GB2628348A - Amelioration of drug-drug interactions - Google Patents

Abstract

A method of ameliorating a drug-drug interaction (DDI) between the compound 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno [7,8-d]imidazol-8-yl) benzonitrile (also known as CF3CN), and compounds which are metabolised via the CYP1A2 enzyme. Preferably the compound which is metabolised via the CYP1A2 enzyme is a clinical medicament, such as phenacetin.

Description

AMELIORATION OF DRUG-DRUG INTERACTIONS

FIELD OF THE INVENTION

[0001] The present invention relates to amelioration of a drug-drug interaction (DDI) between the compound 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d] imidazol-8-yObenzonitrile, also known as CF3CN, and compounds which are metabolised via the CYP1A2 enzyme. Preferably the compound which is metabolised via the CYP1A2 enzyme is a clinical medicament.

BACKGROUND TO THE INVENTION

[0002] The compound tropoflavin, also known as 7,8-dihydroxyflavone (7,8-DHF), is a naturally occurring flavone found in Godmania aesculifolio, Tridax procumbent and primula tree leaves. It is known to act as a potent and selective agonist of tropomyosin receptor kinase B (TrkB), which is the main signaling receptor of neurotrophin brain-derived neurotrophic factor (BDNF).

[0003] Tropoflavin has been shown to have therapeutic efficacy in several animal models including depression, Alzheimer's disease, cognitive deficits in schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral ischemia, fragile X syndrome and Rett syndrome.

[0004] A derivative of tropoflavin, 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl) benzonitrile, also known as CF3CN, referred to herein as the compound of Formula I, has been shown to be useful in the treatment of several different disease areas. [0005] The enzyme cytochrome P450 1A2, which is abbreviated to CYP1A2, is a member of the cytochrome P450 mixed-function oxidase system. This enzyme is involved in the metabolism of chemical substances not naturally occurring in the human body.

[0006] There are many known substrates of the CYP1A2 enzyme which include naringenin; naringin; quercetin; rutin; alosetron; clopidogrel; amitriptyline; clomipramine; imipramine; agomelatine; duloxetine; clozapine; olanzapine; haloperidol; caffeine; ropivacaine; theophylline; zolmitriptan; melatonin; tamoxifen; erlotinib; cyclobenzaprine; estradiol; fluvoxamine; mexiletine; naproxen; ondansetron; phenacetin; paracetamol; propranolol; ramelteon; riluzole; tacrine; tasimelteon; tizanidine; verapamil; warfarin and zileuton.

[0007] Drug-drug interactions (DDI) can occur when two or more drugs are co-administered to a patient. It can lead to changed systemic exposure, resulting in variations in drug response of the co-administered drugs. DDIs generally occur due to inhibition of the metabolism for one drug by the other.

[0008] For example, ACE inhibitors which are used to control blood pressure are known to interact with potassium supplements. When ACE inhibitors and potassium supplements are co-administered there is a potential for elevated levels of potassium in the body which results in a condition called hyperkalaemia. Therefore, when these drugs are administered together then serum electrolyte levels must be monitored throughout treatment in order to ensure potassium levels do not increase to a toxic level.

[0009] The present application provides data which identifies CF3CN as an inhibitor of the cytochrome P450 1A2 or CYP1A2 enzyme. This means that co-administration of CF3CN with a compound which is a substrate of the CYP1A2 enzyme could result in a drug-drug interaction. [0010] The present invention therefore demonstrates a method by which a drug-drug interaction can be avoided in patients being co-administered CF3CN and a compound which is a substrate of CYP1A2. Such a method involves monitoring the blood levels of the patient and altering the dose of either the CF3CN or the compound which is a substrate of CYP1A2 in order to ensure the two compounds can be safely dosed together.

