Combination therapy with tacipimidine and a CYP2D6 inhibitor

Abstract

The present invention relates to the combination of a CYP2D6 inhibitor with tacipimidine or a pharmaceutically acceptable salt thereof to improve the pharmacokinetic profile of tacipimidine by reducing the clearance and inter-individual variability of tacipimidine. The present invention also relates to the combination of tacipimidine or a pharmaceutically acceptable salt thereof with a CYP2D6 inhibitor, and the use of such a combination for the treatment of disorders, conditions, or diseases for which an α2A agonist has been shown to be useful, such as the treatment of neuropsychiatric disorders.

Description

[Technical Field]

[0001] The present disclosure relates to the use of tacipimidine, or a pharmaceutically acceptable salt thereof, in combination with a CYP2D6 inhibitor to improve the pharmacokinetic profile of tacipimidine by reducing the clearance and inter-individual variability of tacipimidine. [Background technology]

[0002] Alpha-2 adrenergic receptor agonists have been in clinical use since the mid-1960s, when clonidine was introduced as an antihypertensive. Alpha-2 adrenergic receptor activation is known to evoke a variety of responses from several organs and tissues. Activation of presynaptic alpha-2 adrenergic receptors located on sympathetic nerve endings inhibits the release of the neurotransmitter norepinephrine. Activation of postsynaptic alpha-2 adrenergic receptors in the central nervous system leads to inhibition of sympathetic nervous activity, resulting in decreased blood pressure and heart rate, decreased alertness, sedation, and relief of anxiety. Activation of alpha-2 adrenergic receptors at the spinal cord level results in sedation. Peripheral alpha-2 adrenergic receptors in blood vessels mediate vascular smooth muscle contraction. There are three distinct subtypes of alpha-2 adrenergic receptors: alpha-2A, alpha-2B, and alpha-2C, each encoded by its own gene. Current knowledge suggests that the majority of alpha-2 adrenergic actions are mediated by the alpha-2A subtype. Other subtypes act as "fine tuners" of related functions, sometimes even exhibiting opposite effects. Some evidence also suggests that stimulation of vascular α-2B receptors is responsible for the transient vasoconstriction seen after α2 agonist administration.

[0003] Currently available centrally acting alpha-2 agonists are indicated for the treatment of hypertension (clonidine), spasticity (tizanidine), attention-deficit hyperactivity disorder (guanfacine), and intensive care and procedural sedation (dexmedetomidine). At sufficiently high dose levels, they produce a decrease in blood pressure and heart rate and sedation, which are the intended therapeutic effects for some compounds; side effects include dry mouth, dizziness, and hypertension at high doses, as well as rare effects such as atrioventricular conduction block and dissociation, especially in conditions of high parasympathetic tone.

[0004] Tacipimidine is the International Nonproprietary Name (INN) of the compound 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole, which has the following structural formula (I): [ka]

[0005] Tacipimidine is a novel, orally active, highly selective α2A-adrenergic receptor agonist. Its high oral bioavailability and α2A-selectivity distinguish it from dexmedetomidine, the most specific α2-adrenergic receptor agonist currently approved. Furthermore, tacipimidine has a shorter elimination half-life (t1 / 2) and a more rapid onset of action than clonidine (clonidine t1 / 2 = 14 h), and is more sedative. In dogs, tacipimidine has been shown to be effective in reducing situational anxiety and fear induced by noise or owner separation.

[0006] Tacipimidine and its pharmaceutically acceptable salts are disclosed in Patent Document 1, which also describes several possible indications for tacipimidine. Tacipimidine and its salts, particularly the sulfate salt, can be prepared, for example, using the method described in Patent Document 2. In addition to the above indications for α2 agonists, tacipimidine has several potential indications with good efficacy and high unmet medical needs, such as agitation in dementia, panic disorder, social anxiety disorder / agoraphobia, insomnia, and MDD (major depressive disorder) with anxiety distress.

[0007] The therapeutic window for α2 agonists is known to be relatively narrow, especially during chronic use, and depends on the target population and indication. Cardiovascular effects, such as orthostatic hypotension, occur at plasma concentrations and exposures close to those mediating therapeutic effects on the central nervous system.

