Cannabidiol and / or Cobicistat Combination Pharmacology

Abstract

Disclosed are compositions comprising cannabidiol and one or more compounds that are inhibitors of the enzymes CYP2C19 and CYP3A4. Also provided are methods for using such compositions to treat pain, epilepsy, sleep deprivation, emesis, nausea, psychosis, anxiety, depression, movement disorders, and other neuropsychiatric or neurogenic disorders. Also provided are compositions comprising cobicistat, or a pharmaceutically acceptable isomer, salt, and / or solvate thereof; and at least one therapeutic agent metabolized by CYP2C19 and, optionally, CYP3A4. Also provided are methods for inhibiting CYP2C19, and optionally CYP3A4, in a patient in need thereof, comprising administering to the patient an amount of cobicistat, or a pharmaceutically acceptable isomer, salt, and / or solvate thereof, effective to inhibit CYP2C19 and, optionally, CYP3A4 in the patient.

Description

[Technical Field]

[0001] Disclosed are compositions comprising cannabidiol and one or more compounds that are inhibitors of the CYP2C19 and CYP3A4 enzymes. Disclosed are compositions comprising cobicistat and at least one therapeutic agent that is metabolized by the CYP2C19 enzyme. Methods of treatment using such compositions are also provided. [Background technology]

[0002] CYP3A4 and CYP2C19 are members of the cytochrome P450 (CYP) family of oxidative enzymes. Cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids, and other lipid components. Many drugs can increase or decrease the activity of various CYP isoenzymes, either by inducing isoenzyme biosynthesis (enzyme induction) or by directly inhibiting CYP activity (enzyme inhibition). CYP2C19 is a hepatic enzyme that acts on at least 10% of commonly prescribed drugs and is involved in the metabolism of xenobiotics, including many proton pump inhibitors and antiepileptic drugs. CYP3A4 is the most abundantly expressed human CYP enzyme, found primarily in the liver and intestine, and metabolizes approximately 30%–50% of commercially available drugs.

[0003] The plant-derived cannabidiol (CBD), Epidiolex®, was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients 2 years of age and older (Epidiolex® label, Greenwich Biosciences, 2008, pg. 1). CBD is the primary non-psychoactive component of cannabis (Cannabis sativa) and accounts for up to 40% of the plant's extract. Campos et al., Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3364-78. CBD is currently being investigated for the treatment of various anxiety, cognitive, and movement disorders, as well as pain. CBD has shown promise for the treatment of a wide range of conditions, including epilepsy, sleep deprivation, vomiting, nausea, psychosis, anxiety, depression, movement disorders, and other neuropsychiatric or neuropathic disorders; and pain relief in patients suffering from headaches, migraines, rheumatoid arthritis, neuropathy, allodynia, overactive bladder, spasticity, multiple sclerosis, HIV, glioblastoma, cancer, and other acute or chronic pain conditions. Urits et al., Pain Ther 2019;8(1):41-51.

[0004] CBD has significant adverse drug reactions that promote intolerance. The Epidiolex® label (pg. 8) reports significant differences in adverse drug reactions between CBD and placebo treatment, as shown in the table below, with most adverse drug reactions being dose-dependent. Administration of a 20 mg / kg / day dose reduced seizure rates somewhat more than the recommended maintenance dose of 10 mg / kg / day, but was accompanied by an increase in adverse reactions (pg. 2, Epidiolex® label). [Table 1]

[0005] Oral CBD (Epidiolex®) dosages are very high due to low bioavailability, with maintenance doses of 5–10 mg / kg twice daily (Epidiolex® label, pg. 1). Oral bioavailability of CBD is only 13–19% due to extensive first-pass metabolism. Mechoulam et al., J Clin Pharmacol. 2002;42:S11–S19. CBD is metabolized in the liver and intestine by CYP2C19 and CYP3A4 enzymes, as well as UGT1A7, UGT1A9, and UGT2B7 isoforms (Epidiolex® label, pg. 14). At steady-state concentrations, the major circulating moiety is 7-COOH-CBD, followed by the parent drug CBD, 7-OH-CBD, and 6-OH-CBD. The major metabolite, 7-COOH-CBD, is inactive, whereas the minor metabolite, 7-OH-CBD, exhibits anticonvulsant effects similar to those of CBD (when tested in a maximal electroconvulsive shock (MES) model in mice). The concentration of the 7-COOH-CBD metabolite was 47 times higher than that of CBD after a 1500 mg CBD administration, representing 97% of the total drug substance. Taylor, CNS Drugs. 2018;32:1053-1067. Thus, anticonvulsant activity is due to only 3% of the active molecules, CBD and 7-OH-CBD, in the systemic circulation, with the majority being CBD (2%). Therefore, therapeutic approaches to increase CBD bioavailability are needed.

