Combination therapy with cannabidiol and / or cobicistat

Abstract

Compositions comprising cannabidiol and one or more compounds that are inhibitors of CYP2C19 and CYP3A4 enzymes are disclosed. Methods of using such compositions to treat pain, epilepsy, sleep deprivation, vomiting, nausea, psychosis, anxiety, depression, movement disorders, and other neuropsychiatric or neurogenic diseases are also provided. 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 are provided. A method for inhibiting CYP2C19 and optionally CYP3A4 in a patient in need thereof is also provided, 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 CYP2C19 and CYP3A4 enzymes.Disclosed are compositions comprising cobicistat and at least one therapeutic agent metabolized by a CYP2C19 enzyme.Also provided are methods of treatment using such compositions. Background Art

[0002] CYP3A4 and CYP2C19 are members of the cytochrome P450 (CYP) family of oxidases. 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 isozymes by inducing the biosynthesis of isozymes (enzyme induction) or by directly inhibiting the activity of CYP (enzyme inhibition). CYP2C19 is a liver enzyme that plays a role in at least 10% of commonly prescribed drugs and is involved in the metabolism of xenobiotics, including the metabolism of many proton pump inhibitors and anti-epileptic drugs. CYP3A4 is the most abundantly expressed human CYP enzyme, mainly present in the liver and intestines, and metabolizes approximately 30 to 50% of marketed drugs.

[0003] Plant-derived cannabidiol (CBD), i.e. It has recently been 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. Label, Greenwich Biosciences, Inc., 2008, p. 1). CBD is the major non-psychoactive component of Cannabis sativa, accounting for up to 40% of plant extracts. Campos et al., Philos Trans R Soc Lond B Biol Sci. 2012; 367(1607): 3364-78. CBD is currently being studied for the treatment of various anxiety, cognitive and movement disorders, and for the treatment of pain. CBD has shown promise in treating a variety of conditions, such as epilepsy, sleep deprivation, vomiting, nausea, psychosis, anxiety, depression, movement disorders, and other neuropsychiatric or neurogenic diseases; and for the relief of pain in patients with 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 effects that promote intolerance. The label (page 8) reports significant differences in adverse drug reactions between CBD and placebo treatments as shown in the table below, with most adverse drug reactions being dose-dependent. Administration of a dose of 20 mg / kg / day resulted in a slight reduction in seizure rate but an increase in adverse reactions compared to the recommended maintenance dose of 10 mg / kg / day (page 2, Label).

[0005]

[0006] Due to low bioavailability, oral administration The maintenance dose is 5 to 10 mg / kg twice daily ( Label, p. 1). Due to extensive first-pass metabolism, the oral bioavailability of CBD is only 13 to 19%. Mechoulam et al., J Clin Pharmacol. 2002;42:S11-S19. CBD is metabolized in the liver and intestine by CYP2C19 and CYP3A4 enzymes and UGT1A7, UGT1A9, and UGT2B7 isoforms ( Label, page 14) metabolism. At steady-state concentrations, the major circulating fraction 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, but the minor metabolite 7-OH-CBD exhibits anticonvulsant effects similar to CBD. 1 After a 1500 mg CBD dose, the concentration of 7-COOH-CBD metabolites was 47 times higher than that of CBD, accounting for 97% of the total amount of drug measured. Taylor, CNS Drugs. 2018; 32: 1053-1067. Therefore, the anticonvulsant activity is attributed to only 3% of the active molecules CBD and 7-OH-CBD in the systemic circulation, most of which is CBD (2%). Therefore, treatment methods for increasing the bioavailability of CBD are needed.

[0007] Cobicistat, It is indicated for use in combination with other antiretroviral agents to treat human immunodeficiency virus (HIV) infection. Cobicistat is a combination of two fixed-dose, four-drug HIV therapies, namely (elvitegravir / cobicistat / emtricitabine / tenofovir disoproxil) and (elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide), a component of the drug. In addition, fixed-dose combinations of cobicistat and the protease inhibitors darunavir and azanavir are available at and Available for sale.

