimus. max And the AUC is increased by 2.3 times and 3.5 times, respectively.

[0044] The FDA labeling for everolimus contraindicates concomitant administration of everolimus with P-gp and strong CYP3A4 inhibitors. Regarding P-gp and moderate CYP3A4 inhibitors, the labeling for everolimus indicates a dose reduction. Specifically, for patients with TSC-associated renal angiomyolipoma, the labeling instructs patients to reduce the everolimus dose to 2.5 mg once daily. The labeling also instructs to increase the dose to 5 mg if tolerable. Three days after discontinuing P-gp and moderate CYP3A4 inhibitors, patients may resume treatment with everolimus at the dose administered before the use of the inhibitors. In patents relating to TSC-associated SEGA and TSC-associated partially originating seizures, the labeling instructs patients to reduce the daily dose (as described herein and in the FDA labeling) by 50%. If the reduced dose is lower than the lowest available strength of everolimus, patients should switch to every other day administration. Three days after discontinuing P-gp and moderate CYP3A4 inhibitors, patients may resume treatment with everolimus at the dose they were receiving before the use of the inhibitors.

[0045] The label also indicates that everolimus exhibits low levels of CYP3A4 or CYP2D6 inhibition, but the interaction was considered "not clinically significant" (Chapter 12.3 of the AFINITOR / AFINITOR DISPERZ Label). Specifically, co-administration of oral midazolam (a sensitive CYP3A4 substrate) with AFINITOR showed that midazolam's C max The AUC of midazolam increased by 25%. 0-inf It increased by 30%. Similarly, co-administration of everolimus with other CYP3A4 substrates, including atorvastatin, pravastatin, and simvastatin, was considered clinically insignificant and did not produce pharmacodynamic results. Therefore, prior to this disclosure, it was not anticipated that everolimus would produce clinically significant drug interactions through CYP3A4 or CYP2D6 inhibition. In light of the above, it was not anticipated that the dosage of drugs such as CBD co-administered with everolimus should be reduced to safely treat TSC patients.

[0046] The pharmacological properties of CBD are not fully understood. As indicated on the FDA-approved labeling of EPIDIOLEX®, CBD is metabolized in the liver and intestines and is a substrate for the CYP2C19 and CYP3A4 enzymes and the UGT1A7, UGT1A9, and UGT2B7 isoforms. 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 may inhibit CYP3A4, but the intensity or clinical significance of this interaction is unknown. CBD may also induce or inhibit CYP1A2 and CYP2B6 at clinically significant concentrations, but the intensity or clinical significance of this interaction is unknown. Therefore, it is unknown whether CBD is a strong, moderate, or weak inhibitor of any CYP isoform, or whether CBD-mediated inhibition of any of these enzymes actually produces clinically significant results. Finally, the applicant has found that 7-COOH-CBD, a metabolite of CBD, is a substrate of P-gp. 7-COOH-CBD is an inhibitor of BCRP and BSEP-mediated transport at clinically significant concentrations.

[0047] The applicant has found that elevated CBD levels result in elevated transaminases, rash, somnolence, sedation, lethargy, diarrhea, fever, weight loss, nasopharyngitis, irritability, oropharyngeal pain, and decreased appetite. Transaminases may cause hepatic dysfunction, including unexplained nausea, vomiting, right upper quadrant pain, fatigue, loss of appetite, or jaundice and / or dark urine. Increased exposure to everolimus is known to cause non-infectious pneumonitis, infection, severe hypersensitivity to reactions, angioedema, stomatitis, renal failure, impaired wound healing, metabolic disorders, bone marrow suppression, risk of infection or reduced immune response due to vaccination, embryo-fetal toxicity, and stomatitis and respiratory tract infections. The methods of the present disclosure reduce the incidence of one or more of the above-mentioned side effects.

[0048] The applicant found that when CBD is administered orally in combination with midazolam at steady state, CBD does not have a clinically significant effect on the pharmacokinetic parameters of midazolam (see Example 2). In other words, from the DDI with midazolam (if any), it is expected that CBD is a weak inhibitor of CYP3A4. Therefore, CBD should not have a clinically significant effect on everolimus (a CYP3A4 substrate drug). Similarly, from the everolimus DDI studies described herein, it is expected that everolimus should not have a clinically significant effect on CBD. However, the applicant unexpectedly found that a potentially clinically significant DDI occurs when everolimus and CBD are co-administered. While not bound by any particular theory, the DDI observed by the applicant may be due to a previously unknown mechanism by which CBD inhibits P-gp-mediated everolimus efflux. The everolimus label does not include instructions for adjusting the dose when administered with P-gp inhibitors that are neither moderate nor strong CYP3A4 inhibitors. Furthermore, the combined CYP3A4 inhibition by both CBD and everolimus may be significant enough to produce novel and unexpected pharmacodynamic effects.

[0049] Prior to the present applicant's invention, administration of everolimus according to FDA-approved labeling instructions was considered sufficient to address drug-induced drug ingestion (DDI). For example, with the combined P-gp and moderate CYP3A4 inhibitor, the everolimus labeling instructs patients to reduce the everolimus dose from 10 mg to 5 mg, and then to 2.5 mg. Although CBD is not known to be a moderate CYP3A4 inhibitor, it was expected that the FDA-approved adjustment of the everolimus dose would be sufficient to address the DDI caused by CBD. However, the present applicant was surprised to find that in patients already treated with everolimus at the time of initiating CBD treatment, the adjustment was insufficient and clinically significant interactions persisted. Further reduction of the everolimus dose was not possible without sacrificing the clinical efficacy of everolimus.

[0050] In several embodiments, the applicant has found that dose reduction of CBD, in addition to the dose reduction of everolimus recommended by FDA labeling, is necessary to safely and effectively manage seizures in patients with TSC. In several embodiments, reduced doses of CBD and everolimus that are effective when co-administered are ineffective when CBD and everolimus are not co-administered (e.g., when the reduced dose of CBD is administered without everolimus, or when everolimus is administered without CBD). In several embodiments, the reduced dose of CBD is below the approved dose for TSC but falls within the approved range for managing seizures associated with other forms of epilepsy (e.g., Lennox-Gastaut syndrome and Dravet syndrome).

[0051] For the purposes of this disclosure, “reduced dose” may also be referred to as dose reduction, down dose, downward dose, or downward tapering. For example, in some embodiments, the recommended dose of CBD for treating seizures associated with TSC is 25 mg / kg / day. When the patient is co-administered with everolimus, the patient may downward adjust the CBD dose to 20 mg / kg / day, 15 mg / kg / day, or 10 mg / kg / day. Similarly, dose reduction, down dose, or downward dose of CBD may be necessary, desired, or considered in order to safely and effectively treat seizures associated with TSC.

[0052] In some embodiments, this disclosure provides a method for treating seizures associated with TSC in everolimus-naive patients, wherein the patient is currently being treated with CBD and requires treatment with everolimus. Herein, “everolimus-naive patient” refers to a patient who is not currently being treated with everolimus. Conversely, an everolimus-naive patient is currently being treated with CBD to reduce seizures and requires everolimus. The term “everolimus-naive patient” includes patients who may have been previously treated with everolimus, provided they were not being treated with everolimus when they began receiving CBD treatment. In some embodiments, the method monitors the patient’s everolimus plasma level and, when the trough plasma level of everolimus exceeds 15 ng / mL, C max The procedure includes reducing the dose of everolimus (for example, by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%) when (ss) is greater than or equal to approximately 46 ng / mL, 40 ng / mL, 35 ng / mL, 30 ng / mL, 25 ng / mL, or 20 ng / mL (including all values ​​and ranges in between).

[0053] Cannabidiol (CBD) CBD has the following structure.

[0054] [ka]

[0055] CBD is a cannabinoid that can be produced by synthesis or extracted from the cannabis plant. In some embodiments, cannabidiol is extracted from the cannabis plant. Non-limiting examples of cannabis plants include Cannabis sativa, Cannabis indica, or Cannabis ruderalis. In some embodiments, CBD is extracted from cannabis hybrids. CBD can be extracted from the cannabis plant according to methods known in the art. Such extracts may be synonymously called CBD extracts, plant extracts, or plant active pharmaceutical ingredients. Non-limiting extraction methods include sonication, reflux heating, Soxhlet extraction, solid-phase microextraction, supercritical fluid extraction, pressurized liquid extraction, microwave-assisted extraction, solid-phase extraction, and surfactant-mediated techniques. In some embodiments, the extraction step may include, but is not limited to, pre-washing, drying or freeze-drying of plant parts and grinding to obtain a homogeneous extract of plant material.

[0056] In some embodiments, cannabidiol is extracted using an alcohol-based extraction. In some embodiments, cannabidiol is extracted with ethanol. In some embodiments, cannabidiol is obtained using a supercritical carbon dioxide-based extraction. Methods for extracting CBD from the cannabis plant are described in the following patent documents, which are incorporated herein by reference in their entirety: U.S. Patent Application Publication 2019 / 0231833A1 (published August 1, 2019), International Publication 2019 / 020738 (published January 31, 2019), International Publication 2004 / 016277A1 (published February 26, 2004), U.S. Patent Application Publication 2019 / 0160393A1 (published May 30, 2019), and International Publication 2004 / 026802 (published January 4, 2004).

[0057] In some embodiments, cannabidiol is produced by synthesis. As described herein, synthetic cannabidiols include CBD analogs, CBD salts, modified CBD, and propylcannabinoids (CBDv). Synthetic CBD has the same or similar therapeutic effects as naturally occurring CBD when administered to a subject. Patent documents describing synthetic cannabinoids, such as U.S. Patent Application Publication 2019 / 0031601 (published January 31, 2019), U.S. Patent No. 9,447,019 (issued September 20, 2016), and U.S. Patent Application Publication 2015 / 0320698 (published November 12, 2015), are incorporated herein by reference in their entirety.

[0058] Methods for synthesizing cannabidiol are described in the following patent documents, which are incorporated herein by reference in their entirety: European Patent Application Publication No. 2578561A1 (published April 10, 2013) and U.S. Patent Application Publication No. 2017 / 0008868A1 (published August 28, 2018). In some embodiments, cannabidiol is produced in microorganisms. Methods for producing cannabidiol in microorganisms are described in U.S. Patent Application Publication No. 2016 / 0010126A1 (published January 14, 2016) and International Publication No. 2017 / 139496 (published August 17, 2016), which are incorporated herein by reference in their entirety.

[0059] In some embodiments, CBD is present in a plant extract. In such an extract, the CBD has a purity of about 95 w / w% to about 100 w / w%. In some embodiments, the CBD has a purity of at least about 95 w / w%, about 96 w / w%, about 97 w / w%, about 98 w / w%, or about 99 w / w%, including all intermediate values ​​and ranges. In some embodiments, the CBD has a purity of at least about 98 w / w%. In some embodiments, the CBD has a purity of at least about 99 w / w%. In view of the foregoing, in this specification, “CBD” refers to CBD having a purity in the range of about 95% to about 100%, for example, CBD with a purity of at least about 98 w / w%.

[0060] In some embodiments, the CBD extract of the Disclosure contains up to about 5 w / w% of other cannabinoids and / or terpenes. In some embodiments, the CBD extract of the Disclosure contains up to about 2 w / w% of other cannabinoids and / or terpenes. In some embodiments, the CBD extract of the Disclosure contains up to about 5 w / w%, about 2 w / w%, or up to about 1% of other cannabinoids, but substantially no terpenes. In fact, the presence of these additional components can affect the pharmacological properties of CBD administered according to the method of the Disclosure. Non-limiting examples of cannabinoids include cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabiclomevalin (CBCV), cannabigerovalin (CBGV), cannabigerol monomethyl ether (CBGM), tetrahydrocannabinol (THC), cannabidiolic acid (CBDA), cannabidiol-C4 (CBD-C4), cannabidiol-C1 (CBD-C1), cannabidiol-C1 type (CBEI), cannabidiol-C2 type (CBEII), 6-OH-cannabidiol, 7-OH-cannabidiol, and tetrahydrocannabinolic acid (THCA). Non-limiting examples of terpenes include α-cedrene, α-humulene, α-pinene, α-terpinene, β-myrcene, β-pinene, borneol, camphene, camphor, caryophyllene oxide, cedrol, α-bisabolol, α-phellandrene, isopuregol, cis-nerolidol, 3-carene, fenquil alcohol, hexahydrothymol, eucalyptol, isoborneol, farnesene, fencone, γ-terpinene, geraniol, geranyl acetate, humulene, guaiol, limonene, linalool, nerol, ocimene, α-phellandrene, pulegone, sabinene, sabinene hydrate, terpineol, terpinolene, trans-caryophyllene, β-caryophyllene, trans-nerolidol, and valencene.