[0006] Cobicistat, Tybost®, is known for the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents. Cobicistat is a component of two fixed-dose, four-drug HIV treatments, Stribild® (elvitegravir / cobicistat / emtricitabine / tenofovir disoproxil) and Genvoya® (elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide). Additionally, fixed-dose combinations of cobicistat and the protease inhibitors darunavir and azanavir are commercially available as Prezcobix® and Evotaz®, respectively.

[0007] Pharmacological enhancement of plasma concentrations of protease inhibitors through coadministration of booster drugs has long been an essential part of HIV antiretroviral therapy. Nils von Hentig, HIV AIDS (Auckl). 2016;8:1–16. Most HIV protease inhibitors are combined with low-dose ritonavir or cobicistat to effectively inhibit cytochrome-mediated metabolism of HIV protease inhibitors in the liver, thereby enhancing plasma concentrations and extending the dosing interval of antiretroviral HIV protease inhibitors. Id.at 1. Cobicistat is similar to ritonavir in that both are substrates of hepatic CYP3A metabolism. However, unlike ritonavir, cobicistat is reported to be a weak inhibitor of CYP2D6 (IC50 = 9.2 μmol / L) and not inhibit CYP1A2, CYP2C8, CYP2C9, or CYP2C19 (IC50 > 25 μmol / L). Id.at 3; Mark Mascolini, “Cobicistat Has Little Impact on Key Drug-Metabolizing Enzyme”, 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Summary of the Invention [Means for solving the problem]

[0008] As described herein, effective inhibition of CBD metabolism has been found to require inhibition of both CYP2C19 and CYP3A4 enzymes. Furthermore, the CYP inhibition studies described herein indicate that CBD has approximately three-fold higher affinity for CYP2C19 than for CYP3A4. While not intending to be limited by any particular theory or mechanism of action, given that the average contribution of CYP2C19 to CBD metabolism may be up to three times that of CYP3A based on their affinity, a significant reduction in the effective CBD dosage may be achieved by coadministering a compound that is an inhibitor of both CYP2C19 and CYP3A4, due to the higher bioavailability and longer effective plasma half-life of CBD upon such coadministration. Reducing the effective CBD dosage reduces adverse reactions, particularly hepatotoxicity, caused by dose-related elevations in hepatic transaminases (pp. 3-4, Epidiolex® label).

[0009] In one aspect, the present invention provides a composition comprising: cannabidiol, or a pharmaceutically acceptable isomer, solvate and / or ester thereof; and One or more compounds that are inhibitors of the CYP2C19 and CYP3A4 enzymes.

[0010] In some embodiments, at least one compound that is an inhibitor of both the CYP2C19 and CYP3A4 enzymes is co-administered with cannabidiol. In other embodiments, two or more compounds are co-administered with cannabidiol, with at least one compound being an inhibitor of the CYP2C19 enzyme and at least another compound being an inhibitor of the CYP3A4 enzyme.

[0011] In another aspect, the present invention provides a method of treating epilepsy, sleep deprivation, vomiting, nausea, psychosis, anxiety, depression, movement disorders, or other neuropsychiatric or neuropathic disorders in a patient, comprising administering to the patient a therapeutically effective amount of: cannabidiol, or a pharmaceutically acceptable isomer, solvate and / or ester thereof; and One or more compounds that are inhibitors of the CYP2C19 and CYP3A4 enzymes The present invention provides a method comprising administering

[0012] In yet another aspect, the present invention provides a method of treating pain in a patient suffering from headache, migraine, rheumatoid arthritis, neuropathy, allodynia, overactive bladder, spasticity, multiple sclerosis, HIV, glioblastoma, cancer, or other acute or chronic pain condition, comprising administering to the patient a therapeutically effective amount of: cannabidiol, or a pharmaceutically acceptable isomer, solvate and / or ester thereof; and One or more compounds that are inhibitors of the CYP2C19 and CYP3A4 enzymes The present invention provides a method comprising administering

[0013] In another aspect, the present invention provides a method of increasing plasma levels of CBD in a human undergoing CBD treatment, the method comprising co-administering one or more compounds that are inhibitors of CYP2C19 and CYP3A4 enzymes with a therapeutically effective amount of CBD, or a pharmaceutically acceptable isomer, solvate and / or ester thereof.