[0008] Cytochrome P450 family 2 subfamily D member 6 (CYP2D6) is a genetically polymorphic drug-metabolizing enzyme. New findings demonstrating that tacipimidine is metabolized by the CYP2D6 enzyme and new data on its pharmacokinetics in humans demonstrate relatively large interindividual variability. This is due to known genetic polymorphisms in CYP2D6. Thus, some individuals excrete tacipimidine rapidly (extrarapid metabolizers) and slowly (poor metabolizers), while others excrete tacipimidine at rates intermediate between those of the rapid and poor metabolizers (intermediate and normal metabolizers). The elimination half-life of tacipimidine in humans is relatively short, resulting in large variability in peak and effluent concentrations when administered 1 to 3 times daily. This large interindividual variability and short elimination half-life may make this compound difficult to administer clinically for a compound with a relatively narrow therapeutic window. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2013 / 150173 [Patent Document 2] International Publication No. 2019 / 106238 Summary of the Invention

[0010] We have now discovered that combining tacipimidine or a pharmaceutically acceptable salt thereof with a CYP2D6 inhibitor reduces interindividual variability in the pharmacokinetics of tacipimidine and prolongs its elimination half-life, facilitating its clinical use. The concomitant use of a CYP2D6 inhibitor converts all metabolizers to poor metabolizers, eliminating the need to determine the patient's genotype before initiating tacipimidine treatment and allowing for the use of less frequent dosing regimens without compromising therapeutic efficacy.

[0011] If a drug is metabolized too quickly, its efficacy may be reduced, and if it is metabolized too slowly, side effects may occur. This can occur if patients are given the same fixed dose of tacipimidine, a CYP2D6 substrate, without knowing their CYP2D6 genotype. Therefore, combining tacipimidine with a CYP2D6 inhibitor to eliminate interindividual variability in CYP2D6 metabolism improves efficacy while reducing the likelihood of adverse events.

[0012] Several CYP2D6 inhibitors are known, classified as strong, moderate, or weak or mild inhibitors. Examples of strong CYP2D6 inhibitors include, but are not limited to, paroxetine, bupropion, fluoxetine, quinidine, terbinafine, dacomitinib, pridopidine, tipranavir, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Examples of moderate inhibitors include, but are not limited to, abiraterone, cinacalcet, darifenacin, darunavir, duloxetine, givosiran, lorcaserin, mirabegron, perhexiline, rolapitant, and thioridazine. Examples of weak inhibitors include, but are not limited to, amiodarone, celecoxib, cimetidine, clobazam, cobicistat, escitalopram, fluvoxamine, labetalol, ritonavir, sertraline, and vemurafenib. These classifications are based on guidance from the U.S. Food and Drug Administration (FDA) and the University of Washington Drug Interaction Database. Other sources may use different classification systems, resulting in some drugs being classified differently.

[0013] These and other features and advantages of the present teachings will be more fully understood from the following description and claims. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 shows the correlation between CYP2D6 activity score and dose-corrected AUCinf and Cmax of tacipimidine. [Figure 2] FIG. 1 shows the plasma concentrations of tacipimidine in individuals after oral administration of 10 μg with or without co-administration of paroxetine. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present disclosure relates to a combination of tacipimidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor. In particular, the present disclosure relates to therapeutic uses and methods of administering a combination of tacipimidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor to a human. Furthermore, the present disclosure relates to such a combination for use in treating a neuropsychiatric disorder in a human in need thereof.

[0016] Thus, in one embodiment, the present disclosure relates to tacipimidine, or a pharmaceutically acceptable salt thereof, in combination with a CYP2D6 inhibitor for use in the treatment of disorders, conditions, or diseases in which alpha2A agonists have been shown to be useful, for example, for use in the treatment of neuropsychiatric disorders such as insomnia, agitation, aggression, anxiety, depression, and panic disorder.