[0008] Increasing plasma concentrations of protease inhibitors by co-administering boosters has long been an integral 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 increasing plasma concentrations and prolonging dosing intervals of antiretroviral HIV protease inhibitors. Ibid. at p. 1. Cobicistat is similar to ritonavir in that both are substrates for hepatic CYP3A metabolism. However, unlike ritonavir, cobicistat is reported to be a weak inhibitor of CYP2D6 (IC50 = 9.2 μmol / L) and does not inhibit CYP1A2, CYP2C8, CYP2C9, or CYP2C19 (IC50>25 μmol / L). Ibid., p. 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

[0009] As described herein, it has been found that effective inhibition of CBD metabolism requires inhibition of both CYP2C19 and CYP3A4 enzymes. Further, the CYP inhibition studies described herein indicate that CBD has an affinity for CYP2C19 that is approximately three times greater than its affinity for CYP3A4. Without intending to be limited by any particular theory or mechanism of action, given that the average contribution of CYP2C19 in metabolizing CBD may be up to three times that of CYP3A based on its affinity, a significant reduction in the effective CBD dose may be achieved by co-administering with a compound that is an inhibitor of both CYP2C19 and CYP3A4, as CBD has a higher bioavailability and longer effective plasma half-life upon such co-administration. Reducing the effective dose of CBD in turn reduces adverse effects, particularly hepatotoxicity, which is caused by dose-related elevations in liver transaminases (pp. 3-4, Label).

[0010] In one aspect, the present invention provides a composition comprising:

[0011] Cannabidiol or a pharmaceutically acceptable isomer, solvate and / or ester thereof; and

[0012] One or more compounds which are inhibitors of CYP2C19 and CYP3A4 enzymes.

[0013] In some embodiments, at least one compound that is an inhibitor of both CYP2C19 and CYP3A4 enzymes is co-administered with cannabidiol. In other embodiments, two or more compounds are co-administered with cannabidiol, wherein at least one compound is an inhibitor of the CYP2C19 enzyme and at least another compound is an inhibitor of the CYP3A4 enzyme.

[0014] In another aspect, the present invention provides a method for treating epilepsy, sleep deprivation, vomiting, nausea, psychosis, anxiety, depression, movement disorders or other neuropsychiatric or neurogenic disorders in a patient, comprising administering to the patient a therapeutically effective amount of:

[0015] Cannabidiol or a pharmaceutically acceptable isomer, solvate and / or ester thereof; and

[0016] One or more compounds which are inhibitors of CYP2C19 and CYP3A4 enzymes.

[0017] In yet another aspect, the present invention provides a method for 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 conditions, comprising administering to the patient a therapeutically effective amount of:

[0018] Cannabidiol or a pharmaceutically acceptable isomer, solvate and / or ester thereof; and

[0019] One or more compounds which are inhibitors of CYP2C19 and CYP3A4 enzymes.

[0020] In another aspect, the present invention provides a method for increasing CBD plasma levels in a human being treated with CBD, 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.

[0021] In another aspect, the present invention provides a method for reducing hepatotoxicity in a human being treated with CBD, comprising administering a therapeutically effective amount of one or more compounds that are inhibitors of CYP2C19 and CYP3A4 enzymes, together with a therapeutically effective amount of CBD or a pharmaceutically acceptable isomer, solvate and / or ester thereof.

[0022] Further, as described herein, it has now been unexpectedly discovered that cobicistat not only inhibits CYP3A4, but also inhibits CYP2C19. Therefore, cobicistat can be used to alter the pharmacokinetic profile of therapeutic agents metabolized solely by CYP2C19 and therapeutic agents metabolized by both CYP2C19 and CYP3A4 enzymes.

[0023] In yet another aspect, the present invention provides a composition comprising:

[0024] Cobicistat or a pharmaceutically acceptable isomer, salt and / or solvate thereof; and

[0025] At least one therapeutic agent that is metabolized by the CYP2C19 enzyme.

[0026] In another aspect, the present invention provides a method for 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.