[0014] In another aspect, the present invention provides a method of reducing hepatotoxicity in a human undergoing CBD treatment, the method comprising co-administering a therapeutically effective amount of one or more compounds that are inhibitors of CYP2C19 and CYP3A4 enzymes with a therapeutically effective amount of CBD, or a pharmaceutically acceptable isomer, solvate and / or ester thereof.

[0015] Furthermore, cobicistat has unexpectedly been found to inhibit not only CYP3A4 but also CYP2C19, as described herein, and therefore can be used to alter the pharmacokinetic profiles of therapeutic agents that are metabolized exclusively by CYP2C19, as well as therapeutic agents that are metabolized by both CYP2C19 and CYP3A4 enzymes.

[0016] In yet another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: Cobicistat, or a pharmaceutically acceptable isomer, salt, and / or solvate thereof; and At least one therapeutic agent metabolized by the CYP2C19 enzyme A composition comprising:

[0017] In another aspect, the present invention provides a method of inhibiting CYP2C19 in a patient in need thereof, comprising administering to the patient an amount of cobicistat, or a pharmaceutically acceptable isomer, salt, and / or solvate thereof, effective to inhibit CYP2C19 in the patient.

[0018] In another aspect, the present invention provides a method of increasing the plasma level of a therapeutic agent that is metabolized by CYP2C19 in a patient undergoing treatment with the therapeutic agent, the method comprising co-administering the therapeutic agent with a therapeutically effective amount of cobicistat, or a pharmaceutically acceptable isomer, salt, and / or solvate thereof.

[0019] Both CYP3A4 and CYP2C19 are involved in the major metabolic pathways of several therapeutic agents. Blocking only one pathway can potentially divert metabolism to the other pathway, so blocking both pathways maximizes metabolic inhibition. Co-administration of cobicistat, which inhibits both CYP3A and CYP2C19, with such therapeutic agents is likely to significantly reduce the metabolism of the therapeutic agents, allowing for significant reductions in the dosage and frequency of administration of such therapeutic agents. Reduced dosage reduces adverse drug reactions, and reduced dosing frequency increases patient compliance with drug regimens.

[0020] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: Cobicistat, or a pharmaceutically acceptable isomer, salt, and / or solvate thereof; and At least one therapeutic agent metabolized by CYP2C19 and CYP3A4 A composition comprising:

[0021] In yet another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: cannabidiol, or a pharmaceutically acceptable isomer, solvate and / or ester thereof; and Cobicistat, or its pharmaceutically acceptable isomers, salts, and / or solvates A composition comprising:

[0022] In another aspect, the present invention provides a method of inhibiting CYP2C19 and CYP3A4 in a patient in need thereof, comprising administering to the patient cobicistat, or a pharmaceutically acceptable isomer, salt, and / or solvate thereof, in an amount effective to inhibit CYP2C19 and CYP3A4 in the patient.

[0023] In yet another aspect, the present invention provides a method of increasing the plasma level of a therapeutic agent that is metabolized by CYP2C19 and CYP3A4 in a patient undergoing treatment with the therapeutic agent, the method comprising co-administering the therapeutic agent with a therapeutically effective amount of cobicistat, or a pharmaceutically acceptable isomer, salt, and / or solvate thereof. [Brief explanation of the drawings]

[0024] [Figure 1] Diagram showing the effects of CYP inhibitors cobicistat, 6,7-dihydroxybergamottin, lansoprazole, and ketoconazole on CBD metabolism in human liver microsomes. [Figure 2] Diagram showing the effects of fluoxetine, bergamottin, ticlopidine, omeprazole, and omeprazole sulfone as CYP inhibitors on CBD metabolism in human liver microsomes. DETAILED DESCRIPTION OF THE INVENTION

[0025] Compounds that are inhibitors of CYP2C19 and CYP3A4, and therapeutic agents that are metabolized by both CYP2C19 and CYP3A4, include CBD, cimetidine, chloramphenicol, voriconazole, fluvoxamine, isoniazid, 6,7-dihydroxybergamottin, lansoprazole, mixtures thereof, and pharmaceutically acceptable salts, isomers, solvates and / or esters thereof.