BRIEF SUMMARY OF THE DISCLOSURE

[0011] In accordance with a first aspect of the present invention there is provided a method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme comprising the steps of: a) Taking a blood sample from the patient being co-administered CF3CN and a compound that is metabolised via the CYP1A2 enzyme; b) Analysing the blood sample to identify increased levels of either CF3CN or the compound that is metabolised via the CYP1A2 enzyme; and c) Altering the dose of CF3CN and / or the compound that is metabolised via the CYP1A2 enzyme.

[0012] Preferably the compound that is metabolised via the CYP1A2 enzyme is a clinical medicament. More preferably the clinical medicament is one or more of the following: naringenin; naringin; quercetin; rutin; alosetron; clopidogrel; amitriptyline; clomipramine; imipramine; agomelatine; duloxetine; clozapine; olanzapine; haloperidol; caffeine; ropivacaine; theophylline; zolmitriptan; melatonin; tamoxifen; erlotinib; cyclobenzaprine; estradiol; fluvoxamine; mexiletine; naproxen; ondansetron; phenacetin; paracetamol; propranolol; ramelteon; riluzole; tacrine; tasimelteon; tizanidine; verapamil; warfarin and zileuton.

[0013] Preferably the dose of CF3CN is reduced. Alternatively, or additionally, the dose of compound that is metabolised via the CYP1A2 enzyme is reduced.

[0014] Preferably the dose of CF3CN is increased. Alternatively, or additionally, the dose of compound that is metabolised via the CYP1A2 enzyme is increased.

[0015] In one embodiment the patient being treated suffers from diseases and conditions associated with neurodegenerative dysfunction.

[0016] In a further embodiment the patient being treated suffers from diseases and conditions associated with movement disorders.

[0017] In a further embodiment the patient being treated suffers from diseases and conditions associated with inflammation or autoimmunity.

[0018] In a further embodiment the patient being treated suffers from diseases and conditions associated with anxiety and / or mood disorders.

[0019] In a further embodiment the patient being treated suffers from schizophrenia.

[0020] In human therapeutics, the physician will determine the dosage regimen that is most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the disease and other factors specific to the subject to be treated. The compositions, in other embodiments, should provide a dosage of from about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day. Dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, or about 1000 mg, and in some embodiments from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form.

[0021] The amount of active ingredient in the formulations provided herein, which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof, will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject.

[0022] Exemplary doses of a formulation include milligram or microgram amounts of the active compound per kilogram of subject (e.g., from about 1 microgram per kilogram to about 50 milligrams per kilogram, from about 10 micrograms per kilogram to about 30 milligrams per kilogram, from about 100 micrograms per kilogram to about 10 milligrams per kilogram, or from about 100 microgram per kilogram to about 5 milligrams per kilogram).

[0023] It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[0024] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the above-described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

[0025] In certain embodiments, administration of the same formulation provided herein may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

DEFINITIONS

[0026] Various definitions are made throughout this document. Most words have the meaning that would be attributed to those words by one skilled in the art. Words specifically defined either below or elsewhere in this document have the meaning provided in the context of the present invention as a whole and as typically understood by those skilled in the art.

[0027] "Subject," "individual" or "patient" is used interchangeably herein and refers to a vertebrate, preferably a mammal. Mammals include, but are not limited to, murines, rodents, simians, humans, farm animals, sport animals and pets.

[0028] "Treating" or "treatment" of any disease or disorder refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof,). Treatment may also be considered to include preemptive or prophylactic administration to ameliorate, arrest or prevent the development of the disease or at least one of the clinical symptoms. Treatment can also refer to the lessening of the severity and/or the duration of one or more symptoms of a disease or disorder. In a further feature, the treatment rendered has lower potential for long term side effects over multiple years. In other embodiments "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the patient. In yet other embodiments, "treating" or "treatment" refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter) or both. In yet other embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0029] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, adsorption, distribution, metabolism and excretion etc., of the patient to be treated.