[0027] In another aspect, the present invention provides a method for increasing the plasma level of a therapeutic agent metabolized by CYP2C19 in a patient being treated with the therapeutic agent, comprising co-administering the therapeutic agent with a therapeutically effective amount of cobicistat or a pharmaceutically acceptable isomer, salt and / or solvate thereof.

[0028] Both CYP3A4 and CYP2C19 are involved in the major metabolic pathways of several therapeutic agents. Blocking of both pathways maximizes metabolic inhibition, because blocking of only one pathway may divert metabolism to another pathway. Co-administration of cobicistat, which inhibits both CYP3A and CYP2C19, with such therapeutic agents is expected to significantly reduce the metabolism of the therapeutic agents, thereby enabling the dosage and frequency of administration of such therapeutic agents to be significantly reduced. Reducing the dosage reduces adverse drug reactions, while reducing the frequency of administration increases the patient's compliance with the drug regimen.

[0029] In another aspect, the present invention provides a composition comprising:

[0030] Cobicistat or a pharmaceutically acceptable isomer, salt and / or solvate thereof; and

[0031] At least one therapeutic agent that is metabolized by CYP2C19 and CYP3A4.

[0032] In yet another aspect, the present invention provides a composition comprising:

[0033] Cannabidiol or a pharmaceutically acceptable isomer, solvate and / or ester thereof; and

[0034] Cobicistat or a pharmaceutically acceptable isomer, salt and / or solvate thereof.

[0035] In another aspect, the present invention provides a method for inhibiting CYP2C19 and 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 CYP3A4 in the patient.

[0036] In yet another aspect, the present invention provides a method for increasing the plasma level of a therapeutic agent metabolized by CYP2C19 and CYP3A4 in a patient being treated with the therapeutic agent, comprising co-administering the therapeutic agent with a therapeutically effective amount of cobicistat or a pharmaceutically acceptable isomer, salt and / or solvate thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The effects of cobicistat, 6,7-dihydroxybergamotine, lansoprazole and ketoconazole as CYP inhibitors on CBD metabolism in human liver microsomes are shown.

[0038] Figure 2 The effects of fluoxetine, bergamottin, ticlopidine, omeprazole and omeprazole sulphone as CYP inhibitors on the metabolism of CBD in human liver microsomes are shown. DETAILED DESCRIPTION

[0039] 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-dihydroxybergamot, lansoprazole, mixtures thereof, and pharmaceutically acceptable salts, isomers, solvates and / or esters thereof.

[0040] 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, modafinil, proguanil, and pharmaceutically acceptable salts, isomers, solvates and / or esters thereof.

[0041] 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.

[0042] Pharmaceutically acceptable isomers include all pharmaceutically active, non-toxic enantiomers, diastereomers and geometric isomers. Pharmaceutically acceptable solvates include hydrates and solvates containing pharmaceutically acceptable solvents such as alcohols.

[0043] Cannabidiol, cobicistat, compounds that are inhibitors of CYP2C19 and / or CYP3A4, and therapeutic agents metabolized by CYP2C19 and / or CYP3A4, or isomers, salts, solvates, and / or esters thereof are commercially available or can be prepared by methods well known in the art. For example, cobicistat can be prepared by methods disclosed in US 9,975,864 B2 or Xu et al., ACS Med. Chem. Lett. 2010, 1(5): 209-213, S10-S14; and CBD can be prepared by methods disclosed in US 2,304,669 A, US 5,227,537 A, or US 7,674,922 B2.

[0044] The amount of the compound of the inhibitor of CYP2C19 and / or CYP3A4 and the therapeutic agent metabolized by CYP2C19 and / or CYP3A4 to be used according to the compositions and methods of the present invention depends on the desired therapeutic effect and can therefore vary within a wide range, but is generally significantly lower than the amount required to achieve the same effect by a monotherapy or without the combination of the claimed active ingredients. A person skilled in the art can easily determine the appropriate amount based on the dosage of the monotherapy known in the art. Generally, the therapeutically effective amount of the therapeutic agent or compound is an amount sufficient to cause any beneficial effect of the therapeutic agent or compound in the patient. For example, a therapeutically effective amount of cobicistat or its pharmaceutically acceptable isomer, salt and / or solvate is an amount sufficient to inhibit or reduce the metabolism of the therapeutic agent metabolized by CYP2C19 and / or CYP3A4.

