Taxcitridine and CYP2D6 inhibitor combination therapy

Abstract

The present invention relates to the co-administration of a CYP2D6 inhibitor with taxipidine, or a pharmaceutically acceptable salt thereof, in order to improve the pharmacokinetic properties of taxipidine by reducing its clearance rate and inter-individual differences. The present invention also relates to combinations of taxipidine or a pharmaceutically acceptable salt thereof with a CYP2D6 inhibitor and the use of such combinations in the treatment of a disorder, condition or disease in which indication of an alpha2A agonist is useful, for example, in the treatment of a neuropsychiatric disorder.

Description

Technical Field

[0001] The present disclosure relates to the use of tasipimidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor in improving the pharmacokinetic properties of tasipimidine by reducing its clearance rate and inter-individual variability. Background of the Invention

[0003] Alpha-2 adrenergic receptor agonists have been in clinical use since the introduction of clonidine as an antihypertensive drug in the mid-1960s. Alpha-2 adrenergic receptor activation is known to result in different responses in multiple organs and tissues. Activation of presynaptic alpha-2 adrenergic receptors located at sympathetic nerve endings inhibits the release of the neurotransmitter norepinephrine. Activation of postsynaptic alpha-2 adrenergic receptors in the central nervous system results in inhibition of sympathetic nerve activity, which results in a decrease in blood pressure and heart rate, reduced arousal, sedation, and anxiety relief. Activation of alpha-2 adrenergic receptors at the spinal level results in analgesia. Peripheral alpha-2 adrenergic receptors in blood vessels mediate contraction of vascular smooth muscle. There are three different subtypes of alpha-2 adrenergic receptors, alpha-2A, alpha-2B, and alpha-2C, each encoded by its own gene. According to current knowledge, the major part of the alpha-2 adrenergic action is mediated by the alpha-2A subtype. The other subtypes act as "fine-tuners" of related functions and may sometimes have opposite effects. Some evidence also suggests that stimulation of vascular alpha-2B receptors is responsible for the transient vasoconstriction observed following administration of alpha-2 agonists.

[0004] Currently available centrally acting α2 agonists are suitable for treating hypertension (clonidine), spasticity (tizanidine), attention deficit hyperactivity disorder (guanfacine), intensive care sedation and surgical sedation (dexmedetomidine). At sufficiently high dose levels, they reduce blood pressure and heart rate and produce sedation, which are the expected therapeutic effects of some of the compounds, while at higher doses, they can also produce adverse reactions such as dry mouth, dizziness, hypertension, and rare reactions such as atrioventricular block or dissociation, especially in cases of parasympathetic hypertonia.

[0005] Tacipiclidine is the international nonproprietary name (INN) of the compound 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole represented by the following structural formula (I):

[0006]

[0007] Tacipiclidine 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. In addition, tacipiclidine has a shorter elimination half-life (t1 / 2) than clonidine (clonidine t1 / 2 = 14h), a faster onset of action, and a more sedative effect. In dogs, tacipiclidine has been shown to effectively relieve situational anxiety and fear triggered by noise or owner departure.

[0008] Tacipicl and its pharmaceutically acceptable salts are disclosed in WO 2013 / 150173, which also lists some possible indications of tacipicl. Tacipicl and its salts, especially sulfates, can be prepared using methods described in, for example, WO 2019 / 106238. In addition to the indications cited above for α2 agonists, tacipicl has several potential indications for which there is good confidence in efficacy, but the demand has not yet been highly met, such as agitation in dementia, panic disorder, social anxiety disorder / agoraphobia, insomnia, and MDD (major depressive disorder) with anxiety.

[0009] It is well known that the therapeutic margin of α2 agonists is relatively narrow, especially during chronic use, and this depends on the target population and indication. Cardiovascular effects, such as orthostatic hypotension, occur at plasma concentrations and exposures close to those that mediate therapeutic CNS effects.

[0010] Cytochrome P450 family 2 subfamily D member 6 (CYP2D6) is a genetically polymorphic drug metabolizing enzyme. New findings indicate that tasipicidine is metabolized by the CYP2D6 enzyme, and new data on human pharmacokinetics indicate that there is relatively large variation between individuals. This is attributed to the known genetic polymorphism of CYP2D6. Therefore, some individuals will eliminate tasipicidine quickly (ultra-rapid metabolizers), while others will eliminate tasipicidine slowly (poor metabolizers), and the remaining individuals will eliminate tasipicidine at a rate somewhere between ultra-rapid and poor metabolism (intermediate metabolizers and normal metabolizers). The elimination half-life of tasipicidine in humans is relatively short, resulting in high fluctuations in peak and through concentrations, provided that the compound is administered 1-3 times a day. For compounds with relatively narrow therapeutic margins, such large inter-individual variability and short elimination half-life may be difficult to handle in clinical practice. SUMMARY OF THE INVENTION

[0012] It has now been found that the combined use of tasipicridine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor can reduce the inter-individual variability in the pharmacokinetics of tasipicridine and prolong the elimination half-life, thereby making the product easier to use in clinical practice, i.e., the combined administration of a CYP2D6 inhibitor converts all types of metabolizers into a poor metabolizer phenotype, so that patients do not need to be genotyped before starting treatment with tasipicridine, and less frequent dosing regimens can be used without loss of therapeutic efficacy.