[0017] It should be noted that the above-mentioned therapeutic uses and methods for treating humans are intended to encompass all potential uses of tacipimidine resulting from its activity as an α2A-adrenergic receptor agonist, including, for example, as an antihypertensive, anxiolytic, analgesic, sedative, etc. The combinations according to the present disclosure are preferably useful for treating insomnia disorders or insomnia disorders coexisting with depression, anxiety, or pain. Furthermore, they are particularly useful for treating anxiety, agitation, or depression. They are especially useful for treating anxiety, agitation, or aggression in patients with dementia, e.g., Alzheimer's disease. The agitation may be chronic or acute. Specifically, the compounds are useful in treating agitation associated with a neurodegenerative condition selected from the group consisting of Alzheimer's disease, frontotemporal dementia, dementia, dementia with Lewy bodies, post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy, senile dementia of the Alzheimer's type; or agitation associated with a neuropsychiatric condition selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, and depression (including dementia and mood disorders in patients with major depression (e.g., stress-related major depression)); or agitation associated with other conditions, such as OPD / IPD procedures (such as MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extractions and other dental procedures); or agitation associated with alcohol, opioid use disorder, opioid withdrawal, and substance abuse withdrawal. Additionally, it is useful in the treatment of delirium, hyperkinetic delirium, benzodiazepine or alcohol or opioid or tobacco withdrawal, premature ejaculation, tachycardia, restless leg syndrome, hot flashes, post-traumatic stress disorder, panic disorder, pain, chronic pelvic pain syndrome, uncontrollable cancer pain, traumatic brain injury, tardive dyskinesia, social anxiety disorder, agoraphobia, and attention deficit hyperactivity disorder (ADHD).

[0018] In one embodiment, the present disclosure relates to tacipimidine, or a pharmaceutically acceptable salt thereof, for use in combination with a CYP2D6 inhibitor.

[0019] In one embodiment, the present disclosure relates to the co-administration of tacipimidine, or a pharmaceutically acceptable salt thereof, with a CYP2D6 inhibitor for use in reducing inter-individual variability in CYP2D6-mediated metabolism in humans in need of treatment with tacipimidine.

[0020] In one embodiment, the present disclosure relates to a combination of tacipimidine, or a pharmaceutically acceptable salt thereof, and a CYP2D6 inhibitor for use in increasing tacipimidine plasma levels in a human in need of treatment with tacipimidine.

[0021] In one embodiment, the present disclosure relates to a combination of tacipimidine, or a pharmaceutically acceptable salt thereof, and a CYP2D6 inhibitor for use in increasing the elimination half-life of tacipimidine in a human in need of treatment with tacipimidine.

[0022] In one embodiment, the present disclosure relates to a CYP2D6 inhibitor for use in inhibiting the metabolism of tacipimidine, wherein tacipimidine or a pharmaceutically acceptable salt thereof is present in the human body simultaneously with the CYP2D6 inhibitor.

[0023] In one embodiment, the present disclosure relates to the administration of a CYP2D6 inhibitor to a human in need of treatment with tacipimidine for use in increasing the metabolic lifespan of tacipimidine, wherein tacipimidine or a pharmaceutically acceptable salt thereof is present in the human body simultaneously with the CYP2D6 inhibitor.

[0024] In one embodiment, the present disclosure relates to a CYP2D6 inhibitor for use in correcting the ultra-rapid metabolism of tacipimidine in a human being in need thereof.

[0025] In one embodiment, the disclosure relates to a CYP2D6 inhibitor administered in combination with tacipimidine, or a pharmaceutically acceptable salt thereof, for use in improving the therapeutic properties of tacipimidine in the treatment of a neuropsychiatric disorder in a human in need thereof.

[0026] In one embodiment, the invention relates to a combination of tacipimidine, or a pharmaceutically acceptable salt thereof, and a CYP2D6 inhibitor for use in the treatment of a neuropsychiatric disorder in a human being in need thereof.

[0027] In one embodiment, the present disclosure relates to a combination of tacipimidine, or a pharmaceutically acceptable salt thereof, and a CYP2D6 inhibitor for use in reducing adverse events associated with tacipimidine treatment in a human being in need of tacipimidine treatment, the human being being at risk of experiencing adverse effects as a result of treatment with tacipimidine.

[0028] In one embodiment, the present disclosure relates to a CYP2D6 inhibitor for use in improving the pharmacokinetic profile of tacipimidine.

[0029] In one embodiment, the present disclosure relates to the use of a combination of tacipimidine, or a pharmaceutically acceptable salt thereof, and a CYP2D6 inhibitor in the manufacture of a medicament for the treatment of a neuropsychiatric disorder.

[0030] In one embodiment, the present disclosure relates to a method of administering tacipimidine, or a pharmaceutically acceptable salt thereof, in combination with a CYP2D6 inhibitor to a human in need of treatment with tacipimidine.

[0031] In one embodiment, the present disclosure relates to a method for reducing inter-individual variability in CYP2D6-mediated metabolism in a human in need of treatment with tacipimidine, comprising administering a CYP2D6 inhibitor to the human concurrently with tacipimidine or a pharmaceutically acceptable salt thereof.