[0030] "Vehicle" refers to a diluent, excipient or carrier with which a compound is administered to a subject. In some embodiments, the vehicle is pharmaceutically acceptable.

[0031] "Active ingredient" or "Active pharmaceutical ingredient" or "API" refers to the compound of the invention.

[0032] "4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl) benzonitrile", also known as "CF3CN" has a SMILES code N#CC1=CC=C(C2=CC(C3=CC=C4C(N=C(C(F)(F)F)N4)=C302)=0)C=C1 and the structure defined below: [0033] "Cytochrome P450 1A2" or "CYP1A2" is a member of the cytochrome P450 mixed-function oxidase system which is involved in the metabolism of xenobiotics in the human body.

[0034] Substrates of the CYP1A2 enzyme include the following: antidepressants; atypical antipsychotics; dietary flavonoids and many other clinical medicaments.

[0035] Clinical medicaments that are substrates for the CYP1A2 enzyme include the following: naringenin; naringin; quercetin; rutin; alosetron; clopidogrel; amitriptyline; clomipramine; imipramine; agomelatine; duloxetine; clozapine; olanzapine; haloperidol; caffeine; ropivacaine; theophylline; zolmitriptan; melatonin; tamoxifen; erlotinib; cyclobenzaprine; estradiol; fluvoxamine; mexiletine; naproxen; ondansetron; phenacetin; paracetamol; propranolol; ramelteon; riluzole; tacrine; tasimelteon; tizanidine; verapamil; warfarin and zileuton. [0036] "Drug-drug interaction" or "DDI" is defined as when two or more drugs are co-administered to a patient and there is a variation in the response of one or both of the co-administered drugs. DDIs generally occur due to inhibition of the metabolism for one drug by the other.

[0037] "Clinical medicament" is defined as a medication that is taken by a patient either through being prescribed by a clinician ("prescription only" or "PO"), obtaining the medication through purchasing in a pharmacy or other retailer ("over the counter" or "OTC"), or as a dietary supplement. CF3CN

DETAILED DESCRIPTION OF THE INVENTION

[0038] The Example below describes the effect of CF3CN in a cytochrome P450 inhibition assay.

EXAMPLE 1: CYTOCHROME P450 INHIBITION ASSAY [0039] The cytochrome P450 inhibition assay is an assay used to determine the effects of a test compound on the different cytochrome P450 enzymes in order to deduce whether a DDI might occur with the test compound and another substance such as a clinical medicament.

[0040] , CF3CN at six different concentrations, (0.1pM, 0.25pM, 1pM, 2.5pM, 10pM, and 25pM) was incubated with human liver microsomes and NADPH in the presence of a cytochrome P450 isoform-specific probe substrate.

[0041] The metabolites are monitored by LC-MS/MS and a decrease in the formation of the metabolite compared to the vehicle control is used to calculate an IC50 value (test compound concentration which produces 50 % inhibition).

Methods CYP1A2 Inhibition [0042] CF3CN at concentrations of 0.1pM, 0.25pM, 1pM, 2.5pM, 10pM, and 25pM in DMSO, (final DMSO concentration 0.28 %) were incubated with human liver microsomes (0.1 mg/mL) and NADPH (1mM) in the presence of the probe substrate phenacetin (18pM) for 5 min at 37°C. [0043] The selective CYP1A2 inhibitor, alpha-naphthoflavone, was screened alongside the test compound as a positive control. Formation of the metabolite acetaminophen was monitored.

CYP2B6 Inhibition [0044] CF3CN at concentrations of 0.1pM, 0.25pM, 1pM, 2.5pM, 10pM, and 25pM in DMSO, (final DMSO concentration 0.28 %) were incubated with human liver microsomes (0.1 mg/mL) and NADPH (1mM) in the presence of the probe substrate bupropion (150pM) for 5 min at 37°C.

[0045] The selective CYP2B6 inhibitor, sertraline, was screened alongside the test compound as a positive control. Formation of the metabolite hydroxybupropion was monitored.