[0013] If a drug is metabolized too quickly, the efficacy of the drug may be reduced, whereas if it is metabolized too slowly, side effects may occur. This may occur if the same fixed dose of the CYP2D6 substrate tasipine is administered to patients without knowing the CYP2D6 genotype. Therefore, combining tasipine with a CYP2D6 inhibitor and eliminating inter-individual differences in CYP2D6-mediated metabolism may enhance efficacy, while on the other hand may reduce the likelihood of adverse events.

[0014] There are several known CYP2D6 inhibitors, which are classified as strong, moderate, 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, amcaserin, 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 guidelines from the US Food and Drug Administration (FDA) and the Washington University Drug Interaction Database. Other sources may use different classification systems, resulting in some active agents being classified differently.

[0015] The above and other features and advantages of the present teachings will be more fully understood from the following description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Correlation between the CYP2D6 activity score and the dose-corrected AUCinf and Cmax of tadalafil was shown.

[0018] Figure 2 Individual plasma concentration profiles of tasipilidine following co-administration with and without a 10 μg oral dose of paroxetine are shown. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present disclosure relates to a combination of tasipicidine or a pharmaceutically acceptable salt thereof with a CYP2D6 inhibitor. In particular, the present disclosure relates to therapeutic uses and methods of treatment, wherein tasipicidine or a pharmaceutically acceptable salt thereof is administered in combination with a CYP2D6 inhibitor to a human. In addition, the present disclosure relates to such combinations for treating neuropsychiatric disorders in a human in need thereof.

[0021] Thus, in one embodiment, the present disclosure relates to a combination of tasipilidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor for use in treating a disorder, condition or disease in which an α2A agonist is useful, for example, for treating neuropsychiatric disorders such as insomnia, restlessness, aggression, anxiety, depression and panic disorder.

[0022] It should be noted that the therapeutic use or method for treating humans is intended to cover all potential uses of tasipicidine: including all potential uses derived from its activity as an α2A adrenergic receptor agonist, such as its use as a hypotensive agent, anxiolytic, analgesic, sedative, etc. The combination of the present disclosure is preferably used to treat insomnia disorders or insomnia disorders accompanied by depression, anxiety or pain. In addition, it is particularly useful in treating anxiety, agitation or depression. It is particularly useful in treating anxiety, agitation or aggression in patients with dementia (e.g., Alzheimer's disease). Agitation may be chronic or acute agitation. It is particularly useful for treating agitation associated with a neurodegenerative disorder 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 disorder selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium and depression, including dementia or mood disorders in patients with major depressive disorder (e.g., stress-related major depressive disorder); or agitation associated with other conditions, such as OPD / IPD procedures (e.g., MRI, CT or CAT scans, lumbar punctures, bone marrow punctures / biopsies, tooth extractions and other dental procedures); or agitation associated with alcohol, opioid use disorder, opioid withdrawal and drug abuse withdrawal. Additionally, it can be used to treat delirium, hyperactive delirium, benzodiazepine or alcohol or opioid or tobacco withdrawal, premature ejaculation, tachycardia, restless legs syndrome, hot flashes, post-traumatic stress disorder, panic disorder, pain, chronic pelvic pain syndrome, breakthrough cancer pain, traumatic brain injury, tardive dyskinesia, social anxiety disorder, agoraphobia, and attention deficit hyperactivity disorder (ADHD).

[0023] In one embodiment, the present disclosure relates to tasipilidine, or a pharmaceutically acceptable salt thereof, for use in combination with a CYP2D6 inhibitor.

[0024] In one embodiment, the present disclosure relates to the co-administration of tasipicridine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor for reducing inter-individual variability in CYP2D6-mediated metabolism in a human in need of tasipicridine treatment.

[0025] In one embodiment, the present disclosure relates to a combination of tasipicidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor for use in increasing plasma levels of tasipicidine in a human in need of tasipicidine treatment.

[0026] In one embodiment, the present disclosure relates to a combination of tasipicidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor for use in extending the elimination half-life of tasipicidine in a human in need of treatment with tasipicidine.

[0027] In one embodiment, the present disclosure relates to a CYP2D6 inhibitor for inhibiting the metabolism of tasipicridine, wherein tasipicridine or a pharmaceutically acceptable salt thereof and the CYP2D6 inhibitor are simultaneously present in the human body.

[0028] In one embodiment, the present disclosure relates to administering a CYP2D6 inhibitor to a human in need of treatment with tasipicidine for increasing the metabolic lifespan of tasipicidine, wherein tasipicidine or a pharmaceutically acceptable salt thereof and the CYP2D6 inhibitor are simultaneously present in the human body.

[0029] In one embodiment, the present disclosure relates to CYP2D6 inhibitors for use in correcting the ultra-rapid metabolism of tasipilidine in a human in need thereof.