[0061] In some embodiments, the CBD extract of this disclosure contains up to about 1 w / w% CBDV. In some embodiments, the CBD extracts of this disclosure contain approximately 0 w / w%, approximately 0.05 w / w%, approximately 0.1 w / w%, approximately 0.15 w / w%, approximately 0.2 w / w%, approximately 0.25 w / w%, approximately 0.30 w / w%, approximately 0.35 w / w%, approximately 0.40 w / w%, approximately 0.45 w / w%, approximately 0.50 w / w%, approximately 0.55 w / w%, approximately 0.60 w / w%, approximately 0.65 w / w%, approximately 0.70 w / w%, approximately 0.75 w / w%, approximately 0.80 w / w%, approximately 0.85 w / w%, approximately 0.90 w / w%, approximately 0.95 w / w%, or approximately 1.0 w / w% CBDV, including all intermediate values ​​and ranges.

[0062] In some embodiments, the CBD extract of this disclosure contains up to about 1 w / w% THC. In some embodiments, the CBD extracts of this disclosure contain approximately 0 w / w%, approximately 0.05 w / w%, approximately 0.1 w / w%, approximately 0.15 w / w%, approximately 0.2 w / w%, approximately 0.25 w / w%, approximately 0.30 w / w%, approximately 0.35 w / w%, approximately 0.40 w / w%, approximately 0.45 w / w%, approximately 0.50 w / w%, approximately 0.55 w / w%, approximately 0.60 w / w%, approximately 0.65 w / w%, approximately 0.70 w / w%, approximately 0.75 w / w%, approximately 0.80 w / w%, approximately 0.85 w / w%, approximately 0.90 w / w%, approximately 0.95 w / w%, or approximately 1.0 w / w% THC, including all intermediate values ​​and ranges.

[0063] In some embodiments, the CBD extract of the Disclosure contains up to about 0.5 w / w% of CBD-C4. In some embodiments, the CBD extract of the Disclosure contains about 0 w / w%, about 0.05 w / w%, about 0.1 w / w%, about 0.15 w / w%, about 0.2 w / w%, about 0.25 w / w%, about 0.30 w / w%, about 0.35 w / w%, about 0.40 w / w%, about 0.45 w / w%, or about 0.50 w / w% of CBD-C4.

[0064] In some embodiments, the CBD extract of this disclosure contains up to about 0.15 w / w% CBD-C1. In some embodiments, the CBD extract of this disclosure contains about 0 w / w%, about 0.005 w / w%, about 0.01 w / w%, about 0.015 w / w%, about 0.02 w / w%, about 0.025 w / w%, about 0.030 w / w%, about 0.035 w / w%, about 0.040 w / w%, and about 0.045 w / w%, including all intermediate values ​​and ranges. Contains CBD-C1 in the following proportions: %, approximately 0.050 w / w%, approximately 0.055 w / w%, approximately 0.060 w / w%, approximately 0.065 w / w%, approximately 0.070 w / w%, approximately 0.075 w / w%, approximately 0.080 w / w%, approximately 0.085 w / w%, approximately 0.090 w / w%, approximately 0.095 w / w%, approximately 0.10 w / w%, or approximately 0.15 w / w%.

[0065] In some embodiments, the CBD extract of the Disclosure contains up to about 0.2 w / w% CBEI. In some embodiments, the CBD extract of the Disclosure contains about 0 w / w%, about 0.005 w / w%, about 0.01 w / w%, about 0.015 w / w%, about 0.02 w / w%, about 0.025 w / w%, about 0.030 w / w%, about 0.035 w / w%, about 0.040 w / w%, about 0.045 w / w%, and about 0. Includes CBEI of 0.050 w / w%, approximately 0.055 w / w%, approximately 0.060 w / w%, approximately 0.065 w / w%, approximately 0.070 w / w%, approximately 0.075 w / w%, approximately 0.080 w / w%, approximately 0.085 w / w%, approximately 0.090 w / w%, approximately 0.095 w / w%, approximately 0.10 w / w%, approximately 0.15 w / w%, or approximately 0.20 w / w%.

[0066] In some embodiments, the CBD extract of the Disclosure contains up to about 0.2 w / w% CBEII. In some embodiments, the CBD extract of the Disclosure contains about 0 w / w%, about 0.005 w / w%, about 0.01 w / w%, about 0.015 w / w%, about 0.02 w / w%, about 0.025 w / w%, about 0.030 w / w%, about 0.035 w / w%, about 0.040 w / w%, about 0.045 w / w%, and about 0. Contains CBEII in amounts of 0.050 w / w%, approximately 0.055 w / w%, approximately 0.060 w / w%, approximately 0.065 w / w%, approximately 0.070 w / w%, approximately 0.075 w / w%, approximately 0.080 w / w%, approximately 0.085 w / w%, approximately 0.090 w / w%, approximately 0.095 w / w%, approximately 0.10 w / w%, approximately 0.15 w / w%, or approximately 0.20 w / w%.

[0067] In some embodiments, the CBD extract of the Disclosure contains a combination of CBEI and CBEII up to about 0.2 w / w%. In some embodiments, the CBD extract of the Disclosure contains about 0 w / w%, about 0.005 w / w%, about 0.01 w / w%, about 0.015 w / w%, about 0.02 w / w%, about 0.025 w / w%, about 0.030 w / w%, about 0.035 w / w%, about 0.040 w / w%, about 0.045 w / w%, and about 0.050 w / w%, including all intermediate values ​​and ranges. This includes combinations of CBEI and CBEII in the following proportions: w / w%, approximately 0.055 w / w%, approximately 0.060 w / w%, approximately 0.065 w / w%, approximately 0.070 w / w%, approximately 0.075 w / w%, approximately 0.080 w / w%, approximately 0.085 w / w%, approximately 0.090 w / w%, approximately 0.095 w / w%, approximately 0.10 w / w%, approximately 0.15 w / w%, or approximately 0.20 w / w%.

[0068] In some embodiments, the CBD extract of this disclosure contains less than about 0.1 w / w% OH-CBD. In some embodiments, the CBD extract of this disclosure contains about 0 w / w%, about 0.005 w / w%, about 0.01 w / w%, about 0.015 w / w%, about 0.02 w / w%, about 0.025 w / w%, about 0.030 w / w%, about 0.035 w / w%, about 0.040 w / w%, and about 0.0 Contains 45 w / w%, approximately 0.050 w / w%, approximately 0.055 w / w%, approximately 0.060 w / w%, approximately 0.065 w / w%, approximately 0.070 w / w%, approximately 0.075 w / w%, approximately 0.080 w / w%, approximately 0.085 w / w%, approximately 0.090 w / w%, approximately 0.095 w / w%, or approximately 0.10 w / w% OH-CBD.

[0069] In some embodiments, the CBD extract of this disclosure comprises CBD of at least 95 w / w% (e.g., 98 w / w% or 99 w / w%) purity, as well as CBDA, CBDV, THC, and CBD-C4. In some embodiments, CBDA is present in amounts of about 0.15 w / w% or less, e.g., about 0.15 w / w%, about 0.1 w / w%, about 0.05 w / w%, or about 0.01 w / w% (including all values ​​and ranges between these values). In some embodiments, CBDV is present in amounts of approximately 1.0 w / w% or less, for example, approximately 1.0 w / w%, approximately 0.9 w / w%, approximately 0.8 w / w%, approximately 0.7 w / w%, approximately 0.6 w / w%, approximately 0.5 w / w%, approximately 0.4 w / w%, approximately 0.3 w / w%, approximately 0.2 w / w%, approximately 0.1 w / w%, approximately 0.09 w / w%, approximately 0.08 w / w%, approximately 0.07 w / w%, approximately 0.06 w / w%, approximately 0.05 w / w%, approximately 0.04 w / w%, approximately 0.03 w / w%, approximately 0.02 w / w%, and approximately 0.01 w / w% (including all values ​​and ranges between these values). In some embodiments, THC is present in amounts of approximately 0.15 w / w% or less, for example, approximately 0.15 w / w%, approximately 0.1 w / w%, approximately 0.05 w / w%, or approximately 0.01 w / w% (including all values ​​and ranges between these values). In some embodiments, CBD-C4 is present in amounts of approximately 0.5 w / w% or less, for example, approximately 0.5 w / w%, approximately 0.4 w / w%, approximately 0.3 w / w%, approximately 0.2 w / w%, approximately 0.1 w / w%, approximately 0.09 w / w%, approximately 0.08 w / w%, approximately 0.07 w / w%, approximately 0.06 w / w%, approximately 0.05 w / w%, approximately 0.04 w / w%, approximately 0.03 w / w%, approximately 0.02 w / w%, or approximately 0.01 w / w% (including all values ​​and ranges between these values).

[0070] In some embodiments, CBD is administered at a dose of approximately 1 mg / kg / day to approximately 25 mg / kg / day. In some embodiments, CBD is administered at a dose of approximately 5 mg / kg / day to approximately 50 mg / kg / day. In some embodiments, CBD is administered at approximately 1 mg / kg / day, approximately 2 mg / kg / day, approximately 3 mg / kg / day, approximately 4 mg / kg / day, approximately 5 mg / kg / day, approximately 6 mg / kg / day, approximately 7 mg / kg / day, approximately 8 mg / kg / day, approximately 9 mg / kg / day, approximately 10 mg / kg / day, approximately 11 mg / kg / day, approximately 12 mg / kg / day, approximately 13 mg / kg / day, approximately 14 mg / kg / day, approximately 15 mg / kg / day, approximately 16 mg / kg / day, approximately 17 mg / kg / day, approximately 18 mg / kg / day, approximately 19 mg / kg / day, approximately 20 mg / kg / day, approximately 21 mg / kg / day, approximately 22 mg / kg / day, approximately 23 mg / kg / day, approximately 24 mg / kg / day, approximately 25 mg / kg / day, It is administered in doses of approximately 26 mg / kg / day, 27 mg / kg / day, 28 mg / kg / day, 29 mg / kg / day, 30 mg / kg / day, 31 mg / kg / day, 32 mg / kg / day, 33 mg / kg / day, 34 mg / kg / day, 35 mg / kg / day, 36 mg / kg / day, 37 mg / kg / day, 38 mg / kg / day, 39 mg / kg / day, 40 mg / kg / day, 41 mg / kg / day, 42 mg / kg / day, 43 mg / kg / day, 44 mg / kg / day, 45 mg / kg / day, 46 mg / kg / day, 47 mg / kg / day, 48 mg / kg / day, 49 mg / kg / day, or 50 mg / kg / day. In some embodiments, CBD is administered at a dose of approximately 5 mg / kg / day. In some embodiments, CBD is administered at a dose of approximately 10 mg / kg / day. In some embodiments, CBD is administered at a dose of approximately 15 mg / kg / day. In some embodiments, CBD is administered at a dose of approximately 20 mg / kg / day. In some embodiments, CBD is administered at a dose of approximately 25 mg / kg / day. In some embodiments, CBD is administered at a dose of approximately 50 mg / kg / day.

[0071] In some embodiments, CBD is administered twice daily at a dose of approximately 2.5 mg / kg to approximately 12.5 mg / kg. In some embodiments, CBD is administered twice daily at a dose of approximately 2.5 mg / kg to approximately 25 mg / kg. In some embodiments, CBD is administered in doses of approximately 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg, approximately 11 mg / kg / day, approximately 12 mg / kg, approximately 12.5 mg / kg, approximately 13 mg / kg, approximately 14 mg / kg, approximately 15 mg / kg, approximately 16 mg / kg, approximately 17 mg / kg, approximately 18 mg / kg, approximately 19 mg / kg, approximately 20 mg / kg, approximately 21 mg / kg, approximately 22 mg / kg, approximately 23 mg / kg, approximately 24 mg / kg, or approximately 25 mg / kg. In some embodiments, CBD is administered twice daily at a dose of approximately 2.5 mg / kg. In some embodiments, CBD is administered twice daily at a dose of approximately 5 mg / kg. In some embodiments, CBD is administered twice daily at a dose of approximately 10 mg / kg. In some embodiments, CBD is administered twice daily at a dose of approximately 12.5 mg / kg.

[0072] As disclosed herein, in some embodiments, when CBD is co-administered with everolimus, CBD is administered at a reduced dose. The “reduced dose” of CBD is lower than the dose that an otherwise identical TSC patient would receive if everolimus were not co-administered. In other words, the reduced dose of CBD administered to a TSC patient as combination therapy is lower than the dose of CBD administered to the same (or similar) TSC patient who is not co-administered with everolimus.

[0073] In some embodiments, the applicant intends the dose of CBD administered to TSC patients to be based on the approved dosage range of EPIDIOLEX® for treating seizures in patients with Lennox-Gastaut or Dravet syndrome. In some embodiments, the applicant intends the approved dosage range of CBD for TSC in the absence of everolimus to be 5 mg / kg / day to 5 mg / kg / day. In some embodiments, the applicant intends the patient to be treated with approximately 10 mg / kg / day, approximately 15 mg / kg / day, approximately 20 mg / kg / day, or approximately 25 mg / kg / day in the absence of everolimus. In certain embodiments, the applicant intends the patient to be treated with approximately 10 mg / kg / day, approximately 15 mg / kg / day, or approximately 20 mg / kg / day in the absence of everolimus.