[0045] Compounds that are inhibitors of CYP2C19 and CYP3A4 increase the plasma concentration of CBD by inhibiting the metabolism of CBD. Cobicistat increases the plasma concentration of compounds that are inhibitors of CYP2C19 and / or CYP3A4 by inhibiting their metabolism.

[0046] CBD shows dose-dependent absorption. Pharmacokinetic data in the single dose range of 200 to 6000 mg 2 The results showed that the absorption of CBD decreased significantly with increasing doses, which may be due to the limited solubility of CBD in gastrointestinal fluids. CBD is highly hydrophobic - Log P (partition coefficient) is 6.1 and the water solubility is 0.0126 mg / ml 3 .

[0047]

[0048] In general, CBD bioavailability depends on two factors - first-pass metabolism (mainly through CYP2C19 and CYP3A4) and dose. CYP3A4 and CYP2C19 inhibitors are expected to increase bioavailability by more than 3-fold by inhibiting first-pass metabolism. Furthermore, the resulting dose reduction will also increase gastrointestinal absorption by several folds.

[0049] Significant interactions between CBD and food have been reported 4 , which is due to the limited solubility of CBD and the resulting lower absorption of CBD at higher doses. Therefore, by co-administering CYP3A4 and CYP2C19 inhibitors to reduce the dose of CBD, the food interaction of CBD can be significantly reduced, making the pharmacokinetic profile more predictable, which in turn improves the safety profile of CBD.

[0050] Further, by inhibiting the metabolism of CBD, compounds that are inhibitors of CYP2C19 and CYP3A4 can prolong the effective half-life of CBD, thereby reducing the frequency of dosing. Cobicistat can increase the effective half-life of therapeutic agents metabolized by CYP2C19 and / or CYP3A4 by inhibiting their metabolism, thereby reducing their frequency of dosing.

[0051] For example, the short half-life of cobicistat of 3 to 5 hours makes it suitable for co-administration with CBD, which has a half-life of 10 to 17 hours, extending the effective half-life (t1 / 2, eff) of CBD to 15 to 22 hours for once-daily dosing therapy by inhibiting the metabolism of systemically available CBD. Once-daily treatment increases patient compliance. In addition, when a patient takes another concurrent medication that is metabolized or inhibited by either or both of the CYP3A4 and CYP2C19 enzymes, the administration of CBD and the concurrent medication can be appropriately staggered throughout the day to minimize drug-drug interactions by administering CBD once daily with cobicistat.

[0052] The total daily dose of CBD administered with cobicistat or other compounds that are inhibitors of CYP2C19 and / or CYP3A4 can be, for example, one-half, one-third, one-quarter, one-fifth, one-tenth, one-fifteenth, or one-twentieth of the conventional dose of CBD when administered alone. The amount of CBD used in the treatment methods of the present invention can be, for example, in the range of 1 mg / kg once a day to 20 mg / kg once a day or from 0.5 mg / kg twice a day to 10 mg / kg twice a day. In some embodiments, the composition according to the present invention comprises 25 to 4000 mg, 50 to 2000 mg, or 100 to 1000 mg of CBD.

[0053] The amount of cobicistat used in the treatment methods of the invention may 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, the composition according to the invention comprises cobicistat in an amount between 100 mg and 1000 mg.

[0054] The co-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 that is metabolized by CYP2C19 and / or CYP3A4, respectively. According to an alternative, a compound that is an inhibitor of CYP2C19 and CYP3A4 or a therapeutic agent that is metabolized by CYP2C19 and / or CYP3A4 is first administered, and CBD or cobicistat is administered secondarily. According to another alternative, CBD or cobicistat is first administered, and a compound that is an inhibitor of CYP2C19 and CYP3A4 or a therapeutic agent that is metabolized by CYP2C19 and / or CYP3A4 is secondarily administered. According to some embodiments, the administration of CBD or cobicistat can be performed up to 2 hours before or after the administration of a compound that is an inhibitor of CYP2C19 and CYP3A4 or a therapeutic agent that is 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 the metabolism of the other drug / therapeutic agent.