[0032] In one embodiment, the present disclosure relates to a method of increasing the plasma level of tacipimidine in a human in need of treatment with tacipimidine, comprising administering a CYP2D6 inhibitor to the human concurrently with tacipimidine or a pharmaceutically acceptable salt thereof.

[0033] In one embodiment, the disclosure relates to a method of increasing the elimination half-life of tacipimidine in a human in need of treatment with tacipimidine, comprising administering a CYP2D6 inhibitor to the human concurrently with tacipimidine or a pharmaceutically acceptable salt thereof.

[0034] In one embodiment, the present disclosure relates to a method for inhibiting the metabolism of tacipimidine, comprising administering a CYP2D6 inhibitor to a human, wherein tacipimidine or a pharmaceutically acceptable salt thereof is present in the human body simultaneously with the CYP2D6 inhibitor.

[0035] In one embodiment, the present disclosure relates to a method for increasing the metabolic lifetime of tacipimidine, comprising administering a CYP2D6 inhibitor to a human being in need of treatment with tacipimidine, wherein tacipimidine or a pharmaceutically acceptable salt thereof is present in the human body simultaneously with the CYP2D6 inhibitor.

[0036] In one embodiment, the present disclosure relates to a method of correcting the ultra-rapid metabolism of tacipimidine, comprising administering a CYP2D6 inhibitor to a human in need thereof, such as a human in need of treatment for a neuropsychiatric disorder.

[0037] In one embodiment, the present disclosure relates to a method of improving the therapeutic properties of tacipimidine in the treatment of a neuropsychiatric disorder, comprising administering a CY2D6 inhibitor in combination with administration of tacipimidine or a pharmaceutically acceptable salt thereof to a human in need thereof.

[0038] In one embodiment, the disclosure relates to a method for reducing an adverse event associated with treatment with tacipimidine, comprising administering tacipimidine, or a pharmaceutically acceptable salt thereof, in combination with a CYP2D6 inhibitor, to a human in need of tacipimidine treatment, wherein the human is at risk of experiencing an adverse event as a result of receiving treatment with tacipimidine.

[0039] In one embodiment, the present disclosure relates to a method for the treatment of a neuropsychiatric disorder, the method comprising administering to a human being in need of such treatment tacipimidine, or a pharmaceutically acceptable salt thereof, in combination with a CYP2D6 inhibitor.

[0040] Tacipimidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor compound may be administered in separate compositions or dosage forms, or in a single composition or dosage form containing both. Furthermore, the two compounds may be administered simultaneously, but this is not required. The two compounds may be administered at different times, as long as they are present in the human body at the same time for at least part of the time that the combined treatment is being administered.

[0041] In one embodiment, the present disclosure relates to a combination therapy in which tacipimidine, or a pharmaceutically acceptable salt thereof, and a CYP2D6 inhibitor are administered together as part of the same pharmaceutical composition.

[0042] In one embodiment, the present disclosure relates to a combination therapy in which tacipimidine, or a pharmaceutically acceptable salt thereof, and a CYP2D6 inhibitor are administered simultaneously in two separate pharmaceutical compositions.

[0043] In one embodiment, the present disclosure relates to a combination therapy in which tacipimidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor are administered separately as part of an appropriate dosing regimen designed to obtain the benefits of the combination therapy. The appropriate dosing regimen, the amount of each dose administered, and the specific interval between administration of each active agent depend on the person being treated and the cause and severity of the condition.

[0044] In one embodiment, the present disclosure relates to a combination therapy in which tacipimidine, or a pharmaceutically acceptable salt thereof, and a CYP2D6 inhibitor are administered sequentially as part of an appropriate dosing regimen, i.e., the delay in administration of the second component should ensure that all drugs are present in the human body so that the synergistic effect of the combination occurs. The appropriate dosing regimen, the amount of each dose, and the interval between doses of each active agent will vary depending on the person being treated and the cause and severity of the condition.

[0045] All common routes of administration are suitable for the administration of the combinations of the present disclosure. When administered separately or sequentially, administration can be via alternative routes.