[0074] The therapeutically effective dose varies depending on the severity of the symptoms. As discussed herein, the method of this disclosure provides a step of administering a reduced dose of CBD compared to a therapeutically effective dose in the absence of everolimus. In some embodiments, the therapeutically effective dose of CBD for TSC is 10 mg / kg / day. In view of the above, in embodiments, the reduced dose of CBD for such patients is less than 10 mg / kg / day, for example, 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, or 9 mg / kg / day.

[0075] In some embodiments, the therapeutically effective dose of CBD for TSC is 15 mg / kg / day. In view of the above, in some embodiments, the reduced dose of CBD for such patients is less than 15 mg / kg / day, for example, 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, 9 mg / kg / day, 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, or 14 mg / kg / day.

[0076] In some embodiments, the therapeutically effective dose of CBD for TSC is 20 mg / kg / day. In view of the above, in some embodiments, the reduced dose of CBD for such patients is less than 20 mg / kg / day, for example, 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, 9 mg / kg / day, 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, 14 mg / kg / day, 15 mg / kg / day, 16 mg / kg / day, 17 mg / kg / day, 18 mg / kg / day, or 19 mg / kg / day.

[0077] In some embodiments, the therapeutically effective dose of CBD for TSC is 25 mg / kg / day. In view of the above, in some embodiments, the reduced dose of CBD for such patients is less than 25 mg / kg / day, for example, 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, 9 mg / kg / day, 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, 14 mg / kg / day, 15 mg / kg / day, 16 mg / kg / day, 17 mg / kg / day, 18 mg / kg / day, 19 mg / kg / day, 20 mg / kg / day, 21 mg / kg / day, 22 mg / kg / day, 23 mg / kg / day, or 24 mg / kg / day.

[0078] In some embodiments, the reduced dose of CBD administered to TSC patients in combination with everolimus is about 10% to about 75% of the dose of CBD administered to the same TSC patients in the absence of everolimus.

[0079] In some embodiments, the reduced dose of CBD administered to TSC patients in combination with everolimus is reduced by at least about 1 mg / kg / day, about 2 mg / kg / day, about 3 mg / kg / day, about 4 mg / kg / day, about 5 mg / kg / day, about 6 mg / kg / day, about 7 mg / kg / day, about 8 mg / kg / day, about 9 mg / kg / day, about 10 mg / kg / day, about 11 mg / kg / day, about 12 mg / kg / day, about 13 mg / kg / day, about 14 mg / kg / day, about 15 mg / kg / day, about 16 mg / kg / day, about 17 mg / kg / day, about 18 mg / kg / day, about 19 mg / kg / day, or about 20 mg / kg / day (including all values ​​and ranges between these values) compared to the dose of CBD the patient would receive in the absence of everolimus. In some embodiments, the reduced dose of CBD administered to TSC patients in combination with everolimus is reduced by at least about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg (including all values ​​and ranges between these values) compared to the dose of CBD the patient would receive in the absence of everolimus.

[0080] In some embodiments, the reduced dose of CBD ranges from approximately 1 mg / kg / day to approximately 23 mg / kg / day. In some embodiments, the reduced dose of CBD is approximately 1 mg / kg / day, approximately 2 mg / kg / day, approximately 2.5 mg / kg / day, approximately 3 mg / kg / day, approximately 4 mg / kg / day, approximately 5 mg / kg / day, approximately 6 mg / kg / day, approximately 7 mg / kg / day, approximately 8 mg / kg / day, approximately 9 mg / kg / day, approximately 10 mg / kg / day, approximately 11 mg / kg / day, approximately 12 mg / kg / day, approximately 12.5 mg / kg / day, approximately 13 mg / kg / day, approximately 14 mg / kg / day, approximately 15 mg / kg / day, approximately 16 mg / kg / day, approximately 17 mg / kg / day, approximately 18 mg / kg / day, approximately 19 mg / kg / day, approximately 20 mg / kg / day, approximately 21 mg / kg / day, approximately 22 mg / kg / day, or approximately 23 mg / kg / day, including all intermediate values ​​and ranges. In some embodiments, the reduced dose of CBD is approximately 5 mg / kg / day. In some embodiments, the reduced dose of CBD is approximately 10 mg / kg / day. In some embodiments, the reduced dose of CBD is approximately 15 mg / kg / day. In some embodiments, the reduced dose of CBD is approximately 20 mg / kg / day.

[0081] In some embodiments, co-administration of CBD (25 mg / kg / day) with everolimus resulted in a reduction in the pharmacokinetic parameters of everolimus (C max The pharmacokinetic parameters (C) of everolimus (AUC) increase 2.5 times. In some embodiments, the dose of CBD is increased to match the pharmacokinetic parameters (C) of everolimus. max The performance (and AUC) is reduced to increase to 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, or 1.0 or less.

[0082] According to current FDA guidelines, CBD is administered at a starting dose of 5 mg / kg / day in patients with normal liver function or mild hepatic impairment. CBD causes dose-dependent increases in hepatic transaminases (alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST)). A low starting dose (e.g., the lowest dose of the drug that achieves efficacy and minimizes side effects) is important for the liver to adapt to CBD so that it can increase CBD metabolism and reduce the incidence of dose-dependent increases in hepatic transaminases ALT and / or AST.

[0083] If the initial dose is well-tolerated and additional seizure reduction is required, the maintenance dose of CBD may be increased to a maximum dose of 25 mg / kg / day (in the absence of everolimus). Serum levels of these enzymes should be monitored as CBD may cause elevated hepatic transaminase levels.

[0084] For DDI with everolimus, in some embodiments, the starting dose of CBD is reduced from the currently approved starting dose of 5 mg / kg / day. In some embodiments, CBD (when co-administered with everolimus) is administered at a starting dose of approximately 1 mg / kg / day to approximately 4 mg / kg / day (e.g., approximately 1 mg / kg / day, approximately 1.5 mg / kg / day, approximately 2 mg / kg / day, approximately 2.5 mg / kg / day, approximately 3 mg / kg / day, approximately 3.5 mg / kg / day, or approximately 4 mg / kg / day), and the dose of CBD is increased up to a maximum dose of, for example, approximately 10 mg / kg / day, approximately 15 mg / kg / day, approximately 20 mg / kg / day, or 24 mg / kg / day.

[0085] In some embodiments, the starting dose of CBD may be increased for efficacy. In some embodiments, the dose of CBD may be increased to about 5 mg / kg / day in increments of about 0.5 mg / kg / day. In some embodiments, the dose of CBD may be increased to about 0.5 mg / kg / day, about 1.0 mg / kg / day, about 1.5 mg / kg / day, about 2.0 mg / kg / day, about 2.5 mg / kg / day, about 3.0 mg / kg / day, about 3.5 mg / kg / day, about 4.0 mg / kg / day, about 4.5 mg / kg / day, or about 5.0 mg / kg / day.

[0086] In some embodiments, the dose of CBD may be increased daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or every 7 days, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, monthly, every 2 months, or annually. In some embodiments, the dose of CBD may be increased from the starting dose after 1 week. Dose increases may then be made once every week.

[0087] In some embodiments, the dosage ranges from approximately 1 mg / kg / day to approximately 50 mg / kg / day (for example, approximately 1.0 mg / kg / day, approximately 2.0 mg / kg / day, approximately 2.5 mg / kg / day, approximately 3.0 mg / kg / day, approximately 3.5 mg / kg / day, approximately 4.0 mg / kg / day, approximately 5.0 mg / kg / day, approximately 6.0 mg / kg / day, approximately 7.5 mg / kg / day, approximately 8 mg / kg / day, approximately 9 mg / kg / day, approximately 10 mg / kg / day) day, about 11 mg / kg / day, about 12 mg / kg / day, about 13 mg / kg / day, about 14 mg / kg / day, about 15 mg / kg / day, about 16 mg / kg / day, about 17 mg / kg / day, about 18 mg / kg / day day, about 19 mg / kg / day, about 20 mg / kg / day, about 21 mg / kg / day, about 22 mg / kg / day, about 23 mg / kg / day, about 24 mg / kg / day, about 25 mg / kg / day, about 26 mg / kg / day day, about 27 mg / kg / day, about 28 mg / kg / day, about 29 mg / kg / day, about 30 mg / kg / day, about 31 mg / kg / day, about 32 mg / kg / day, about 33 mg / kg / day, about 34 mg / kg / day day, about 35 mg / kg / day, about 36 mg / kg / day, about 37 mg / kg / day, about 38 mg / kg / day, about 39 mg / kg / day, about 40 mg / kg / day, about 41 mg / kg / day, about 42 mg / kg / day After administering CBD at doses of approximately 43 mg / kg / day, 44 mg / kg / day, 45 mg / kg / day, 46 mg / kg / day, 47 mg / kg / day, 48 mg / kg / day, 49 mg / kg / day, or 50 mg / kg / day, patients exhibit a steady-state area (AUCt1-t2) under the concentration-time curve from time zero (t1) to 5 hours (t2) of 25 ng*hr / mL to 4000 ng*hr / mL.In some embodiments, AUCt1-t2 includes all intermediate ranges and values, approximately 25 ng*hr / mL, approximately 50 ng*hr / mL, approximately 75 ng*hr / mL, approximately 100 ng*hr / mL, approximately 125 ng*hr / mL, approximately 150 ng*hr / mL, approximately 175 ng*hr / mL, approximately 200 ng*hr / mL, approximately 225 ng*hr / mL, approximately 250 ng*hr / mL, approximately 275 ng*hr / mL, and approximately 300 ng* hr / mL, approximately 325ng*hr / mL, approximately 350ng*hr / mL, approximately 375ng*hr / mL, approximately 400ng*hr / mL, approximately 500ng*hr / mL, approximately 600ng*hr / mL, approximately 700ng*hr / mL, approximately 800ng*hr / mL, approximately 900ng*hr / mL, approximately 1000ng*hr / mL, approximately 1100ng*hr / mL, approximately 1200ng*hr / mL, approximately 1300ng*hr / mL, approximately 1400ng* hr / mL, approx. 1500ng*hr / mL, approx. 1600ng*hr / mL, approx. 1700ng*hr / mL, approx. 1800ng*hr / mL, approx. 1900ng*hr / mL, approx. 2000ng*hr / mL, approx. 21 00ng*hr / mL, approximately 2200ng*hr / mL, approximately 2300ng*hr / mL, approximately 2400ng*hr / mL, approximately 2500ng*hr / mL, approximately 2600ng*hr / mL, approximately 2700ng*hr / mL These values ​​are approximately 2800 ng*hr / mL, 2900 ng*hr / mL, 3000 ng*hr / mL, 3100 ng*hr / mL, 3200 ng*hr / mL, 3300 ng*hr / mL, 3400 ng*hr / mL, 3500 ng*hr / mL, 3600 ng*hr / mL, 3700 ng*hr / mL, 3800 ng*hr / mL, 3900 ng*hr / mL, or 4000 ng*hr / mL. In some embodiments, AUCt1-t2 is 80% to 125% of the above values.

[0088] In some embodiments, AUC t1-t2 This is reported as the geometric mean (coefficient of variation (%)). In some embodiments, after administration of everolimus and CBD, the patient has a bioequivalent AUC of CBD to 25 mg / kg / day of CBD. t1-t2That is, it has an AUCt1-t2 in the range of 80% to about 125% of 2520 (52.4%) ng*hr / mL. In some embodiments, after administration of everolimus and CBD, the patient has an AUCt1-t2 of 50 mg / kg / day of CBD. t1-t2 CBD AUC below t1-t2 , that is, less than 2730 (87.2%) ng*hr / mL (for example, 2700 ng*hr / mL, 2600 ng*hr / mL, 2500 ng*hr / mL, 2400 ng*hr / mL, 2300 ng*hr / mL, 2200 ng*hr / mL, 2100 ng*hr / mL, 2000 ng*hr / mL, 1900 ng*hr / mL, 1800 ng*hr / mL, 1700 ng*hr / mL, 1600 ng*hr / mL, 1500 ng*hr / mL, 1400 ng*hr / mL, 1300 ng*hr / mL, 1200 ng*hr / mL, 1100 ng*hr / mL, or less than 1000 ng*hr / mL, etc.).

[0089] In some embodiments, after administration of everolimus and CBD, the patient's steady-state AUC (AUC) of CBD from zero time to a final detectable dose (t) that is bioequivalent to 5 mg / kg / day of CBD. 0-t ), that is, AUC in the range of 80% to approximately 125% of 241 (101%) ng*hr / mL 0-t It has. In some embodiments, after administration of everolimus and CBD, the patient has a bioequivalent AUC of CBD to 10 mg / kg / day of CBD. 0-t That is, AUC in the range of 80% to approximately 125% of 722 (79.9%) ng*hr / mL 0-t It has. In some embodiments, after administration of everolimus and CBD, the patient has an AUC of CBD that is bioequivalent to 20 mg / kg / day of CBD. 0-t That is, AUC in the range of 80% to approximately 125% of 963 (93.4%) ng*hr / mL 0-t It has.