[0026] Compounds that are inhibitors of CYP2C19 and therapeutic agents metabolized by CYP2C19 include xenobiotics, including many proton pump inhibitors and antiepileptic drugs. In particular, compounds that are inhibitors of CYP2C19 and therapeutic agents metabolized by CYP2C19 include clopidogrel, indomethacin, methadone, mephenytoin, phenylbutazone, ticlopidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, eslicarbazepine, felbamate, oxcarbazepine, efavirenz, diazepam, topiramate, fluoxetine, probenecid, modafil, proguanil, and pharmaceutically acceptable salts, isomers, solvates, and / or esters thereof.

[0027] The term "pharmaceutically acceptable salt" refers to a salt prepared by treating a compound with a pharmaceutically acceptable non-toxic acid or base. Suitable pharmaceutically acceptable acid addition salts of Cobicistat include dihydrochloride, methanesulfonate, acetate, hydrobromide, salicylate, nitrate, dinitrate, pamoate, oxalate, p-toluenesulfonate, salicylate, tartrate, formate, and citrate.

[0028] Pharmaceutically acceptable isomers include all pharmaceutically active non-toxic enantiomers, diastereomers, and geometric isomers. Pharmaceutically acceptable solvates include hydrates and solvates with pharmaceutically acceptable solvents such as alcohols.

[0029] Cannabidiol, cobicistat, compounds that are inhibitors of CYP2C19 and / or CYP3A4, and therapeutic agents metabolized by CYP2C19 and / or CYP3A4, or their isomers, salts, solvates, and / or esters, are commercially available or can be prepared by methods known in the art. For example, cobicistat can be prepared by the method disclosed in U.S. Patent No. 9,975,864 or Xu et al., ACS Med.Chem.Lett. 2010,1(5):209-213,S10-S14; and CBD can be prepared by the method disclosed in U.S. Patent No. 2,304,669, U.S. Patent No. 5,227,537, or U.S. Patent No. 7,674,922.

[0030] The amounts of compounds that are inhibitors of both CYP2C19 and / or CYP3A4 and therapeutic agents metabolized by CYP2C19 and / or CYP3A4 used in accordance with the compositions and methods of the present invention depend on the desired therapeutic effect and can therefore vary within a wide range, but are generally significantly lower than the amounts required to achieve the same effect through monotherapy or without using the claimed combination of active ingredients. Those skilled in the art can easily identify appropriate amounts based on the dosages for monotherapy known in the art. Generally, a therapeutically effective amount of a therapeutic agent or compound is an amount sufficient to induce any of the beneficial effects of the therapeutic agent or compound in a patient. For example, a therapeutically effective amount of cobicistat, or a pharmaceutically acceptable isomer, salt, and / or solvate thereof, is an amount sufficient to inhibit or reduce the metabolism of a therapeutic agent metabolized by CYP2C19 and / or CYP3A4.

[0031] Compounds that are inhibitors of CYP2C19 and CYP3A4 increase plasma concentrations of CBD by inhibiting its metabolism, and cobicistat increases plasma concentrations of compounds that are inhibitors of CYP2C19 and / or CYP3A4 by inhibiting their metabolism.

[0032] CBD exhibits dose-dependent absorption. Pharmacokinetic data for single doses ranging from 200 mg to 6000 mg (Taylor 2018, CNS Drugs 2018;32:1053-1067; Clinical pharmacology and biopharmaceutics review(s), Epidiolex®) show that CBD absorption decreases significantly with increasing dose, likely due to CBD's limited solubility in gastrointestinal fluids. CBD is highly hydrophobic, with a Log P (partition coefficient) of 6.1 and a water solubility of 0.0126 mg / mL (Drug Bank: Cannabidiol_https: / / go.drugbank.com / drugs / DB09061). [Table 2]

[0033] Overall, CBD bioavailability depends on two factors: first-pass metabolism (primarily by CYP2C19 and CYP3A4) and dose. CYP3A4 and CYP2C19 inhibitors are expected to increase bioavailability by more than three-fold by inhibiting first-pass metabolism. Furthermore, the resulting dose reduction would also increase absorption across the gastrointestinal tract many times over.

[0034] Significant interactions between CBD and food have been reported (Taylor 2018, CNS Drugs 2018;32:1053-1067; Clinical pharmacology and biopharmaceutics review(s), Epidiolex®), due to limited solubility and consequently poor absorption of CBD at higher doses. Therefore, reducing the CBD dose by coadministering CYP3A4 and CYP2C19 inhibitors can significantly reduce CBD food interactions, leading to a more predictable pharmacokinetic profile and ultimately improving the safety profile of CBD.