[0046] The therapeutic dose administered to a human in need of treatment varies depending on the combination administered, the species, age, and sex of the person being treated, the specific condition being treated, and the route and method of administration. A suitable amount of a CYP2D6 inhibitor is an amount sufficient to inhibit the metabolism of tacipimidine, and a suitable amount of tacipimidine or a pharmaceutically acceptable salt thereof is an amount sufficient to treat the neuropsychiatric disorder in question. In one embodiment, tacipimidine or a pharmaceutically acceptable salt thereof is administered to a patient for the treatment of a neuropsychiatric disorder in an amount of 600 μg or less, generally 300 μg or less, preferably 150 μg, e.g., about 5 μg to about 600 μg, typically about 5 μg to about 300 μg, preferably about 5 μg to about 200 μg, e.g., about 10 μg to about 150 μg, per day. The dose can be administered once daily or in divided doses, e.g., twice or three times daily.

[0047] Any CYP2D6 inhibitor can be used in combination with tacipimidine or a pharmaceutically acceptable salt thereof. Examples of CYP2D6 inhibitor compounds that may be used in combination with tacipimidine or a pharmaceutically acceptable salt thereof according to the present disclosure include, but are not limited to, paroxetine, bupropion, fluoxetine, quinidine, terbinafine, dacomitinib, pridopidine, tipranavir, 3,4-methylenedioxymethamphetamine, abiraterone, cinacalcet, darifenacin, darunavir, duloxetine, givosiran, lorcaserin, mirabegron, perhexiline, rolapitant, thioridazine, amiodarone, celecoxib, cimetidine, clobazam, cobicistat, escitalopram, fluvoxamine, labetalol, ritonavir, sertraline, and vemurafenib, and pharmaceutically acceptable salts, esters, and prodrugs thereof. The CYP2D6 inhibitor according to the present disclosure is preferably a strong CYP2D6 inhibitor, such as paroxetine, bupropion, fluoxetine, quinidine, terbinafine, dacomitinib, pridopidine, tipranavir, or 3,4-methylenedioxymethamphetamine; e.g., paroxetine or bupropion. In addition to the compounds listed above, other compounds are also effective in enhancing the delivery of tacipimidine by inhibiting the CYP2D6 enzyme.

[0048] In one embodiment, the present disclosure relates to a combination comprising (i) tacipimidine or a pharmaceutically acceptable salt thereof, and (ii) a CYP2D6 inhibitor.

[0049] In one embodiment, the present disclosure relates to a combination of tacipimidine or a pharmaceutically acceptable salt thereof with a CYP2D6 inhibitor or a pharmaceutically acceptable salt thereof selected from paroxetine, bupropion, fluoxetine, quinidine, terbinafine, dacomitinib, pridopidine, tipranavir, and 3,4-methylenedioxymethamphetamine. For example, the present disclosure relates to a combination comprising tacipimidine or a pharmaceutically acceptable salt thereof with paroxetine, bupropion, fluoxetine, quinidine, or terbinafine, or a pharmaceutically acceptable salt thereof. Preferably, the present disclosure relates to a combination comprising tacipimidine or a pharmaceutically acceptable salt thereof with paroxetine, bupropion, or fluoxetine, or a pharmaceutically acceptable salt thereof. Even more preferably, the present disclosure relates to a combination comprising tacipimidine, or a pharmaceutically acceptable salt thereof, and paroxetine or bupropion, or a pharmaceutically acceptable salt thereof; for example, a combination comprising tacipimidine, or a pharmaceutically acceptable salt thereof, and paroxetine, or a pharmaceutically acceptable salt thereof.

[0050] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising: (i) tacipimidine or a pharmaceutically acceptable salt thereof; (ii) a CYP2D6 inhibitor; and (iii) one or more pharmaceutically acceptable excipients and / or carriers.

[0051] In one embodiment, the present disclosure relates to a pharmaceutical composition for combination therapy comprising (i) a therapeutically effective amount of tacipimidine or a pharmaceutically acceptable salt thereof; (ii) a CYP2D6 inhibitor; and (iii) one or more pharmaceutically acceptable excipients and / or carriers, wherein the tacipimidine or a pharmaceutically acceptable salt thereof and the CYP2D6 inhibitor are administered together or separately.

[0052] The pharmaceutical compositions can be prepared by a generally known method, for example, by mixing the active ingredient with one or more conventional excipients and / or one or more carriers known in the art; fillers, binders, diluents, disintegrants, lubricants, solvents, gel-based formulations, emulsifiers, stabilizers, colorants, and / or preservatives. The pharmaceutical compositions can be, for example, tablets, capsules, tablets, suppositories, emulsions, suspensions, or solutions. Depending on the route of administration and the form of the galenic preparation, the amount of the active ingredient in the preparation can usually vary between 0.01% and 100% by weight.