[0090] Everolimus Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase located downstream of the PI3K / AKT pathway. Everolimus binds to the intracellular protein FKBP-12, forming an inhibitory complex with mTOR complex 1 (mTORC1) and inhibiting mTOR kinase activity. Everolimus reduces the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic extension factor 4E-binding protein (4E-BP1), which are downstream effectors of mTOR involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the estrogen receptor activation region 1, thereby resulting in ligand-independent activation of the receptor. Furthermore, everolimus inhibits the expression of hypoxia-inducible factors (e.g., HIF-1) and reduces the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and / or in vivo studies.

[0091] Constitutive activation of the PI3K / Akt / mTOR pathway can be a factor in endocrine resistance in breast cancer. In vitro studies have shown that estrogen-dependent and HER2-positive breast cancer cells are sensitive to the inhibitory effect of everolimus, and that combination therapy with everolimus and Akt, HER2, or aromatase inhibitors synergistically enhances the antitumor activity of everolimus.

[0092] The two regulators of mTORC1 signaling are the oncogene suppressors tuberin sclerosis complexes 1 and 2 (TSC1 and TSC2). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In tuberous sclerosis, inactivating mutations in the TSC1 or TSC2 genes lead to hamartoma formation throughout the body.

[0093] Everolimus is approved by the FDA for the treatment of the following conditions: postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole; adults with unresectable, locally advanced or metastatic advanced neuroendocrine neoplasms (PNETs) of pancreatic origin; adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib; adults with renal angiomyolipoma and TSCs but not requiring immediate surgery; and pediatric and adult TSC patients with subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected; and prevention of organ rejection in adult patients, including in kidney transplants in combination with basiliximab, cyclosporine (reduced dose), and corticosteroids, and in liver transplants in combination with tacrolimus (reduced dose), and corticosteroids.

[0094] Everolimus has the following structure.

[0095] [ka]

[0096] The recommended dose of everolimus for TSC-associated renal angiomyolipoma is 10 mg orally once daily. The recommended dose of everolimus for TSC-associated subependymal giant cell astrocytoma (SEGA) is 4.5 mg / 2 It is administered orally once daily. The recommended dose of everolimus for TSC-associated partial-origin seizures is 5 mg / 2 It is administered orally once a day.

[0097] In some embodiments, everolimus is administered in doses ranging from about 2 mg to about 10 mg. In some embodiments, doses of about 2 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 8.5 mg, about 9.0 mg, about 9.5 mg, or about 10.0 mg of everolimus are administered. In some embodiments, the dose of everolimus is 2.5 mg. In some embodiments, the dose of everolimus is 5 mg. In some embodiments, the dose of everolimus is 7.5 mg. In some embodiments, the dose of everolimus is 10 mg. In some embodiments, the patient's body surface area (BSA) is 0.5 m². 2 ~1.2m 2 If the patient's BSA is within the range, the dose of everolimus is 2.5 mg once daily. In some embodiments, the patient's BSA is 1.3 m 2 ~2.1m 2 If the patient's BSA is within the range of 2.2m, the dose of everolimus is 5 mg once daily. In some embodiments, the patient's BSA is 2.2m 2 In the above cases, the dose of everolimus is 7.5 mg once daily.

[0098] In some embodiments, everolimus is approximately 2.5 mg / m² 2 ~about 5.5mg / m 2 A range, for example, approximately 2.5 mg / m² 2 , about 3.0mg / m 2 , about 3.5mg / m 2 , about 4.0mg / m 2 , about 4.5mg / m 2 , about 5.0mg / m 2 , or approximately 5.5 mg / m² 2 It is administered in doses (including all values ​​and ranges between these values). In some embodiments, the dose of everolimus is 5.0 mg / m². 2 This is everolimus. In some embodiments, the dose of everolimus is 4.5 mg / m².2 This is everolimus. In some embodiments, the dose of everolimus is 2.5 mg / m². 2 This is Everolimus.

[0099] In some embodiments, sufficient everolimus is administered to achieve a trough concentration of 5 ng / mL to 15 ng / mL.

[0100] In some embodiments, everolimus is administered once daily.

[0101] In some embodiments, everolimus is administered daily, every other day, every three days, every four days, every five days, every six days, weekly, every two weeks, monthly, or annually. In some embodiments, everolimus is administered daily. In some embodiments, everolimus is administered every other day.

[0102] In some embodiments, the starting dose of everolimus is approximately 4.5 mg / m². 2 The drug is administered, and the dose of everolimus is adjusted to obtain a trough concentration of approximately 5 ng / mL to approximately 15 ng / mL.

[0103] In some embodiments, the starting dose of everolimus is approximately 5.0 mg / m². 2 The drug is administered, and the dose of everolimus is adjusted to obtain a trough concentration of approximately 5 ng / mL to approximately 15 ng / mL. In some embodiments, the dose is approximately 5.5 mg / m². 2 , about 6mg / m 2 , about 6.5mg / m 2 , about 7mg / m 2 , about 7.5mg / m 2 , about 8mg / m 2 , about 8.5mg / m 2 , 9 mg / m² 2 , about 9.5mg / m 2 , or approximately 10 mg / m² 2 It is adjusted to include all values ​​and ranges between these values.

[0104] In some embodiments, the dose of everolimus is increased from the starting dose. In some embodiments, the dose of everolimus is decreased from the starting dose. In some embodiments, the dose of everolimus administered is reduced by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% (including all values ​​and ranges in between). In some embodiments, the dose reduction of everolimus

[0105] Everolimus is metabolized by CYP3A4, CYP3A5, and CYP2C8. After oral administration of everolimus, it is the main circulating component of the blood. Six major everolimus metabolites were detected in human blood, including three monohydroxylated metabolites, two hydrolysis ring-opening products, and a phosphatidylcholine conjugate.

[0106] Everolimus is a substrate of CYP3A4 and P-gp. The FDA designation for everolimus suggests avoiding concomitant use of strong P-gp and strong CYP3A4 inhibitors, and instead reducing the dose of everolimus using P-gp and a moderate CYP3A4 inhibitor (Table 1 (Table 3) and Table 2 (Table 4)).

[0107] [Table 3]

[0108] [Table 4]

[0109] In patients with advanced solid tumors, after administration of everolimus, the concentration of everolimus reaches its peak 1-2 hours after administration of oral doses ranging from 5 mg to 70 mg. After a single dose, C max For daily doses of 5 mg to 10 mg, the effect is dose-proportional. For single doses of 20 mg or more, C maxThe increase in AUC is less than dose-proportional. However, AUC shows dose-proportionality over the dose range of 5 mg to 70 mg. Steady state was achieved within 2 weeks after once-daily administration. In TSC-associated SEGA patients, everolimus Cmin was administered at 1.35 mg / m². 2 ~14.4 mg / m² 2 Within the dosage range, the response was approximately proportional to the dose.

[0110] The area under the everolimus curve (AUC) is linear in the dose range of 2.5 mg to 70 mg.

[0111] In some embodiments, after administering everolimus in doses of approximately 1 mg to approximately 20 mg (e.g., 1.0 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg), patients observed the maximum plasma drug concentration (C) max ss) is 1 ng / mL to 200 ng / mL. In some embodiments, C max ss includes all intermediate ranges and values, approximately 1 ng / mL, 5 ng / mL, 10 ng / mL, 15 ng / mL, 20 ng / mL, 21.6 ng / mL, 25 ng / mL, 30 ng / mL, 35 ng / mL, 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, 60 ng / mL, 65 mg / mL, 70 ng / mL, 75 ng / mL, 80 ng / mL, 85 ng / mL, 90 ng / mL, 95 ng / mL, and 10 The values ​​are 0 ng / mL, approximately 105 ng / mL, approximately 110 ng / mL, approximately 115 ng / mL, approximately 120 ng / mL, approximately 125 ng / mL, approximately 130 ng / mL, approximately 135 ng / mL, approximately 140 ng / mL, approximately 145 ng / mL, approximately 150 ng / mL, approximately 155 ng / mL, approximately 160 ng / mL, approximately 165 ng / mL, approximately 170 ng / mL, approximately 175 ng / mL, approximately 180 ng / mL, approximately 185 ng / mL, approximately 190 ng / mL, approximately 195 ng / mL, or approximately 200 ng / mL. In some embodiments, C max ss is 80% to 125% of either the above value or a range between the above values.

[0112] In some embodiments, C max ss is reported as geometric mean ± standard deviation (SD). In some embodiments, after administration of everolimus and CBD, the patient receives 2.5 mg of everolimus and bioequivalent everolimus CBD. max ss, i.e., C in the range of 80% to approximately 125% of 62.1 ± 13.1 ng / mL max It has ss. In some embodiments, after administration of everolimus and CBD, the patient receives 5 mg of everolimus with the bioequivalent everolimus C. max ss, i.e., C in the range of 80% to approximately 125% of 114±36 ng / mL max It has ss. In some embodiments, after administration of everolimus and CBD, the patient receives 10 mg of everolimus with the bioequivalent everolimus C. max ss, i.e., C in the range of 80% to approximately 125% of 139 ng / mL max It has ss. In some embodiments, after administration of everolimus and CBD, the patient takes 2.5 mg of C. max ss~10mg C max C of Everolimus within the range of ss max It has ss.

[0113] In some embodiments, after administering everolimus in doses of approximately 1 mg to approximately 20 mg (e.g., 1.0 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg), the patient observed the minimum steady-state plasma drug concentration (C) of everolimus. min ss) is 1 ng / mL to 100 ng / mL. In some embodiments, C minss is about 1 ng / mL, about 5 ng / mL, about 10 ng / mL, about 15 ng / mL, about 20 ng / mL, about 21.6 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 mg / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / mL, or about 100 ng / mL, including all intermediate ranges and values. In some embodiments, C min ss is 80% to 125% of any of the above values or ranges between the above values.

[0114] In some embodiments, C min ss is reported as geometric mean ± standard deviation (SD). In some embodiments, after administration of everolimus and CBD, the patient has a C min ss of everolimus biologically equivalent to 2.5 mg of everolimus, i.e., in the range of 80% to about 125% of 13.6 ± 9.0 ng / mL min In some embodiments, after administration of everolimus and CBD, the patient has a C min ss of everolimus biologically equivalent to 5 mg of everolimus, i.e., in the range of 80% to about 125% of 17.4 ± 4.5 ng / mL min In some embodiments, after administration of everolimus and CBD, the patient has a C min ss of everolimus biologically equivalent to 10 mg of everolimus, i.e., in the range of 80% to about 125% of 16.5 ng / mL min In some embodiments, after administration of everolimus and CBD, the patient has a C min ss from 2.5 mg to a C min ss within the range of 10 mg max has ss.

[0115] In some embodiments, after administration of about 1.0 mg to about 20 mg of everolimus, the patient has a C max (t maxThe time to reach ([0]]) is 0.1 hour to 2 hours. In some embodiments, t max is about 0.1 hour, about 0.2 hour, about 0.3 hour, about 0.4 hour, about 0.5 hour, about 0.6 hour, about 0.7 hour, about 0.8 hour, about 0.9 hour, about 1.0 hour, about 1.1 hour, about 1.2 hour, about 1.3 hour, about 1.4 hour, about 1.5 hour, about 1.6 hour, about 1.7 hour, about 1.8 hour, about 1.9 hour, or about 2.0 hours. In some embodiments, t max is about 80% to about 125% of any of the above values or the ranges between the above values.

[0116] In some embodiments, t max is reported as the median (range). In some embodiments, the patient has a t max in the range of 80% to about 125% 1.0 hour (1.0 hour to 1.5 hours) after administration of 2.5 mg of everolimus. In some embodiments, the patient has a t max in the range of about 80% to about 125% 0.8 hour (0.8 hour to 1.5 hours) after administration of 5 mg of everolimus. In some embodiments, the patient has a t max in the range of about 80% to about 125% 1.0 hour after administration of 10 mg of everolimus.

[0117] In some embodiments, after administering about 1.0 mg to about 20 mg (e.g., 1.0 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg) of everolimus, the patient has an area under the concentration-time curve (AUC 24 ) from zero time to 24 hours of 100 ng*hr / mL to 2000 ng*hr / mL. In some embodiments, AUC 24This includes all intermediate ranges and values, approximately 25 ng*hr / mL, approximately 50 ng*hr / mL, approximately 75 ng*hr / mL, approximately 100 ng*hr / mL, approximately 125 ng*hr / mL, approximately 150 ng*hr / mL, approximately 175 ng*hr / mL, approximately 200 ng*hr / mL, approximately 225 ng*hr / mL, approximately 250 ng*hr / mL, approximately 275 ng*hr / mL, approximately 300 ng*hr / mL, approximately 325 ng*hr / mL, approximately 350 ng*hr / mL, approximately 375 ng*hr / mL, and approximately 400 ng*hr / mL. The AUC is approximately 500 ng*hr / mL, 600 ng*hr / mL, 700 ng*hr / mL, 800 ng*hr / mL, 900 ng*hr / mL, 1000 ng*hr / mL, 1100 ng*hr / mL, 1200 ng*hr / mL, 1300 ng*hr / mL, 1400 ng*hr / mL, 1500 ng*hr / mL, 1600 ng*hr / mL, 1700 ng*hr / mL, 1800 ng*hr / mL, 1900 ng*hr / mL, or 2000 ng*hr / mL. In some embodiments, the AUC is approximately 500 ng*hr / mL, 600 ng*hr / mL, 700 ng*hr / mL, 800 ng*hr / mL, 900 ng*hr / mL, or 2000 ng*hr / mL. 24 This is 80% to 125% of the above value.