[0055] Thus, the claimed combination of active ingredients, CBD, cobicistat, a compound that is an inhibitor of CYP2C19 and CYP3A4, a therapeutic agent metabolized by CYP2C19 and / or CYP3A4, may be included in a single pharmaceutical composition or separately in two separate pharmaceutical compositions.

[0056] The active ingredient can be formulated into tablets or capsules together with pharmaceutically acceptable carriers and / or excipients. The composition is prepared according to conventional methods known in the art.

[0057] When the combination of active ingredients claimed is contained in two separate pharmaceutical compositions, the two pharmaceutical compositions may constitute different dosage forms and administration routes. For example, one of the pharmaceutical compositions may be a tablet, while the other may be a capsule. In particular, cobicistat may be formulated into coated or uncoated tablets or capsules together with a pharmaceutically acceptable carrier and / or excipient. CBD, therapeutic agents metabolized by CYP2C19 and / or CYP3A4, or compounds that are inhibitors of CYP2C19 and CYP3A4 may be formulated into oral solutions or suspensions, tinctures, self-microemulsifying drug delivery systems, chewable gum, gel capsules, sublingual drops, tablets, e-cigarette oils, smoking compositions, or any other oral, topical or nasal administration methods together with pharmaceutically acceptable carriers and / or excipients.

[0058] Compositions comprising CBD can be administered orally, sublingually, topically, or via inhalation. Compositions comprising therapeutic agents metabolized by CYP2C19 and / or CYP3A4 can be administered orally, sublingually, topically, via inhalation, or any other route of administration. Compositions comprising compounds that are inhibitors of CYP2C19 and / or CYP3A4 can be administered orally, sublingually, topically, via inhalation, or any other route of administration. Compositions comprising cobicistat alone or in combination with compounds that are inhibitors of CYP2C19 and / or CYP3A4 can typically be administered orally.

[0059] experiment

[0060] Cytochrome P450 Inhibition in Human Liver Microsomes (HLM)

[0061] Example 1: Many CYP3A4 and CYP2C19 inhibitors have a pre-specified Km 5 Direct inhibition potential of CBD metabolism using pooled human liver microsomes at 4 °C (substrate concentration at which the reaction rate is 50% of Vmax, where Vmax is the maximum rate achieved by the system).

[0062] Km / Vmax

[0063] HLM diluted in potassium phosphate buffer was mixed with compound working solution and 5X cofactor (0.44mM NADP, 5.5mM G6P, 0.4U / mL G6PDH) to reach final concentrations of 0.033, 0.1, 0.33, 1, 3.3, 10, 33 and 100 μM test compound, 1 μM was used for positive control midazolam, and 0.1 mg / mL was used for liver microsomes. Spiked liver microsomes were incubated at 200 rpm at 37°C and 5% CO2. At 0, 15, 45, 90 and 120 minutes, 50 μL aliquots of spiked liver microsomes were collected and quenched with 200 μL 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 deep 96-well plate. The samples were then analyzed using liquid chromatography tandem mass spectrometry (LC-MS / MS). Km and Vmax values ​​were determined based on regression analysis of test compound disappearance and metabolite formation versus test compound concentration.

[0064] IC50 determination

[0065] The microsomal mixture was prepared in 100 mM KPi with 100X positive control working solution and 5X cofactor; and the reaction was started with 5X substrate working solution in a final volume of 250 μL. The final incubation concentration was 0.1 mg / mL microsomal protein; 1X cofactor; 0.033, 0.1, 0.33, 1, 3.3, 10, 33 μM test inhibitor; 0.5% DMSO, inhibitor (positive control) and substrate concentrations are listed in the table below. The samples were incubated at 37°C and 5% CO2 with orbital shaking at 200 rpm for 15 minutes. The reaction was terminated by adding 500 μL of cold stop solution (acetonitrile containing internal standard). The 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 deep 96-well plate. The samples were analyzed for substrate disappearance and metabolite formation by LC-MS / MS.