[0053] Terms used in this specification have the following meanings:

[0054] As used herein, the term "tacipimidine" refers to the free form of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole and its pharmaceutically acceptable salts, particularly the sulfate salt.

[0055] As used herein, the term "CYP2D6 inhibitor" refers to a drug that reduces the activity of the CYP2D6 enzyme.

[0056] As used herein, the term "potent CYP2D6 inhibitor" refers to a drug that causes at least a 5-fold increase in the plasma AUC value of sensitive substrates metabolized by CYP2D6 or a greater than 80% decrease in their clearance.

[0057] As used herein, the term "moderate CYP2D6 inhibitor" refers to a drug that causes at least a 2-fold increase in the plasma AUC value of sensitive substrates metabolized by CYP2D6 or a 50-80% decrease in their clearance.

[0058] As used herein, the term "weak CYP2D6 inhibitor" refers to a drug that causes at least a 1.25-fold but less than a 2-fold increase in the plasma AUC value of sensitive substrates metabolized by CYP2D6, or a 20-50% decrease in their clearance.

[0059] According to the present disclosure, "pharmaceutically acceptable salts" include therapeutically active, non-toxic base and acid salt forms that tacipimidine or CYP2D6 inhibitors are able to form with both organic and inorganic bases and acids.

[0060] As used herein, the term "neuropsychiatric disorder" refers to disorders or conditions that involve sleep, eating, learning, language development and motor skill problems, mood swings, anxiety or compulsivity, and sensory processing sensitivity.Examples of neuropsychiatric disorders include, but are not limited to, sleep disorders (e.g., insomnia with or without comorbidities), emotional (mood) disorders (e.g., depression), psychiatric disorders (e.g., eating disorders, addiction, agitation, anxiety, or psychosis), brain dysfunction, movement disorders, degenerative disorders (e.g., dementia), traumatic brain injury, chronic traumatic encephalopathy, neurotic disorders (e.g., post-traumatic stress disorder (PTSD)), motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0061] As used herein, the term "Cmax" means the highest drug concentration in plasma after a dose has been administered.

[0062] As used herein, the term "AUCinf" means the definite integral of the drug concentration in plasma as a function of time.

[0063] As used herein, the term "t1 / 2" means elimination half-life.

[0064] The present disclosure is further illustrated by the following examples, which are for illustrative purposes only and are not intended to limit the scope of the invention as defined in the claims. [Example]

[0065] Example 1: In vitro testing The purpose of these studies was to identify the enzymes involved in the metabolism of tacipimidine in humans. The test substrate tacipimidine and the reference compounds as the major tacipimidine metabolites, 1-(4,5-dihydro-1H-imidazol-2-yl)isochroman-5-ol (metabolite 1), 2-(5-methoxyisochroman-1-yl)-1H-imidazole (metabolite 2), and 1-(1H-imidazol-2-yl)isochroman-5-ol (metabolite 3), were supplied by Orion Pharma. Tacipimidine was incubated with recombinant human (rh) cytochrome P450 (CYP) enzymes listed in Table 1. To further support the findings from incubation with the recombinant enzymes, tacipimidine was incubated with two enzyme inhibitors, 1-aminobenzotriazole (ABT, a nonselective CYP inhibitor) and quinidine (a CYP2D6 inhibitor), in human hepatocytes. Additionally, the enzyme kinetics of tacipimidine metabolism was investigated using rhCYP2D6.

[0066] [Table 1]

[0067] In vitro incubations with hepatocytes were performed as detailed in Table 2.

[0068] [Table 2]

[0069] The enzyme kinetics of tacipimidine metabolism by rhCYP2D6 was investigated by incubating test compounds at concentrations of 0.16, 0.41, 1, 2.6, 6.4, 16, 40, and 100 μM with 10 pmol / ml of CYP enzyme for 0, 5, 10, 20, and 30 minutes. The enzyme kinetics was measured using the CL values ​​measured for various concentrations of test compounds. int values ​​and no characterization of metabolites was performed.

[0070] Analysis of the disappearance of tacipimidine and identification of the metabolites formed were performed using high-resolution liquid chromatography-mass spectrometry (UPLC-HRMS) with precision mass spectrometry. First, the metabolic stability of tacipimidine in different in vitro matrices was determined by monitoring the disappearance of the parent compound as a function of time. Furthermore, the structures of the formed metabolites were characterized from their respective product ion spectra. Synthetic reference compounds of the metabolites were used to confirm the identity of the specific metabolites.