CYP2C8 Inhibition [0046] CF3CN at concentrations of 0.1pM, 0.25pM, 1pM, 2.5pM, 10pM, and 25pM in DMSO, (final DMSO concentration 0.28 %) were incubated with human liver microsomes (0.05 mg/mL) and NADPH (1mM) in the presence of the probe substrate amodiaquine (2pM) for 5 min at 37°C.

[0047] The selective CYP2C8 inhibitor, montelukast, was screened alongside the test compound as a positive control. Formation of the metabolite n-desethylamodiaquine was monitored.

CYP2C9 Inhibition [0048] CF3CN at concentrations of 0.1pM, 0.25pM, 1pM, 2.5pM, 10pM, and 25pM in DMSO, (final DMSO concentration 0.28 %) were incubated with human liver microsomes (0.5 mg/mL) and NADPH (1mM) in the presence of the probe substrate diclofenac (7pM) for 5 min at 37°C.

[0049] The selective CYP2C9 inhibitor, sulfaphenazole, was screened alongside the test compound as a positive control. Formation of the metabolite 4-hydroxydiclofenac was monitored.

CYP2C19 Inhibition [0050] CF3CN at concentrations of 0.1pM, 0.25pM, 1pM, 2.5pM, 10pM, and 25pM in DMSO, (final DMSO concentration 0.28 %) were incubated with human liver microsomes (0.5 mg/mL) and NADPH (1mM) in the presence of the probe substrate s-mephenytoin (50pM) for 15 min at 37 °C.

[0051] The selective CYP2C19 inhibitor, (+)-N-3-benzylnirvanol, was screened alongside the test compound as a positive control. Formation of the metabolite 4-hydroxymephenytoin was monitored.

CYP2D6 Inhibition [0052] CF3CN at concentrations of 0.1pM, 0.25pM, 1pM, 2.5pM, 10pM, and 25pM in DMSO, (final DMSO concentration 0.28 %) were incubated with human liver microsomes (0.1 mg/mL) and NADPH (1mM) in the presence of the probe substrate dextromethorphan (2pM) for 5 min at 37°C.

[0053] The selective CYP2D6 inhibitor, quinidine, was screened alongside the test compound as a positive control. Formation of the metabolite dextrorphan was monitored.

CYP3A4 Inhibition (Midazolam) [0054] CF3CN at concentrations of 0.1pM, 0.25pM, 1pM, 2.5pM, 10pM, and 25pM in DMSO, (final DMSO concentration 0.28 %) were incubated with human liver microsomes (0.1 mg/mL) and NADPH (1mM) in the presence of the probe substrate midazolam (2.5pM) for 5 min at 37°C.

[0055] The selective CYP3A4 inhibitor, ketoconazole, was screened alongside the test compound as a positive control. Formation of the metabolite 1-hydroxymidazolam was monitored.

CYP3A4 Inhibition (Testosterone) [0056] CF3CN at concentrations of 0.1pM, 0.25pM, 1pM, 2.5pM, 10pM, and 25pM in DMSO, (final DMSO concentration 0.28 %) were incubated with human liver microsomes (0.1 mg/mL) and NADPH (1mM) in the presence of the probe substrate testosterone (50pM) for 5 min at 37°C.

[0057] The selective CYP3A4 inhibitor, ketoconazole, was screened alongside the test compound as a positive control. Formation of the metabolite 6R-hydroxytestosterone was monitored.

Sample Analysis [0058] The reactions were terminated by addition to methanol. The termination plates were centrifuged at 2500 rpm for 30 min at 4°C and an aliquot of the supernatant was transferred to fresh 96-well plates.

[0059] Formic acid in deionised water (final concentration 0.1 %) containing internal standard was added to the supernatants prior to cassette analysis by LC MS/MS using generic methods.