[0118] In some embodiments, AUC 24 This is reported as geometric mean ± standard deviation (SD). In some embodiments, after administration of everolimus and CBD, patients have a bioequivalent AUC to that of 2.5 mg of everolimus. 24 That is, AUC in the range of 80% to approximately 125% of 570±195 ng*hr / mL 24 In some embodiments, after administration of everolimus and CBD, the patient has a bioequivalent AUC to 5 mg of everolimus. 24 That is, AUC in the range of 80% to approximately 125% of 716±123 ng*hr / mL 24 In some embodiments, after administration of everolimus and CBD, the patient has a bioequivalent AUC to 10 mg of everolimus. 24 That is, an AUC in the range of 80% to approximately 125% of 1470 ng*hr / mL 24 It has.

[0119] In some embodiments, the methods of the present disclosure provide dose reduction to achieve everolimus trough plasma concentrations in the range of 5 to 15 ng / mL, for example, about 5 ng / mL, about 6 ng / mL, about 7 ng / mL, about 8 ng / mL, about 9 ng / mL, about 10 ng / mL, about 11 ng / mL, about 12 ng / mL, about 13 ng / mL, about 14 ng / mL, or 15 ng / mL (including all values ​​and ranges between these values).

[0120] In some embodiments, the method of the present disclosure is less than 46 mg / mL, for example, about 45 ng / mL, about 44 ng / mL, about 43 ng / mL, about 42 ng / mL, about 41 ng / mL, about 40 ng / mL, about 39 ng / mL, about 38 ng / mL, about 37 ng / mL, about 36 ng / mL, 35 ng / mL, about 34 ng / mL, about 33 ng / mL, about 32 ng / mL, about 31 ng / mL, about 30 ng / mL, about 29 mg / mL Dose reductions are provided to achieve the maximum plasma concentrations of everolimus (including all values ​​and ranges between these values) of g / mL, approximately 28 ng / mL, approximately 27 ng / mL, approximately 26 ng / mL, 25 ng / mL, approximately 24 ng / mL, approximately 23 ng / mL, approximately 22 ng / mL, approximately 21 ng / mL, approximately 20 ng / mL, approximately 19 ng / mL, approximately 18 ng / mL, approximately 17 ng / mL, approximately 16 ng / mL, and 15 ng / mL.

[0121] In some embodiments, the method of the present disclosure is less than 500 n*ng / mL, for example, about 490 n*ng / mL, about 480 n*ng / mL, about 460 n*ng / mL, about 450 n*ng / mL, about 440 n*ng / mL, about 430 n*ng / mL, about 420 n*ng / mL, about 410 n*ng / mL, about 400 n*ng / mL, about 390 n*ng / mL, about 380 n*ng / mL, about 360 n*ng / mL, about 350 n*ng / mL AUC values ​​of approximately 340 n*ng / mL, 330 n*ng / mL, 320 n*ng / mL, 310 n*ng / mL, 200 n*ng / mL, 190 n*ng / mL, 180 n*ng / mL, 160 n*ng / mL, 150 n*ng / mL, 140 n*ng / mL, 130 n*ng / mL, 120 n*ng / mL, 110 n*ng / mL, or 100 n*ng / mL (including all values ​​and ranges in between). 0-last To achieve this, dose reduction is provided.

[0122] In some embodiments, the method of the present disclosure is less than 530 n*ng / mL, for example, about 520 n*ng / mL, about 510 n*ng / mL, about 500 n*ng / mL, about 490 n*ng / mL, about 480 n*ng / mL, about 460 n*ng / mL, about 450 n*ng / mL, about 440 n*ng / mL, about 430 n*ng / mL, about 420 n*ng / mL, about 410 n*ng / mL, about 400 n*ng / mL, about 390 n*ng / mL, about 380 n*ng / mL, about 360 n*ng / mL AUC of *ng / mL, approximately 350n*ng / mL, approximately 340n*ng / mL, approximately 330n*ng / mL, approximately 320n*ng / mL, approximately 310n*ng / mL, approximately 200n*ng / mL, approximately 190n*ng / mL, approximately 180n*ng / mL, approximately 160n*ng / mL, approximately 150n*ng / mL, approximately 140n*ng / mL, approximately 130n*ng / mL, approximately 120n*ng / mL, approximately 110n*ng / mL, or approximately 100n*ng / mL (including all values ​​and ranges in between). 0-inf To achieve this, dose reduction is provided.

[0123] Methods for evaluating the effectiveness of CBD / everolimus The therapeutically effective dose of CBD can be determined in clinical trials. For example, in some embodiments, dose escalation can determine the therapeutically effective dose of CBD. Dose escalation studies are described, for example, in NCT02544750. The effectiveness of a particular dose can be evaluated by determining the incidence of adverse events and the effectiveness of that particular dose. Non-limiting examples of means for determining effectiveness include changes in seizure frequency, the number of treatment responders, the number of patients with worsening, no change, or improvement in seizure frequency, changes in composite focus seizure score, changes in seizure-free days, changes in the number of seizures by subtype, changes in general condition as assessed by participant / caregiver, changes in general condition as assessed by physician, changes in Binnelland-II score, changes in Wechsler score by subtest, changes in abnormal behavior checklist score, changes in social communication questionnaire score, changes in quality of life score, changes in serum IGF-1 levels, the number of participants with changes in Tanner stage, and the incidence of suicidal tendencies. Clinical outcomes are generally evaluated based on changes from baseline. Hereinafter, “baseline” refers to the four weeks prior to the start of treatment with CBD in which clinical outcomes are measured.

[0124] In some embodiments, the effectiveness of treatment by the method of the Disclosure is determined by measuring the change in seizure frequency from baseline. In some embodiments, patients treated according to the method of the Disclosure exhibit a reduction in seizure frequency of at least 5%. In some embodiments, patients treated according to the method of the Disclosure exhibit a reduction in seizure frequency of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more, including all intermediate values ​​and ranges. In some embodiments, patients treated according to the method of the Disclosure exhibit a reduction in seizure frequency of at least about 50%.

[0125] In some embodiments, after treatment by the method of disclosure, patients exhibit a reduction from baseline in the number of seizures selected from the group consisting of absence, myoclonic, focal, infantile, and epileptic seizures. In some embodiments, patients treated according to the method of the disclosure exhibit a reduction in myoclonic seizure frequency of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, including all intermediate values ​​and ranges. In some embodiments, patients treated according to the methods of the present disclosure exhibit a reduction in focal sensory seizure frequency of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, including all intermediate values ​​and ranges. In some embodiments, patients treated according to the methods of the present disclosure exhibit a reduction in absence seizure frequency of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, including all intermediate values ​​and ranges. In some embodiments, patients treated according to the methods of the present disclosure exhibit a reduction in infant seizure frequency of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, including all intermediate values ​​and ranges. In some embodiments, patients treated according to the methods of the present disclosure exhibit a reduction in epileptic seizure frequency of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, including all intermediate values ​​and ranges.

[0126] In some embodiments, the effectiveness of treatment by the method of the Disclosure is determined by measuring the number of treatment responders. In some embodiments, at least about 20% of patients show improved TSC symptoms after treatment by the method of the Disclosure. In some embodiments, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more, including all intermediate values ​​and ranges, show improved TSC symptoms after treatment by the method of the Disclosure. In some embodiments, the rate of change in seizures is used to classify the effectiveness of the treatment. Patients are classified into the following groups: (a) Increased frequency of TSC seizures >25% = worsening (b) Change in TSC seizure frequency -25%~25% = No change in TSC (c) Reduction in TSC seizure frequency: 25%~50% = Improvement in TSC (d) Reduction in TSC seizure frequency: 50%~75% = Improvement in TSC (e) Reduction in TSC seizure frequency >75% = Improvement in TSC

[0127] In some embodiments, the effectiveness of treatment by the method of the Disclosure is determined by measuring the number of patients whose seizure frequency worsens, remains unchanged, or improves. In some embodiments, the effectiveness of treatment by the method of the Disclosure is determined by measuring the number of patients whose seizure frequency improves compared to before the treatment. In some embodiments, about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of patients show improvement in seizure frequency after treatment by the method of the Disclosure compared to before the treatment.

[0128] In some embodiments, patients treated by the methods of the present disclosure show a reduction in seizure frequency compared to before the treatment. In some embodiments, patients show a reduction of approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% in seizure frequency compared to before the treatment. In some embodiments, patients show a reduction of ≥50% in TSC-related seizure frequency.

[0129] In some embodiments, patients treated by the methods of the present disclosure show a reduction in the number of episodes of convulsive and non-convulsive status epilepticus. In some embodiments, after treatment according to the methods of the present disclosure, the number of episodes of convulsive and non-convulsive status epilepticus decreased by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% compared to baseline, including all intermediate values ​​and ranges. In some embodiments, patients treated by the methods of the present disclosure show a reduction in the number of episodes of convulsive status epilepticus. In some embodiments, after treatment according to the method of the present disclosure, the number of episodes of convulsive status epilepticus decreases by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all intermediate values ​​and ranges. In some embodiments, patients treated by the method of the present disclosure show a reduction in the number of episodes of non-convulsive status epilepticus. In some embodiments, after treatment according to the methods of the present disclosure, the number of episodes of nonconvulsive status epilepticus decreases by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% compared to baseline, including all intermediate values ​​and ranges.

[0130] In some embodiments, the effectiveness of treatment by the method of the present disclosure is determined by evaluating the patient's use of rescue medication. Non-limiting examples of rescue medications include benzodiazepines, including diazepam, lorazepam, and midazolam. In some embodiments, after treatment according to the method of the present disclosure, the patient's use of rescue medication decreases by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all intermediate values ​​and ranges.

[0131] In some embodiments, the effectiveness of treatment by the method of the present disclosure is determined by measuring the change in the compound focal seizure score. In some embodiments, the compound focal seizure score is calculated as the sum of (1 × number of focal motion seizures without impaired consciousness or state of consciousness) + (2 × number of focal seizures with impaired consciousness or state of consciousness) + (3 × number of focal seizures that develop into bilateral convulsive seizures). In some embodiments, after treatment according to the method of the present disclosure, the compound focal seizure score decreases compared to before the treatment. In some embodiments, the compound focal seizure score decreases by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, or about 100%, including all intermediate values ​​and ranges.

[0132] In some embodiments, the effectiveness of treatment by the method of the present disclosure is determined by measuring the change in seizure-free days. In some embodiments, after treatment according to the method of the present disclosure, seizure-free days increase by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, or more, including all intermediate values ​​and ranges.

[0133] In some embodiments, the effectiveness of treatment by the method of the Disclosure is determined by measuring the change in the number of seizures by subtype. Non-limiting examples of seizure subtypes experienced by TSC patients include infantile seizures, focal, partial, tonic-clonic, atonic, myoclonic, and absence seizures. In some embodiments, treatment according to the method of the Disclosure reduces one or more seizure subtypes. In some embodiments, treatment according to the method of the Disclosure reduces the frequency of one or more seizure subtypes by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more.

[0134] In some embodiments, the effectiveness of treatment by the method of this disclosure is determined by measuring changes in the Binnelland Adaptive Behavior Scale (VABS). The Binnelland Adaptive Behavior Scale (VABS), 3rd edition, is a standardized scale of adaptive behavior used to assess an individual's personal and social skills from birth to adulthood. An individual may be assessed on the VABS scale by either a teacher or a caregiver. According to the VABS, an individual is assigned a VABS Adaptive Behavior Synthesis Score, which measures their functioning compared to others of the same age. An individual is also assigned domain scores in communication, daily living skills, socialization, and motor skills to assess the strength of their adaptive behavior. An individual receives scores of 20–140 in each of the domain scores and in the VABS Adaptive Behavior Synthesis Score. Scores of 20–70 represent a low level of adaptation. Scores of 71–85 represent a moderately low level of adaptation. Scores of 86–114 represent a moderately adequate level of adaptation. Scores of 115–129 represent a moderately high level of adaptation. A score of 130-140 indicates a high level of adaptation.

[0135] In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with TSC, characterized by an increase of at least 1 point in the VABS Adaptive Behavior Synthesis Score compared to before the treatment. In some embodiments, the increase in the VABS Adaptive Behavior Score is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, and approximately The scores are approximately 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70.

[0136] In some embodiments, the increase in the VABS adaptive behavior synthesis score is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% compared to before the treatment.