[0035] Furthermore, by inhibiting the metabolism of CBD, compounds that are inhibitors of CYP2C19 and CYP3A4 may increase the effective half-life of CBD, thereby reducing the frequency of dosing. Cobicistat may increase the effective half-life of therapeutic agents metabolized by CYP2C19 and / or CYP3A4 by inhibiting their metabolism, thereby reducing the frequency of their administration.

[0036] For example, the short half-life of cobicistat, 3-5 hours, extends the effective half-life (t) of CBD to 15-22 hours via inhibition of systemically absorbed CBD metabolism, making it suitable for coadministration with CBD, which has a half-life of 10-17 hours, for once-daily treatment. Furthermore, if a patient is receiving another concomitant medication that is metabolized or inhibited by either or both of the CYP3A4 and CYP2C19 enzymes, drug-drug interactions can be minimized by administering CBD once daily with cobicistat, provided that the CBD administration and the concomitant medication are appropriately staggered throughout the day.

[0037] The total daily dose of CBD administered with cobicistat or other compounds that are inhibitors of CYP2C19 and / or CYP3A4 can be, for example, half, one-third, one-quarter, one-fifth, one-tenth, one-fifteenth, or one-twentieth of the usual dose of CBD when administered alone. The amount of CBD used in the therapeutic methods of the present invention can range, for example, from 1 mg / kg once daily to 20 mg / kg once daily, or from 0.5 mg / kg twice daily to 10 mg / kg twice daily. In some embodiments, compositions according to the present invention contain 25 mg to 4000 mg, 50 mg to 2000 mg, or 100 mg to 1000 mg of CBD.

[0038] The amount of cobicistat used in the treatment methods of the invention can range, for example, from 100 mg once daily to 1000 mg once daily, or from 50 mg twice daily to 500 mg twice daily. In some embodiments, compositions according to the invention contain cobicistat in an amount of 100 mg to 1000 mg.

[0039] The simultaneous administration or administration of CBD or cobicistat according to the present invention can be carried out simultaneously with, before, or after the administration of a compound that is an inhibitor of CYP2C19 and CYP3A4, or a therapeutic agent metabolized by CYP2C19 and / or CYP3A4, respectively. According to one option, the compound that is an inhibitor of CYP2C19 and CYP3A4, or a therapeutic agent metabolized by CYP2C19 and / or CYP3A4, is administered first, and CBD or cobicistat is administered second. According to another option, CBD or cobicistat is administered first, and the compound that is an inhibitor of CYP2C19 and CYP3A4, or a therapeutic agent metabolized by CYP2C19 and / or CYP3A4, is administered second. According to some embodiments, administration of CBD or cobicistat can occur up to two hours before or after administration of a compound that is an inhibitor of CYP2C19 and CYP3A4 or a therapeutic agent metabolized by CYP2C19 and / or CYP3A4. For example, CBD or cobicistat can be administered 15 minutes, 30 minutes, 45 minutes, 1 hour, or 1.5 hours before or after administration of a compound that is an inhibitor of CYP2C19 and CYP3A4 or a therapeutic agent metabolized by CYP2C19 and / or CYP3A4 to maximize or control metabolism of the other drug / therapeutic agent.

[0040] Thus, the claimed combination of active ingredients, CBD, cobicistat, a compound that is an inhibitor of CYP2C19 and CYP3A4, and a therapeutic agent metabolized by CYP2C19 and / or CYP3A4 may be contained in a single pharmaceutical composition or may be contained separately in two independent pharmaceutical compositions.

[0041] The active ingredient may be formulated as a tablet or capsule together with pharmaceutically acceptable carriers and / or excipients. The compositions are prepared according to conventional methods known in the art.

[0042] When the claimed active ingredient combination is contained separately in two independent pharmaceutical compositions, the two pharmaceutical compositions may be in different dosage forms and administration routes. For example, one pharmaceutical composition may be a tablet and the other a capsule. In particular, cobicistat may be formulated as a coated or uncoated tablet or capsule with a pharmaceutically acceptable carrier and / or excipient. CBD, a therapeutic agent metabolized by CYP2C19 and / or CYP3A4, or a compound that is an inhibitor of CYP2C19 and CYP3A4 may be formulated with a pharmaceutically acceptable carrier and / or excipient as an oral solution or suspension, a tincture, a self-microemulsifying drug delivery system, a chewable gum, a gel capsule, sublingual drops, a tablet, a vaping oil, a smoke, or any other means of oral, topical, or nasal administration.