[0066] Subtype Substrate Material concentration (mM) Working concentration (μM) Final reaction concentration (μM) NA Cannabidiol 10 8.2 1.64 2C19 S-Mephenytoin 50 125 25 3A4 Midazolam 7.5 6.25 1.25

[0067]

[0068] The results are provided in the table below:

[0069]

[0070] Positive Control IC50 Average historical IC50 Ketoconazole 0.0314 0.0229 Ticlopidine 0.690 0.591

[0071] The data showed that cobicistat is a strong inhibitor of CBD metabolism. 6,7-Dihydroxybergamot and lansoprazole were also found to be potent inhibitors of CBD metabolism. It is well known that 6,7-Dihydroxybergamot inhibits not only CYP3A4 but also CYP2C19. H. Seki et al. Drug Metab. Pharmacokinet. 2019;34(3):181-186. It is well known that lansoprazole is primarily an inhibitor of CYP2C19 and CYP3A4. Meyer et al. Eur J Gastroenterol Hepatol 1996;8(Suppl 1):S21-5. The results also showed that ticlopidine and fluoxetine, inhibitors of CYP2C19 but not CYP3A4, did not inhibit the metabolism of CBD. The results also showed that ketoconazole, an inhibitor of CYP3A4, also inhibited CBD metabolism, but not as effectively as cobicistat, 6,7-dihydroxybergamotrin, and lansoprazole. Cobicistat was found to be a 1.53-fold more potent inhibitor of CBD metabolism than ketoconazole, the only inhibitor of CYP3A4. Figure 1 and 2 The graph in shows the effect of the tested CYP inhibitors on CBD metabolism in human liver microsomes.

[0072] It can be inferred that although CYP2C19-based metabolism is the main pathway, when CYP2C19 is inhibited, the metabolism of CBD shifts to other pathways, such as CYP3A4-based metabolism. The results show that CYP2C19 inhibition alone does not inhibit the metabolism of CBD, while inhibition of CYP3A4 alone does not seem to be sufficient. Therefore, combined inhibition of CYP3A4 and CYP2C19 pathways is necessary for effective inhibition of CBD metabolism.

[0073] Previous clinical kinetic studies have reported that ketoconazole, the only inhibitor of CYP3A4, increases the AUC(0-t) of CBD by 2.65-fold. Stott et al. Springer Plus 2013, 2: 236. Therefore, cobicistat was expected to increase the AUC of CBD significantly more than three-fold.

[0074] Example 2:

[0075] Cytochrome P450 (CYP) direct inhibition studies were performed using pooled human liver microsomes and isoform-specific probe substrates to evaluate the direct inhibitory potential of test compounds on human liver (CYP) isoforms. The incubation mixture was prepared with:

[0076] (a) potassium phosphate buffer;

[0077] (b) 0.1 mg / mL microsomal protein;

[0078] (c) subtype-specific probe substrate;

[0079] (d) Specific concentrations of test compound, solvent blank, or positive control (subtype-specific inhibitor); and

[0080] (e) NADPH regeneration cofactor solution.

[0081] The mixture was incubated at 37°C and 5% carbon dioxide with orbital shaking at 200 rpm for 5 to 20 minutes, depending on the substrate. Once the incubation was complete, the reaction was quenched with an acetonitrile solution containing an internal standard. The samples were processed and analyzed by LC-MS / MS to monitor the formation of substrate metabolites. The enzyme activity in the presence of the compound was normalized to the enzyme activity in the absence of the compound and expressed as a percentage of activity. The inhibitory potential (IC50) of the compound was determined using nonlinear regression of the percentage of activity against the concentration of the compound. The test results are provided in the following table:

[0082]

[0083] *Compounds used as enzyme substrates. #Compounds used as positive controls for enzyme inhibition.

[0084] The data showed that CBD has approximately 3-fold higher affinity for CYP2C19 than for CYP3A4.

Claims

1. A composition comprising: cannabidiol; and Cobicistat or a pharmaceutically acceptable salt thereof.

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

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