[0137] In some embodiments, after the treatment, the patient experiences an increase in sociability characterized by an increase in the VABS Adaptive Behavior Social Domain score compared to before the treatment. In some embodiments, the increase in the VABS Adaptive Behavior Social Domain score is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 The scores are approximately 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70.

[0138] In some embodiments, the increase in the VABS adaptive behavior social domain score is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% compared to before the treatment. In some embodiments, the patient experiences at least a 10% improvement in the VABS social domain score after the treatment. In some embodiments, the patient experiences at least a 35% improvement in the VABS social domain score after the treatment.

[0139] In some embodiments, after the treatment, the patient experiences improved communication characterized by an increase in the VABS Adaptive Behavior Communication domain score compared to before the treatment. In some embodiments, the increase in the VABS Adaptive Behavior Communication domain score is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 The scores are approximately 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70.

[0140] In some embodiments, the increase in the VABS Adaptive Behavior Communication domain score is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% compared to before the treatment.

[0141] In some embodiments, the effectiveness of treatment by the method of the Disclosure is determined by measuring the change in the Wechsler Adult Intelligence Scale, 4th Edition (WAIS-IV) score for each subtest. The Wechsler Adult Intelligence Scale (WAIS-IV) is an IQ test designed to measure intelligence and cognitive abilities in adults and older adolescents. In some embodiments, after treatment according to the method of the Disclosure, the Wechsler Child Intelligence Scale shows an improvement of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% in the intellectual abilities of an adult or older adolescent. In some embodiments, the effectiveness of treatment by the method of the Disclosure is determined by measuring the change in the Wechsler Preschool and School-Age Intelligence Scales. In some embodiments, the composite score increases after treatment according to the method of the present disclosure. In some embodiments, the composite score after treatment according to the method of the present disclosure increases by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all intermediate values ​​and ranges. In some embodiments, the effectiveness of treatment by the method of the present disclosure is determined by measuring the change in the Wechsler Pediatric Intelligence Scale. In some embodiments, after treatment according to the methods of the present disclosure, the Wechsler Child Intelligence Scale shows an improvement of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% in the child's cognitive ability.

[0142] In some embodiments, the effectiveness of treatment by the method of this disclosure is determined by measuring changes in abnormal behavior checklist scores. The Abnormal Behavior Checklist (ABC) is a behavioral assessment scale used to evaluate an individual on five subscales: (1) Irritability, agitation, and crying; (2) Lethargy, withdrawal; (3) Stereotyped behavior; (4) Hyperactivity and medication non-compliance; and (5) Inappropriate speech. An individual may be evaluated on the ABC by any adult who knows the individual well. The ABC includes a 58-item questionnaire used to assess the five subscales. Each item on the 58-item questionnaire is rated from 0 to 3. A score of 0 means that no symptoms are present. A score of 3 means that the individual experiences symptoms of high severity. Items within each subscale are added together to obtain a subscale score. Possible subscale scores in the ABC range from 0 to 48, with higher subscores indicating behavioral disorders. In some embodiments, after treatment according to the method of the present disclosure, the patient experiences a reduction in symptoms associated with TSC, characterized by a decrease of at least one point in the ABC Irritability, Agitation and Crying (ABC-I) subscore. In some embodiments, after the treatment, the patient experiences a reduction in irritability, characterized by a decrease in the ABC-I communication domain score compared to before the treatment.

[0143] In some embodiments, the effectiveness of treatment by the method of the present disclosure is determined by measuring the change in Social Communication Questionnaire scores. Patients with TSC often have autism spectrum disorder (ASD). The Social Communication Questionnaire is a tool used by physicians to screen for patients with ASD. Individual caregivers rate verbal individuals on a scale of 0 to 39 or non-verbal individuals on a scale of 0 to 33. Individuals with ASD are characterized by more than 15 Social Communication Questionnaire scores. In some embodiments, after the treatment, patients experience a reduction in symptoms associated with ASD, characterized by a decrease of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% in Social Communication Questionnaire scales compared to before the treatment.

[0144] In some embodiments, the effectiveness of treatment by the method of the Disclosure is determined by measuring changes in the patient's quality of life. In some embodiments, the effectiveness of the method of the Disclosure is determined by utilizing changes in the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire. The maximum QOLCE score is 100. Higher scores are correlated with improvements in quality of life. In some embodiments, the QOLCE score increases by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% after treatment by the method of the Disclosure, including all intermediate values ​​and ranges. In some embodiments, the effectiveness of treatment by the method of the Disclosure is evaluated using the Quality of Life in Epilepsy (QOLIE-31-P) score. In some embodiments, the QOLIE-31-P score decreases after treatment by the method of the present disclosure compared to before the treatment. In some embodiments, the QOLIE-31-P decreases by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all intermediate values ​​and ranges.

[0145] In some embodiments, the patient's quality of life is assessed using a Global Improvement Indication (PGIC) score by the investigator. In some embodiments, the patient is assigned a score from 1 to 7, where 1 means the patient has greatly improved, and 7 means the patient's condition has worsened. In some embodiments, after treatment according to the method of this disclosure, the PGIC decreases by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all intermediate values ​​and ranges.

[0146] In some embodiments, the effectiveness of treatment by the method of the present disclosure is determined by measuring the change in serum insulin-like growth factor-1 (IGF-1) levels. IGF-1 is released after activation of the mTOR pathway. In some embodiments, after treatment according to the method of the present disclosure, IGF-1 is reduced by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% compared to before the treatment.

[0147] In some embodiments, the effectiveness of treatment by the method of the present disclosure is determined by assessing the patient's suicide risk using the Columbia Suicide Severity Rating Scale (C-SSRS; 19 years and older or C-SSRS Pediatric (6–18 years) score).

[0148] In some embodiments, the effectiveness of treatment by the method of the present disclosure is determined by measuring the number of hospital-bound hospitalizations due to epilepsy. In some embodiments, the number of hospital-bound hospitalizations of a patient decreases after treatment according to the method of the present disclosure. In some embodiments, the number of hospital-bound hospitalizations decreases by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%.

[0149] Patient population In some embodiments, the methods disclosed herein are used to treat TSC patients.

[0150] More than half of patients with TSC also develop autism spectrum disorder (ASD). In some embodiments, the methods of this disclosure are used to treat TSC patients who have ASD.

[0151] In some embodiments, the methods of the Disclosure are used to treat patients aged 0 to 80 years. In some embodiments, the methods of the Disclosure are used to treat patients aged approximately 0 to 22 years. In some embodiments, the patients are approximately 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 years old.

[0152] In some embodiments, patients are administered CBD and / or everolimus based on their body surface area (BSA). In some embodiments, patients have a BSA of approximately 0.25 to 2.5. In some embodiments, a patient has a BSA of approximately 0.25, or approximately 0.30, or approximately 0.35, or approximately 0.40, or approximately 0.45, or approximately 0.50, or approximately 0.55, or approximately 0.60, or approximately 0.65, or approximately 0.70, or approximately 0.75, or approximately 0.80, or approximately 0.85, or approximately 0.90, or approximately 0.95, or approximately 1.0, or approximately 1.1, or approximately 1.2, or approximately 1.3, or approximately 1.4, or approximately 1.5, or approximately 1.6, or approximately 1.7, or approximately 1.8, or approximately 1.9, or approximately 2.0, or approximately 2.1, or approximately 2.2, or approximately 2.3, or approximately 2.3, or approximately 2.4, or approximately 2.5 or higher, including all intermediate values ​​and ranges. In some embodiments, the patient's body surface area is calculated according to the following formula: BSA = body weight (kg) 0.425 × Height (cm) 0.725 ×0.007184. In some embodiments, the patient's body surface area is calculated according to the following formula:

[0153]

number

[0154] In some embodiments, the Disclosure provides a method of co-administering everolimus and CBD (for example, having a purity of at least 95 w / w% or 98 w / w%) to treat patients with TSC with moderate or severe hepatic impairment. In some embodiments, such patients can receive lower starting, maintenance, and maximum doses compared to the doses that otherwise identical patients with moderate or severe hepatic impairment would receive in the absence of everolimus. Table 3 (Table 5) lists the doses of CBD for patients with moderate or severe hepatic impairment in the absence of everolimus.

[0155] [Table 5]

[0156] In some embodiments, TSC patients with mild renal impairment are co-administered 2.5 or 5 mg of everolimus with an initial dose of CBD less than 5 mg / kg / day (e.g., about 1, about 2, about 3, about 4, or about 5 mg / kg / day). In some embodiments, the initial dose is increased in increments of about 1 mg / kg / day to about 5 mg / kg / day (e.g., about 1, about 2, about 3, about 4, or about 5 mg / kg / day) up to a maximum dose of less than 25 mg / kg / day (e.g., about 24, about 23, about 22, about 21, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, or about 5 mg / kg / day (including all values ​​and ranges between these values)). In some embodiments, patients with mild hepatic impairment are treated with CBD in doses ranging from approximately 5 to approximately 20 mg / kg / day.

[0157] In some embodiments, TSC patients with moderate renal impairment are co-administered with 2.5 or 5 mg of everolimus and an initial dose of CBD less than 2.5 mg / kg / day (e.g., about 0.5 mg / kg / day or about 1 mg / kg / day). In some embodiments, the initial dose is increased in increments of about 0.5 mg / kg / day to about 2.5 mg / kg / day (e.g., about 0.5, about 1, about 1.5, or about 2 mg / kg / day) up to a maximum dose of less than 12.5 mg / kg / day (e.g., about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2.5 mg / kg / day (including all values ​​and ranges between these values)). In some embodiments, patients with moderate hepatic impairment are treated with CBD in doses ranging from about 2.5 to about 10 mg / kg / day.

[0158] In some embodiments, patients with TSC with severe renal impairment are co-administered 2.5 or 5 mg of everolimus with an initial dose of CBD of less than 1 mg / kg / day (e.g., about 0.25 mg / kg / day or about 0.5 mg / kg / day). In some embodiments, the initial dose is increased by about 0.5 mg / kg / day increments up to a maximum dose of less than 5 mg / kg / day (e.g., about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, or 4.5 mg / kg / day).

[0159] In some embodiments, patients were diagnosed with TSC, and seizures were poorly controlled with at least one concomitant antiepileptic drug (AED), with or without vagus nerve stimulation or ketogenic diet therapy. In some embodiments, the AED was valproate, vigabatrin, levetiracetam, clobazam, or a combination thereof. [Examples]

[0160] (Example 1) Preparation of CBD extract A highly purified (>98 w / w%) cannabidiol extract (CBD) was prepared for the treatment of TSC patients. The production of this extract is also described in U.S. Patent No. 10,111,840 and U.S. Patent Application Publication No. 2016 / 0166514 (each of which is incorporated herein by reference in whole).

[0161] Summary: CBD was extracted from high-CBD-containing chemotypes of Cannabis sativa L. using a liquid carbon dioxide extraction method. The CBD extract was further purified using a solvent crystallization method to obtain CBD. Specifically, the crystallization method removes other cannabinoids to obtain a CBD extract containing over 95 w / w% CBD, typically over 98 w / w% CBD.

[0162] Procedure: The Cannabis sativa L. plant is cultivated, harvested, and processed to produce a plant extract (intermediate). The plant starting material is called the plant-derived raw material (BRM). The active pharmaceutical ingredient (API), also called the active pharmaceutical ingredient, is CBD.

[0163] BRM and plant extracts (intermediates) are controlled by the specifications. The specifications for the active pharmaceutical ingredient are listed in Table 4 (Table 6).

[0164] [Table 6A]

[0165] [Table 6B]

[0166] The achieved purity of the CBD active ingredient exceeds 98%. Other cannabinoids that may be found in the extract include CBDA, CBDV, CBD-C4, and THC.

[0167] To maximize the production of cannabinoids, a specific chemical component, distinct chemotypes of the Cannabis sativa L. plant were developed. One species of the plant overwhelmingly produces CBD. Only the (-)-trans isomer exists naturally, and further purification does not affect the stereochemistry of CBD.

[0168] The following is an overview of the steps involved in producing plant extracts and intermediates: (i) Cultivation (ii) Decarboxylation (iii) Extraction number 1: Using liquid CO2 (iv) Extraction number 2: "Dewaxing" using ethanol (v) Filtration (vi) evaporation

[0169] High-CBD chemical variants were cultivated, harvested, dried, and stored in a drying room until needed. The vegetable raw materials (BRM) were finely chopped using an Apex mill fitted with a 1mm sieve. The milled BRM was stored in a freezer for up to 3 months before extraction.

[0170] Using a large Heraeus tray oven, CBDA was decarboxylated into CBD. The batch size for decarboxylation in the Heraeus was approximately 15 kg. The tray was placed in the oven and heated to 105°C. The BRM took 96.25 minutes to reach 105°C. It was held at 105°C for 15 minutes. The oven was then set to 150°C. The BRM took 75.7 minutes to reach 150°C. The BRM was held at 150°C for 130 minutes. The total time in the oven was 380 minutes, including 45 minutes of cooling and 15 minutes of ventilation.