[0043] Compositions containing CBD can be administered orally, sublingually, topically, or via inhalation. Compositions containing therapeutic agents metabolized by CYP2C19 and / or CYP3A4 can be administered orally, sublingually, topically, via inhalation, or via any other route of administration. Compositions containing compounds that are inhibitors of CYP2C19 and / or CYP3A4 can be administered orally, sublingually, topically, via inhalation, or via any other route of administration. Compositions containing cobicistat alone or in combination with compounds that are inhibitors of CYP2C19 and / or CYP3A4 can generally be administered orally. [Example]

[0044] Cytochrome P450 inhibition in human liver microsomes (HLM) Example 1: Direct inhibitory potency of a number of CYP3A4 and CYP2C19 inhibitors on the metabolism of CBD at a given Km (substrate concentration at which the reaction rate is 50% of Vmax, the maximum rate achieved by the system) using pooled human liver microsomes (Km is an indicator of the affinity an enzyme has for its substrate; the lower the Km value, the more efficient the enzyme is at performing its function at lower substrate concentrations).

[0045] Km / Vmax HLM diluted in potassium phosphate buffer was mixed with compound working solution and 5x cofactors (0.44 mM NADP, 5.5 mM G6P, 0.4 U / mL G6PDH) to achieve final concentrations of 0.033, 0.1, 0.33, 1, 3.3, 10, 33, and 100 μM test compound, 1 μM for the positive control midazolam, and 0.1 mg / mL for liver microsomes. Spiked liver microsomes were incubated at 37°C with 5% CO2 at 200 rpm. At 0, 15, 45, 90, and 120 minutes, 50 μL aliquots of spiked liver microsomes were collected and quenched with 200 μL of cold stop solution (acetonitrile containing internal standard) in a deep 96-well collection plate. At the end of the incubation, the collection plate was vortexed at 1700 rpm for 3 minutes and centrifuged at 3500 rpm for 10 minutes. The resulting supernatant was mixed with water (1:1, v / v) in a new 96-well deep plate. The samples were then analyzed using liquid chromatography-tandem mass spectrometry (LC-MS / MS). Km and Vmax values ​​were determined from regression analysis of test compound disappearance and metabolite formation against test compound concentration.

[0046] IC50 specific Microsome mixtures were prepared in 100 mM KPi containing a 100x positive control working solution and 5x cofactor; reactions were also initiated with a 5x substrate working solution for a final volume of 250 μL. Final incubation concentrations were as follows: 0.1 mg / mL microsomal protein; 1x cofactor; 0.033, 0.1, 0.33, 1, 3.3, 10, and 33 μM test inhibitor; and 0.5% DMSO. Inhibitor (positive control) and substrate concentrations are listed in the table below. Samples were incubated at 37°C and 5% CO2 with orbital shaking at 200 rpm for 15 minutes. The reaction was stopped by adding 500 μL of cold stop solution (acetonitrile containing the internal standard). Samples were vortexed at 1700 rpm for 3 minutes and centrifuged at 3500 rpm for 15 minutes. The resulting supernatant was mixed with water (3:1, v / v) in a new 96-well deep plate. Samples were analyzed by LC-MS / MS for substrate disappearance and metabolite formation. [Table 3] [Table 4]

[0047] The results are shown in the table below: [Table 5]

[0048] The data indicate that cobicistat is a potent inhibitor of CBD metabolism. 6,7-Dihydroxybergamottin and lansoprazole were also found to be effective inhibitors of CBD metabolism. 6,7-Dihydroxybergamottin is known to inhibit not only CYP3A4 but also CYP2C19. H. Seki et al. Drug Metab. Pharmacokinet. 2019;34(3)181-186. Lansoprazole is known to primarily inhibit CYP2C19 and CYP3A4. Meyer et al. Eur J Gastroenterol Hepatol 1996;8(Suppl.1):S21 5. The results also indicate that ticlopidine and fluoxetine, which are inhibitors of CYP2C19 but not CYP3A4, are unable to inhibit CBD metabolism. The results also show that ketoconazole, an inhibitor of CYP3A4, also inhibits CBD metabolism, but with less potency than cobicistat, 6,7-dihydroxybergamottin, and lansoprazole. Cobicistat was found to be a 1.53-fold more potent inhibitor of CBD metabolism than ketoconazole, a sole inhibitor of CYP3A4. The graphs in Figures 1 and 2 show the effects of the tested CYP inhibitors on CBD metabolism in human liver microsomes.