[0071] in vitro results Tacipimidine was metabolized primarily by CYP enzymes, particularly CYP2D6, in human in vitro systems. This finding was supported by (I) recombinant CYP incubations and (II) hepatocyte incubations with the general CYP inhibitor ABT and the selective CYP2D6 inhibitor quinidine.

[0072] Measured intrinsic clearance (CL) of tacipimidine (1 μM) in rhCYP2D6 int ) was 1.75 μl / min / pmolCYP, and the apparent enzyme kinetic parameters Km and Vmax were 0.53 μM and 3.1 pmol / min / pmolCYP, respectively.

[0073] CYP1A1, CYP1A2, and CYP2C19 were identified as minor contributors to tacipimidine metabolism.

[0074] The following metabolic pathways were found for tacipimidine metabolites: O-dealkylation to metabolite 1 followed by further oxidation (N- or O-) and dehydrogenation to metabolite 2 (catalyzed by CYP2D6>>CYP1A1, CYP1A2, CYP2C19) Oxidation (N- or O-) and dehydrogenation to metabolite 2 (catalyzed by CYP2D6>>CYP2C19) CYP2D6 catalyzed the formation of all detected metabolites

[0075] In conclusion, CYP2D6 has been identified as the major enzyme catalyzing the metabolism of tacipimidine in humans.

[0076] Example 2: First-in-man testing The first-in-man study was a randomized, double-blind, placebo-controlled, single-ascending-dose study in healthy female and male subjects aged 18 to 44 years. Subjects were assigned to cohorts of eight, six of whom received the active treatment and two received a placebo. Each subject received either a single dose of tacipimidine oral solution or a single dose of placebo oral solution during the study. The study doses of tacipimidine were 10, 25, 50, 100, and 150 μg as an oral solution.

[0077] Subjects were genotyped for CYP2D6 at screening. Translation of CYP2D6 genotype to CYP2D6 phenotype was performed according to the national consensus published by the Dutch Pharmacogenetics Working Group from the KNMP (https: / / www.knmp.nl / index.php / media / 113). Subjects with CYP2D6 poor metabolizer genotypes were excluded from the study. Translation of CYP2D6 genotype to activity score was performed according to the CYP2D6 Allele Functionality Table from PharmGKB (https: / / www.pharmgkb.org / page / cyp2d6RefMaterials).

[0078] Blood samples were collected frequently via a venous cannula to assess plasma concentrations of tacipimidine and its metabolite 1. The sampling times were before administration of the study treatment (0 h) and at 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after administration of the study treatment. PK parameters were calculated from the plasma concentration-time data by noncompartmental methods using commercially available Phoenix WinNonlin software version 8.3.

[0079] The available pharmacokinetic data from the single-dose portion of this study provide strong support for the role of CYP2D6 as the primary elimination pathway for tacipimidine by showing a correlation of tacipimidine AUCinf and Cmax with CYP2D6 activity score (Figure 1). Furthermore, the reduced variability (CV%) of tacipimidine AUCinf after CYP2D6 activity score adjustment supports this finding (Table 3).

[0080] [Table 3]

[0081] Example 3: PK simulation using the PBPK model A physiologically based pharmacokinetic (PBPK) model was used to simulate the plasma exposure of tacipimidine in fasting subjects (70 kg, 30-year-old healthy men with different CYP2D6 phenotypes). Simulations were performed using commercially available GastroPlus® 9.8.2 software. The input parameters of the model are listed in Table 4.

[0082] [Table 4]

[0083] PBPK simulations predicted that the AUCinf, Cmax, and t1 / 2 of tacipimidine would be significantly increased in subjects with a CYP2D6 poor metabolizer phenotype (CYP2D6 activity = 0) compared with subjects with average CYP2D6 activity (Table 5).

[0084] [Table 5]

[0085] Example 4: Observed effects of concomitant use of paroxetine (a strong CYP2D6 inhibitor) on the PK of tacipimidine The effects of concomitant treatment with paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics of tacipimidine were investigated. This study was an open-label, crossover study in five healthy women and / or men aged 26 to 51 years. Patients began with 8 days of once-daily treatment with paroxetine 20 mg tablets. On the last day of paroxetine treatment, after an overnight fast, a single 10 μg dose of tacipimidine was administered as an oral solution 1 hour after paroxetine administration.