Data Analysis [0060] A decrease in the formation of the metabolite compared to vehicle control was used to calculate an 1050 value (test compound concentration which produces 50 % inhibition).

[0061] Metabolite peak area ratio response as a percentage of vehicle control was plotted against the test compound concentration and fitted to a simple inhibitory model using the Levenberg-Marquardt algorithm.

Results [0062] The various 1050 values and the corresponding inhibition potential of CF3CN in the cytochrome P450 inhibition assays are detailed in Table 1 below.

Table 1. IC50 values and inhibition potential of the various CYP enzymes :::,Eii v * :,::.1Co,I. M 4r re itic n sat fitta CYP1A2 1.7 Relatively potent CYP2C8 18.1 Weak CYP2C9 21.1 Weak CYP3A4 (testosterone) 22.8 Weak CYP2C19 >25 None CYP2D6 >25 None CYP3A4 (midazolam) >25 None CYP2B6 >25 None [0063] As can be seen, CF3CN was a weak inhibitor or had no inhibition potential at all of the CYP enzymes except for CYP1A2 where it was a relatively potent inhibitor.

Conclusion

[0064] These data suggest that the compound CF3CN as a relatively potent inhibitor of the CYP1A2 enzyme will interact with compounds that are metabolised by this enzyme in the human body.

[0065] Therefore, there is a need to ensure that patients that are co-administered CF3CN and a compound that is a substrate for CYP1A2 are closely monitored to ensure that blood or serum levels of either compound or their metabolites do not reach levels which could be toxic or cause and under-or over-dosing effect.

Claims (7)

1. CLAIMS1. A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme comprising the steps of: a) Taking a blood sample from the patient being co-administered CF3CN and a compound that is metabolised via the CYP1A2 enzyme.b) Analysing the blood sample to identify increased levels of either CF3CN or the compound that is metabolised via the CYP1A2 enzyme; and c) Altering the dose of CF3CN and / or the compound that is metabolised via the CYP1A2 enzyme.
2. 2. A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in claim 1, wherein the compound that is metabolised via the CYP1A2 enzyme is a clinical medicament.
3. 3. A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in claim 2, wherein the clinical medicament is one or more of the following: naringenin; naringin; quercetin; rutin; alosetron; clopidogrel; amitriptyline; clomipramine; imipramine; agomelatine; duloxetine; clozapine; olanzapine; haloperidol; caffeine; ropivacaine; theophylline; zolmitriptan; melatonin; tamoxifen; erlotinib; cyclobenzaprine; estradiol; fluvoxamine; mexiletine; naproxen; ondansetron; phenacetin; paracetamol; propranolol; ramelteon; riluzole; tacrine; tasimelteon; tizanidine; verapamil; warfarin and zileuton.
4. 4. A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in any of the preceding claims, wherein the compound that is metabolised via the CYP1A2 enzyme is clozapine.
5. 5. A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in claim 1, wherein the dose of CF3CN is reduced.
6. 6. A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in claim 1, wherein the dose of compound that is metabolised via the CYP1A2 enzyme is reduced. 9. 10. 11. 12. 13.
7. 7. A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in claim 1, wherein the dose of CF3CN is increased.A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in claim 1, wherein the dose of compound that is metabolised via the CYP1A2 enzyme is increased.A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in any of the preceding claims, wherein the patient being treated suffers from diseases and conditions associated with neurodegenerative dysfunction.A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in any of claims 1 to 8, wherein the patient being treated suffers from diseases and conditions associated with movement disorders.A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in any of claims 1 to 8, wherein the patient being treated suffers from diseases and conditions associated with inflammation or autoimmunity.A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in any of claims 1 to 8, wherein the patient being treated suffers from diseases and conditions associated with anxiety and / or mood disorders.A method of ameliorating a drug-drug interaction between CF3CN and a compound that is metabolised via the CYP1A2 enzyme as described in any of claims 1 to 8, wherein the patient being treated suffers from schizophrenia.