[0049] Although CYP2C19-based metabolism is the primary pathway, it can be speculated that CBD metabolism will shift to other pathways, such as CYP3A4-based metabolism, when CYP2C19 is inhibited. The results indicate that CYP2C19 inhibition alone does not inhibit CBD metabolism, and inhibition of CYP3A4 alone does not appear to be sufficient. Therefore, combined inhibition of both the CYP3A4 and CYP2C19 pathways is required for effective inhibition of CBD metabolism.

[0050] Previous clinical kinetic studies have reported that ketoconazole, a single CYP3A4 inhibitor, increases the AUC(0-t) of CBD by 2.65-fold (Stott et al. SpringerPlus 2013, 2:236). Therefore, cobicistat is expected to significantly increase the AUC of CBD by more than 3-fold.

[0051] Example 2: Cytochrome P450 (CYP) direct inhibition studies were performed to evaluate the direct inhibitory potential of test compounds against human hepatic (CYP) isoforms using pooled human liver microsomes and isoform-specific probe substrates. Incubation mixtures were prepared using: (a) Potassium phosphate buffer; (b) 0.1 mg / mL microsomal protein; (c) isoform-specific probe substrate; (d) a specific concentration of the test compound, blank solvent, or positive control (isoform-specific inhibitor); and (e) NADPH regeneration cofactor solution.

[0052] The mixture was incubated at 37°C and 5% carbon dioxide with orbital shaking at 200 rpm for 5-20 minutes, depending on the substrate. After incubation was complete, the reaction was quenched with an acetonitrile solution containing an internal standard. Samples were processed and analyzed by LC-MS / MS to monitor substrate metabolite formation. Enzyme activity in the presence of compound was normalized to enzyme activity in the absence of compound and expressed as a percentage of activity. The inhibitory potency (IC50) of the compound was determined using nonlinear regression of the percentage of activity against compound concentration. The test results are shown in the table below: [Table 6]

[0053] The data show that CBD has approximately three-fold higher affinity for CYP2C19 than for CYP3A4.

Claims

1. Cannabidiol, or its pharmaceutically acceptable active non-toxic enantiomers, diastereomers, and geometric isomers, and / or solvates; and One or more compounds selected from the group consisting of cobicistat, 6,7-dihydroxybergamottin, lansoprazole, and their pharmaceutically acceptable active non-toxic enantiomers, diastereomers, and geometric isomers, and / or solvates. A composition comprising:

2. 10. The composition of claim 1, further comprising one or more pharmaceutically acceptable carriers or excipients.

3. 3. The composition of claim 1 or 2 for use in the treatment of epilepsy, sleep deprivation, vomiting, nausea, psychosis, anxiety, depression, movement disorders, and other neuropsychiatric or neurogenic disorders.

4. 3. The composition of claim 1 or 2 for use in treating pain caused by headache, migraine, rheumatoid arthritis, neuropathy, allodynia, overactive bladder, spasticity, multiple sclerosis, HIV, glioblastoma, cancer, and other acute or chronic pain conditions.

5. 3. A composition according to claim 1 or 2 for use in reducing hepatotoxicity during cannabidiol treatment.

6. 1. A composition for increasing cannabidiol plasma levels during cannabidiol therapy, comprising: a therapeutically effective amount of a compound selected from the group consisting of cobicistat, 6,7-dihydroxybergamottin, lansoprazole, mixtures thereof, and pharmaceutically acceptable salts, active non-toxic enantiomers, diastereomers, and geometric isomers, and / or solvates thereof; and A therapeutically effective amount of cannabidiol, or a pharmaceutically acceptable geometric isomer and / or solvate thereof. A composition comprising:

7. Cannabidiol, or its pharmaceutically acceptable active non-toxic enantiomers, diastereomers, and geometric isomers, and / or solvates; and Cobicistat or its pharmaceutically acceptable active non-toxic enantiomers, diastereomers, and geometric isomers, salts, and / or solvates A composition comprising:

8. 8. The composition of claim 7, further comprising one or more pharmaceutically acceptable carriers or excipients.

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