[0171] Extraction number 1 was performed using liquid CO2 at 60 bar / 10°C to produce a plant-derived active pharmaceutical ingredient (BDS), which was then used for crystallization to produce the test material.

[0172] Crude CBD BDS was dewaxed in extraction no. 2 under standard conditions (2 volumes of ethanol, -20°C for approximately 50 hours). The precipitated wax was removed by filtration.

[0173] The manufacturing steps for producing the active pharmaceutical ingredient (CBD) from the intermediate plant extract are as follows: (i) Crystallization using C5-C12 straight-chain or branched alkanes (ii) Filtration (iii) Optional recrystallization from C5-C12 straight-chain or branched alkanes (iv) Vacuum drying

[0174] The intermediate plant extract (12 kg) produced using the method described above was dispersed in C5-C12 linear or branched alkanes (9000 ml, 0.75 vol) in a 30-liter stainless steel container. The mixture was manually stirred to break up any lumps, and the sealed container was then placed in a freezer for approximately 48 hours.

[0175] The crystals were isolated by vacuum filtration, washed with a fixed amount of cold C5-C12 linear or branched alkanes (12,000 ml in total), and dried at 60°C under a vacuum of <10 mb until dry before the active pharmaceutical ingredient was subjected to analysis. The dried product was stored in a -20°C freezer in a pharmaceutical-grade stainless steel container equipped with FDA-approved silicone seals and clamps.

[0176] The pharmaceutical product is presented as an oral solution containing the active ingredient. The oral solution contains 25 mg / ml or 100 mg / ml of CBD with additives of sesame oil, ethanol, sucralose, and flavoring agents. The two product strengths allow for dose adjustment over a wide dose range. The 25 mg / ml solution is suitable for lower doses, while the 100 mg / ml solution is suitable for higher doses.

[0177] The pharmaceuticals are listed in Table 5 (Table 7) below.

[0178] [Table 7]

[0179] The active ingredient, CBD, is insoluble in water. Sesame oil was selected as an additive to solubilize the active ingredient. Sweeteners and fruit flavorings are necessary to improve the palatability of the sesame oil solution. Ethanol was required to solubilize the sweeteners and flavorings. The composition may be substantially identical, meaning that the functional components may vary by up to 10% from the qualitative composition specified in Table 6 (Table 8).

[0180] (Example 2) CBD inhibits CYP450 An in vitro study was conducted to measure the inhibition of CYP450 by CBD. CBD inhibited CYP3A4-mediated testosterone hydroxylation. 50 It has a concentration of 1.42 μM. CBD is mediated by CYP3A4-mediated testosterone hydroxylation. I = 1.5 μM, K inact =0.14 minutes -1 It also possesses.

[0181] In vitro data clearly demonstrate that CBD has the potential to inhibit multiple CYP450 enzymes in vivo.

[0182] In vitro data suggest that CBD may produce DDI with CYP3A4 substrates, but a clinical DDI study using midazolam (GWEP17028, incorporated herein by reference) showed no clinically significant effect on the PK parameters of orally administered midazolam when co-administered with CBD in a steady state (750 mg twice daily).

[0183] (Example 3) A Phase 1 open-label pharmacokinetic drug interaction study to investigate the effect of cannabidiol on the pharmacokinetics (PK) of everolimus. Principle Explanation: Everolimus is an mTOR inhibitor approved as an oral treatment for managing TSC-related seizures in patients with tuberous sclerosis (TSC) and can be used in combination with CBD. Non-clinical ADME data have shown that CBD may interact with pathways involved in the absorption and elimination of everolimus. The primary objective of this study was to assess the effect of CBD on the pharmacokinetic (PK) parameters of everolimus.

[0184] Primary objective: To investigate the effect of CBD treatment after repeated administration on the pharmacokinetic effects of a single dose of everolimus in healthy participants.

[0185] Primary endpoints: PK parameter endpoints derived from the plasma concentration-time profile of everolimus on day 1 after monotherapy, and PK parameter endpoints derived from a single dose of everolimus in participants who reached a steady state of CBD after receiving CBD at a dose of 12.5 mg / kg twice daily (bid) for 5 days.

[0186] Secondary objectives: To evaluate the safety and tolerability of CBD when administered in conjunction with a single dose of everolimus in healthy participants; to investigate the effect of a single dose of everolimus on steady-state PK parameters of CBD in healthy participants.

[0187] Secondary endpoints for safety include the incidence and severity of adverse events (AEs), incidence of abnormal laboratory values ​​based on blood, clinical chemistry, and urinalysis results; 12-lead electrocardiogram (ECG) parameters, vital signs measurements, physical examination, and Colombian Suicide Severity Scale (C-SSRS) questionnaire score; PK parameter endpoints derived from the plasma concentration-time profile of everolimus on day 1 after monotherapy, and PK parameter endpoints derived from a single dose of everolimus in participants who reached a steady state of CBD after receiving CBD at a dose of 12.5 mg / kg twice daily (bid) (total daily dose of 25 mg / kg / day) for 5 days.

[0188] Exploratory objective: To investigate the potential effects of the CYP3A genotype on any interaction between everolimus exposure and CBD.

[0189] Exploratory endpoint: Pharmacogenetic assessment of common genetic variants in the CYP3A enzyme (this information may correlate with PK results).

[0190] Design: This was a phase 1 open-label, single-center trial to investigate the effect of multiple doses of CBD on the pharmacokinetics (PK) of everolimus in healthy participants. The trial period was approximately 9 weeks, including a screening period (up to 4 weeks), a treatment period (18 days), and a safety follow-up period (2 weeks). After signing an Informed Consent Form (ICF), participants entered the screening period (-28 to -1 day). On -1 day, participants who had been screened and continued to meet the eligibility criteria were admitted to the Clinical Research Unit (CRU) around 2 pm and enrolled in the trial. On day 1, participants received everolimus 30 minutes after starting a standard diet. From days 2 to 8, participants had a 7-day drug-free period. From days 9 to 12, participants received CBD 30 minutes after starting a standard diet. On day 13, participants received everolimus and CBD 30 minutes after starting a standard diet. From day 14 to day 18, participants received CBD 30 minutes after starting a standard diet. On day 18, participants were discharged from the CRU after all assessments were completed. A safety follow-up visit was conducted on day 32, 14 days (±3 days) after the final dose of the investigational drug (IMP) CBD.

[0191] In the initial trial, patients received 5 mg of everolimus and 12.5 mg / kg of CBD twice daily (total daily dose of 25 mg / kg / day).

[0192] As shown in Table 6 (Table 8), a wide range of doses of CBD and everolimus were tested according to the study design outlined above. CBD was administered twice daily at the doses listed in Table 6 (Table 8).

[0193] [Table 8A]

[0194] [Table 8B]

[0195] Formulation, mode of administration, dosage, and regimen: The CBD preparation is a clear, colorless to yellow oral liquid formulation (100 mg / mL of CBD in sesame oil, anhydrous ethanol, added sweetener (sucralose), and strawberry flavoring). The oral liquid formulation is administered by syringe. The CBD preparation was taken twice daily, 30 minutes after starting a standard diet.

[0196] Everolimus was administered orally (PO) 30 minutes after a standard meal.

[0197] Procedure: All visits were scheduled to take place at approximately the same time of day (i.e., morning or afternoon) whenever possible. Cannabis or benzodiazepines were not permitted throughout the trial. Alcohol was not permitted from 48 hours prior to each admission to the CRU throughout the hospital stay, and from 48 hours prior to each safety follow-up visit.

[0198] Pharmacokinetic assessment: PK blood samples were collected for everolimus and CBD, 7-hydroxycannabidiol (7-OH-CBD) and 7-carboxycannabidiol (7-COOH-CBD) during the treatment period, at the times listed in the assessment schedule. The time of meals consumed at the facility on the day of IMP administration was recorded relative to the collection time, as the IMP dose and administration time were recorded (if necessary).

[0199] The following assessments were performed: vital signs, medical history, physical examination, vital signs, weight, height, 12-lead ECG, adverse events (AEs), recorded prior and concomitant medications. The principal investigator or agent completes the C-SSRS. Laboratory samples include chemistry, hematology, serology, urinary drug screening, alcohol testing, and pharmacogenetics.

[0200] Treatment Period Assessment: Participants who continued to meet all inclusion criteria and none of the exclusion criteria were enrolled and received everolimus and CBD. The following assessments were performed: physical examination, vital signs, 12-lead ECG, recorded concomitant medications, and adverse events were reviewed. The principal investigator or their representative completed the C-SSRS. Laboratory samples included samples for chemistry, coagulation, hematology, and PK analysis.

[0201] Safety follow-up visit assessment: The following assessments were performed: physical examination, vital signs, 12-lead ECG, adverse events (AEs), and recorded concomitant medications. The C-SSRS was completed by the principal investigator or their representative. Laboratory samples included chemical and hematological tests.

[0202] To assess the changes in pharmacokinetic parameters of CBD, 7-OH-CBD, and 7-COOH-CBD in steady state after a single dose of everolimus, pharmacokinetic parameter estimates were evaluated.

[0203] Everolimus' logarithmic transformation C max AUC (0-∞) , and AUC (0-t) The parameters were analyzed using a linear mixed-effects model with fixed effects on the treatment and random effects on the participants. The treatment difference was inversely transformed to present the ratio of the geometric mean and the corresponding 90% confidence interval (CI).

[0204] t max For this, a non-parametric analysis of the same comparison was performed using the Wilcoxon signed-rank test. The median and median difference between treatments are presented along with the approximately 90% confidence interval (CI) of the median difference.

[0205] Geometric mean ratios and 90% confidence intervals (CIs) are used to estimate the magnitude of any interaction and are interpreted based on clinical relevance.

[0206] CBD, 7-OH-CBD and 7-COOH-CBD トラフList the values and summarize them as appropriate.

[0207] List all AEs and summarize them using a descriptive method. The incidence rate of AEs for each treatment period is presented according to the severity and the relevance to the IMP determined by the investigator (or nominee) responsible for the clinical trial. List all safety data and summarize them using a descriptive method. List the pharmacogenetic data.

[0208] Results: First, patients received 5 mg of everolimus, or 5 mg of everolimus and 12.5 mg / kg of CBD, twice daily (total daily dose of 25 mg / kg / day) according to the above test design. Refer to Figure 1. 5 mg of everolimus and 25 mg / kg / day of CBD each represent the doses of everolimus and CBD that TSC patients should receive based on the current FDA indication.

[0209] The plasma concentration profiles of everolimus and CBD were measured at the above time points. Figure 2 shows the blood concentration profiles (ng / mL) of everolimus in patients who received everolimus alone and patients who received both everolimus and CBD. As shown in Figure 2, CBD unexpectedly and surprisingly caused an increase in the plasma concentration of everolimus, even though CBD was not considered a moderate or strong CYP3A4 and P-gp inhibitor. Summarize the results in Table 7 (Table 9) below.

[0210] [Table 9]

[0211] As shown in Table 7 (Table 9) and Figure 2 above, CBD (in SS) maxand increased AUC by at least 2.5 times. This is a clinically significant moderate interaction (Clinical Drug Interaction Studies—Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry, FDA, January 2020). As a result, the dose of CBD was reduced (e.g., as described herein) to mitigate the DDI with everolimus.

[0212] Figures 3 to 5 show that everolimus did not have a clinically significant effect on the pharmacokinetics of CBD, or its metabolites 7-OH-CBD and 7-COOH-CBD, respectively.

[0213] As pointed out above, CBD (in SS) is the C of everolimus. max and increased the AUC by at least 2.5 times. To mitigate the effect of CBD on everolimus plasma concentration and reduce the risk of adverse effects associated with everolimus overexposure, the dose of CBD administered to the TSC is reduced as described herein. It is important to note that it is not necessary to reduce the dose of CBD to 1 / 2.5 (but reducing CBD to 1 / 2.5 is encompassed by this disclosure) for safe and effective co-administration of everolimus and CBD. In some embodiments, the dose of CBD is reduced to the AUC (or C) of everolimus. max It is sufficient to reduce the AUC (or C) of everolimus to less than two times. While not bound by any particular theory, this can be achieved by administering 20 mg / kg / day of CBD in combination with everolimus. max This is because an increase of less than twice the given value is not considered clinically significant.

[0214] As another example, the dose of everolimus is reduced as described herein to mitigate the effect of CBD on everolimus plasma concentrations and to reduce the risk of adverse effects associated with everolimus overexposure. It is important to note that it is not necessary to reduce the dose of everolimus to 1 / 2.5 (however, reducing the dose of CBD to 1 / 2.5 is encompassed by this disclosure) in order to safely and effectively co-administer everolimus and CBD. In some embodiments, the dose of CBD is reduced by the AUC (or C) of everolimus. max The dose only needs to be reduced so that it increases by more than two times. While not bound by any particular theory, this can be achieved by reducing the dose of everolimus by 10%, 15%, 20%, and / or 25%.