[0086] Subjects were genotyped for CYP2D6 at screening. Translation of CYP2D6 genotypes to CYP2D6 phenotypes was performed according to the national consensus published by the Dutch Pharmacogenetics Working Group from the KNMP (https: / / www.knmp.nl / index.php / media / 113). Subjects with CYP2D6 poor metabolizer genotypes were excluded from the study. Translation of CYP2D6 genotypes to activity scores was performed according to the CYP2D6 Allele Functionality Table from PharmGKB (https: / / www.pharmgkb.org / page / cyp2d6RefMaterials).

[0087] Blood samples were collected frequently via a venous cannula to assess plasma concentrations of tacipimidine and its metabolite 1. The sampling times were before administration of the study treatment (0 h) and at 20, 40, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, and 48 h after administration of the study treatment. PK parameters were calculated from the plasma concentration-time data by noncompartmental methods using commercially available Phoenix WinNonlin software, version 8.3.

[0088] The AUCinf, Cmax, and t1 / 2 of tacipimidine were significantly increased when paroxetine was coadministered (Figure 2, Table 6).

[0089] [Table 6]

[0090] Those skilled in the art will appreciate that the embodiments described herein can be modified without departing from the concepts of the present invention, and will understand that the disclosure is not limited to the particular embodiments disclosed, but is intended to cover modifications of the embodiments that fall within the scope of the present disclosure.

Claims

1. A combination comprising tacipimidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor.

2. 10. The combination of claim 1 for use in the treatment of a neuropsychiatric disorder in a human in need thereof.

3. 3. The combination according to claim 1 or 2, wherein the neuropsychiatric disorder is anxiety, depression, agitation, insomnia disorder, or insomnia disorder with coexisting depression, anxiety or pain.

4. 2. A combination according to claim 1 for use in increasing tacipimidine plasma levels in a human in need of treatment with tacipimidine.

5. A combination according to any one of claims 1 to 4, wherein the CYP2D6 inhibitor is a strong CYP2D6 inhibitor.

6. 6. The combination of any one of claims 1 to 5, wherein the CYP2D6 inhibitor is paroxetine, bupropion, fluoxetine, quinidine, terbinafine, dacomitinib, pridopidine, tipranavir or 3,4-methylenedioxymethamphetamine.

7. 7. The combination of any one of claims 1 to 6, wherein the CYP2D6 inhibitor is paroxetine or bupropion.

8. 10. Use of a combination according to any one of claims 1, 5, 6 or 7 in the manufacture of a medicament for the treatment of a neuropsychiatric disorder.

9. Tacipimidine or a pharmaceutically acceptable salt thereof for use in combination with a CYP2D6 inhibitor.

10. A method of administering tacipimidine, or a pharmaceutically acceptable salt thereof, in combination with a CYP2D6 inhibitor to a human in need of tacipimidine treatment.

11. 1. A method for the treatment of a neuropsychiatric disorder, the method comprising administering tacipimidine, or a pharmaceutically acceptable salt thereof, in combination with a CYP2D6 inhibitor to a human in need of treatment with tacipimidine.

12. A method for inhibiting the metabolism of tacipimidine in the treatment of a neuropsychiatric disorder, comprising administering to a patient suffering from the neuropsychiatric disorder a CYP2D6 inhibitor in an amount sufficient to inhibit the metabolism of tacipimidine and tacipimidine or a pharmaceutically acceptable salt thereof in an amount sufficient to treat the neuropsychiatric disorder.

13. 13. The method of claim 11 or 12, wherein the neuropsychiatric disorder is anxiety, depression, agitation, an insomnia disorder, or an insomnia disorder with coexisting depression, anxiety, or pain.

14. The method of any one of claims 10 to 13, wherein the CYP2D6 inhibitor is a potent CYP2D6 inhibitor.

15. 15. The method of claim 14, wherein the CYP2D6 inhibitor is paroxetine, bupropion, fluoxetine, quinidine, terbinafine, dacomitinib, pridopidine, tipranavir, or 3,4-methylenedioxymethamphetamine.

16. 10. A pharmaceutical composition comprising a combination according to any one of claims 1, 5, 6 or 7 and one or more pharmaceutically acceptable excipients and / or carriers.

17. 17. A pharmaceutical composition according to claim 16 for use in the treatment of a neuropsychiatric disorder.

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