[0215] Numbered Embodiments of the Present Disclosure Notwithstanding the attached claims, this disclosure describes the following numbered embodiments:

[0216] Embodiment 1. A method for treating a seizure associated with tuberous sclerosis (TSC) in a patient requiring treatment for a seizure associated with TSC, comprising the step of administering everolimus in combination with a reduced dose of cannabidiol (CBD).

[0217] Embodiment 2. The method of Embodiment 1, wherein the reference dose of CBD is 25 mg / kg / day, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is selected from the group consisting of approximately 5 mg / kg / day, approximately 10 mg / kg / day, approximately 15 mg / kg / day, and approximately 20 mg / kg / day.

[0218] Embodiment 3. The method of Embodiment 1 or 2, wherein the reference dose of CBD is 25 mg / kg / day, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is approximately 5 mg / kg / day.

[0219] Embodiment 4. The method of Embodiment 1 or 2, wherein the reference dose of CBD is 25 mg / kg / day, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is approximately 10 mg / kg / day.

[0220] Embodiment 5. The method of Embodiment 1 or 2, wherein the reference dose of CBD is 25 mg / kg / day, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is approximately 15 mg / kg / day.

[0221] Embodiment 6. The method of Embodiment 1 or 2, wherein the reference dose of CBD is 25 mg / kg / day, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is approximately 20 mg / kg / day.

[0222] Embodiment 7. The method of Embodiment 1, wherein the reference dose of CBD is 20 mg / kg / day, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is selected from the group consisting of approximately 5 mg / kg / day, approximately 10 mg / kg / day, and approximately 15 mg / kg / day.

[0223] Embodiment 8. The method of Embodiment 1 or 7, wherein the reference dose of CBD is 20 mg / kg / day, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is approximately 5 mg / kg / day.

[0224] Embodiment 9. The method of Embodiment 1 or 7, wherein the reference dose of CBD is 20 mg / kg / day, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is approximately 10 mg / kg / day.

[0225] Embodiment 10. The method of Embodiment 1 or 7, wherein the reference dose of CBD is 20 mg / kg / day, the patient is administered 2.5 mg of everolimus, and the reduced dose of CBD is approximately 15 mg / kg / day.

[0226] Embodiment 11. The method of Embodiment 1, wherein the reference dose of CBD is 15 mg / kg / day, 2.5 mg of everolimus is administered to the patient, and the reduced dose of CBD is selected from the group consisting of about 5 mg / kg / day and about 10 mg / day.

[0227] Embodiment 12. The method of Embodiment 1 or 11, wherein the reference dose of CBD is 15 mg / kg / day, 2.5 mg of everolimus is administered to the patient, and the reduced dose of CBD is about 5 mg / kg / day.

[0228] Embodiment 13. The method of Embodiment 1 or 11, wherein the reference dose of CBD is 25 mg / kg / day, 2.5 mg of everolimus is administered to the patient, and the reduced dose of CBD is about 10 mg / kg / day.

[0229] Embodiment 14. The method of Embodiment 1 or 7, wherein the reference dose of CBD is 10 mg / kg / day, 2.5 mg of everolimus is administered to the patient, and the reduced dose of CBD is about 5 mg / kg / day.

[0230] Embodiment 15. The method of Embodiment 1, wherein the reference dose of CBD is 25 mg / kg / day, 5 mg of everolimus is administered to the patient, and the reduced dose of CBD is selected from the group consisting of about 5 mg / kg / day, about 10 mg / kg / day, about 15 mg / kg / day, and about 20 mg / kg / day.

[0231] Embodiment 16. The method of Embodiment 1 or 15, wherein the reference dose of CBD is 25 mg / kg / day, 5 mg of everolimus is administered to the patient, and the reduced dose of CBD is about 5 mg / kg / day.

[0232] Embodiment 17. The method of Embodiment 1 or 15, wherein the reference dose of CBD is 25 mg / kg / day, 5 mg of everolimus is administered to the patient, and the reduced dose of CBD is about 10 mg / kg / day.

[0233] Embodiment 18. The method of Embodiment 1 or 15, wherein the reference dose of CBD is 25 mg / kg / day, the patient is administered 5 mg of everolimus, and the reduced dose of CBD is approximately 15 mg / kg / day.

[0234] Embodiment 19. The method of Embodiment 1 or 15, wherein the reference dose of CBD is 25 mg / kg / day, the patient is administered 5 mg of everolimus, and the reduced dose of CBD is approximately 20 mg / kg / day.

[0235] Embodiment 20. The method of Embodiment 1, wherein the reference dose of CBD is 20 mg / kg / day, the patient is administered 5 mg of everolimus, and the reduced dose of CBD is selected from the group consisting of approximately 5 mg / kg / day, approximately 10 mg / kg / day, and approximately 15 mg / kg / day.

[0236] Embodiment 21. The method of Embodiment 1 or 20, wherein the reference dose of CBD is 20 mg / kg / day, the patient is administered 5 mg of everolimus, and the reduced dose of CBD is approximately 5 mg / kg / day.

[0237] Embodiment 22. The method of Embodiment 1 or 20, wherein the reference dose of CBD is 20 mg / kg / day, the patient is administered 5 mg of everolimus, and the reduced dose of CBD is approximately 10 mg / kg / day.

[0238] Embodiment 23. The method of Embodiment 1 or 20, wherein the reference dose of CBD is 20 mg / kg / day, the patient is administered 5 mg of everolimus, and the reduced dose of CBD is approximately 15 mg / kg / day.

[0239] Embodiment 24. The method of Embodiment 1, wherein the reference dose of CBD is 15 mg / kg / day, the patient is administered 5 mg of everolimus, and the reduced dose of CBD is selected from the group consisting of approximately 5 mg / kg / day and approximately 10 mg / kg / day.

[0240] Embodiment 25. The method of Embodiment 1 or 24, wherein the reference dose of CBD is 15 mg / kg / day, the patient is administered 5 mg of everolimus, and the reduced dose of CBD is approximately 5 mg / kg / day.

[0241] Embodiment 26. The method of Embodiment 1 or 24, wherein the reference dose of CBD is 25 mg / kg / day, the patient is administered 5 mg of everolimus, and the reduced dose of CBD is approximately 10 mg / kg / day.

[0242] Embodiment 27. The method of Embodiment 1 or 15, wherein the reference dose of CBD is 10 mg / kg / day, the patient is administered 5 mg of everolimus, and the reduced dose of CBD is approximately 5 mg / kg / day.

[0243] Embedding by reference All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated in their entirety by reference for all purposes. However, no reference to any reference, article, publication, patent, patent publication, or patent application cited herein should, and should not, be considered, as an acknowledgment or suggestion in any form that they constitute prior art in effect in any country of the world or form part of common general knowledge.

Claims

1. Cannabidiol (CBD) for use in the treatment of seizures associated with tuberous sclerosis, characterized in that the CBD is administered in a reduced dose and in combination with everolimus.

2. Cannabidiol (CBD) for use according to claim 1, wherein the dose of everolimus is approximately 2 mg to approximately 10 mg.

3. Cannabidiol (CBD) for use according to claim 1 or 2, wherein the reduced dose of CBD is at least about 10% less than the dose of CBD that would normally be administered in the absence of everolimus.

4. Cannabidiol (CBD) for use according to any one of claims 1 to 3, wherein the reduced dose of CBD is 10% to 90% less than the dose of CBD that would normally be administered in the absence of everolimus.

5. Cannabidiol (CBD) for use according to any one of claims 1 to 4, wherein the reduced dose of CBD is in the range of approximately 5 mg / kg / day to approximately 20 mg / kg / day.

6. Cannabidiol (CBD) for use according to any one of claims 1 to 5, wherein the dose of everolimus is 2.5 mg to 5 mg and the reduced dose of CBD is approximately 20 mg / kg / day.

7. Cannabidiol (CBD) for use according to any one of claims 1 to 6, wherein CBD is present in a highly purified plant-derived active pharmaceutical ingredient.

8. Cannabidiol (CBD) for use according to claim 7, wherein the CBD has a purity of at least 95 w / w%.

9. Cannabidiol (CBD) for use according to any one of claims 1 to 6, wherein the CBD is synthetic CBD.

10. Cannabidiol (CBD) for use according to any one of claims 1 to 9, wherein the seizure is a focal seizure.

11. Cannabidiol (CBD) for use according to claim 10, wherein the focal seizure is a focal motor seizure without impairment of consciousness or state of consciousness; a focal seizure with impairment of consciousness or state of consciousness; or a focal seizure that develops into a bilateral generalized seizure or generalized seizure.

12. Cannabidiol (CBD) for use according to any one of claims 1 to 9, wherein the seizure is a generalized seizure.

13. Cannabidiol (CBD) for use according to claim 12, wherein the generalized seizure is tonic-clonic, tonic, clonic, or cataplexy.

14. Cannabidiol (CBD) for use according to any one of claims 1 to 13, wherein the total number of seizures is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline.

15. Cannabidiol (CBD) for use according to any one of claims 1 to 14, wherein the total number of seizures is reduced by at least 50% compared to baseline.

16. Cannabidiol (CBD) for use in the treatment of seizures associated with tuberous sclerosis, characterized in that CBD is administered in a dose ranging from approximately 10 mg / kg / day to approximately 20 mg / kg / day, everolimus is administered in a dose of 2.5 to 10 mg of everolimus, and the CBD has a purity of at least 95 w / w%.

17. Cannabidiol (CBD) for use according to claim 16, wherein the seizure is a focal seizure.

18. Cannabidiol (CBD) for use according to claim 17, wherein the focal seizure is a focal motor seizure without impairment of consciousness or state of consciousness; a focal seizure with impairment of consciousness or state of consciousness; or a focal seizure that develops into a bilateral generalized seizure or generalized seizure.

19. Cannabidiol (CBD) for use according to claim 16, wherein the seizure is a generalized seizure.

20. Cannabidiol (CBD) for use according to claim 19, wherein the generalized seizure is a tonic-clonic, tonic, clonic, or cataplexy seizure.

21. Cannabidiol (CBD) for use according to any one of claims 16 to 20, wherein the total number of seizures is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline.

22. Cannabidiol (CBD) for use according to any one of claims 16 to 21, wherein the total number of seizures is reduced by at least 50% compared to baseline.

23. Cannabidiol (CBD) for use in the treatment of seizures associated with tuberous sclerosis, wherein CBD is administered to everolimus-naïve patients currently being treated with CBD. a) The step of co-administering everolimus to everolimus-naïve patients, b) A step of monitoring the patient's everolimus plasma concentration, c) If the patient's everolimus plasma trough concentration exceeds 15 ng / mL, reduce the dose of everolimus by at least 10%. Cannabidiol (CBD) for use, characterized by containing [the specified ingredient].

24. Cannabidiol (CBD) for use according to claim 23, wherein the patient is treated with 25 mg / kg / day of CBD.

25. Step (a) is 5 mg / m² 2 Cannabidiol (CBD) for use according to claim 23 or 24, comprising the step of administering everolimus once daily.

26. Cannabidiol (CBD) for use according to claim 25, wherein the dose of everolimus is adjusted upward by 5 mg or less until the patient's everolimus trough plasma concentration is in the range of 5–15 ng / mL.

27. Cannabidiol (CBD) for use according to claim 26, wherein the dose of everolimus is adjusted every 1 to 2 weeks until the patient's everolimus trough plasma concentration is within the range of 5 to 15 ng / mL.

28. The monitoring in step (b) is performed for 1 to 2 weeks after the patient starts everolimus administration, for cannabidiol (CBD) for use according to any one of claims 23 to 27.

29. Cannabidiol (CBD) for use in the treatment of seizures associated with tuberous sclerosis, wherein CBD is administered to everolimus-naïve patients currently being treated with CBD. (a) The step of co-administering everolimus to everolimus-naïve patients, (b) A step of monitoring the patient's everolimus plasma concentration, (c) Patient C max If the AUC exceeds 50 ng / mL, 0-24 If the value exceeds 500 hNg / mL, the dose of everolimus is reduced by at least 10%. Cannabidiol (CBD) for use, characterized by containing [the specified ingredient].

30. Cannabidiol (CBD) for use according to claim 29, wherein the patient is treated with 25 mg / kg / day of CBD.

31. Step (a) is 5 mg / m² 2 Cannabidiol (CBD) for use according to claim 29 or 30, comprising the step of administering everolimus once daily.

32. Cannabidiol (CBD) for use according to claim 31, wherein the dose of everolimus is adjusted upward by 5 mg or less until the patient's everolimus trough plasma concentration is in the range of 5–15 ng / mL.

33. Cannabidiol (CBD) for use according to claim 32, wherein the dose of everolimus is adjusted every 1 to 2 weeks until the patient's everolimus trough plasma concentration is within the range of 5 to 15 ng / mL.

34. The monitoring in step (b) is performed for 1 to 2 weeks after the patient starts everolimus administration of cannabidiol (CBD) for use according to any one of claims 29 to 33.

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