[0030] In one embodiment, the disclosure relates to a CY2D6 inhibitor administered in combination with tasipicidine or a pharmaceutically acceptable salt thereof for improving the therapeutic properties of tasipicidine in treating a neuropsychiatric disorder in a human in need of treatment for the neuropsychiatric disorder.

[0031] In one embodiment, the present disclosure relates to a combination of tasipilidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor for use in treating a neuropsychiatric disorder in a human in need thereof.

[0032] In one embodiment, the present disclosure relates to a combination of tasipicidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor for use in reducing adverse events associated with treatment with tasipicidine in a human in need of treatment with tasipicidine, wherein the human is at risk of experiencing an adverse event as a result of treatment with tasipicidine.

[0033] In one embodiment, the disclosure relates to CYP2D6 inhibitors for improving the pharmacokinetic properties of tasipilidine.

[0034] In one embodiment, the present disclosure relates to the use of a combination of tasipilidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor for the preparation of a medicament for the treatment of a neuropsychiatric disorder.

[0035] In one embodiment, the disclosure relates to a method of administering tasipicidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor to a human in need of tasipicidine treatment.

[0036] In one embodiment, the disclosure relates to a method of reducing inter-individual variability in CYP2D6-mediated metabolism in a human in need of treatment with tasipicidine, comprising co-administering a CYP2D6 inhibitor with tasipicidine or a pharmaceutically acceptable salt thereof to the human.

[0037] In one embodiment, the disclosure relates to a method of increasing plasma levels of tasipicidine in a human in need of treatment with tasipicidine, comprising co-administering a CYP2D6 inhibitor with tasipicidine or a pharmaceutically acceptable salt thereof to the human.

[0038] In one embodiment, the disclosure is directed to a method of extending the elimination half-life of tasipicidine in a human in need of treatment with tasipicidine, comprising co-administering a CYP2D6 inhibitor with tasipicidine or a pharmaceutically acceptable salt thereof to the human.

[0039] In one embodiment, the present disclosure relates to a method of inhibiting the metabolism of tasipicidine, comprising administering a CYP2D6 inhibitor to a human, and wherein tasipicidine or a pharmaceutically acceptable salt thereof and the CYP2D6 inhibitor are simultaneously present in the human body.

[0040] In one embodiment, the present disclosure relates to a method of increasing the metabolic lifespan of tasipicridine, comprising administering a CYP2D6 inhibitor to a human in need of treatment with tasipicridine, and wherein tasipicridine or a pharmaceutically acceptable salt thereof and the CYP2D6 inhibitor are simultaneously present in the human body.

[0041] In one embodiment, the disclosure relates to a method of correcting ultra-rapid metabolism of tasipilidine comprising administering a CYP2D6 inhibitor to a human in need thereof, e.g., a human in need of treatment for a neuropsychiatric disorder.

[0042] In one embodiment, the present disclosure relates to a method of improving the therapeutic properties of tasipicidine in treating a neuropsychiatric disorder comprising administering a CY2D6 inhibitor in combination with tasipicidine or a pharmaceutically acceptable salt thereof to a human in need of treatment for the neuropsychiatric disorder.

[0043] In one embodiment, the disclosure relates to a method of reducing adverse events associated with the use of a treatment comprising administering tasipicidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor to a human in need of tasipicidine treatment, wherein the human is at risk for an adverse event as a result of receiving tasipicidine treatment.

[0044] In one embodiment, the disclosure relates to a method for treating a neuropsychiatric disorder comprising administering tasipilidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor to a human in need of such treatment.

[0045] The tasipilidine or a pharmaceutically acceptable salt thereof and the CYP2D6 inhibitor compound can be administered in separate compositions or dosage forms, or can be administered in a single composition or dosage form containing both of them. In addition, the two compounds can be administered simultaneously, but this is not required. The compounds can be administered at different times, as long as they are present in the human body at the same time during at least a portion of the time of the co-administration treatment.

[0046] In one embodiment, the present disclosure relates to combination therapy wherein tasipilidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor are co-administered as part of the same pharmaceutical composition.

[0047] In one embodiment, the present disclosure relates to a combination therapy wherein tasipilidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor are administered simultaneously in two separate pharmaceutical compositions.

[0048] In one embodiment, the present disclosure relates to combination therapy, wherein tasipilidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor are administered separately as part of an appropriate dosage regimen designed to obtain the benefits of the combination therapy. The appropriate dosage regimen, the amount of each dose administered, and the specific intervals between doses of each active agent depend on the person being treated and the source and severity of the condition.

[0049] In one embodiment, the present disclosure relates to combination therapy in which tasipilidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor are administered sequentially as part of an appropriate dosage regimen, i.e., the delay in administering the second component should allow all active agents to be present in the human body, thereby producing a synergistic effect of the combination. The appropriate dosage regimen, the amount of each dose administered, and the specific intervals between doses of each active agent depend on the person being treated and the source and severity of the condition.

[0050] All common administration routes are suitable for administration of the combinations of the present disclosure. When administered separately or sequentially, administration may be by alternative routes.

[0051] The therapeutic dose given to a person in need of treatment will vary according to the combination administered, the species, the 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 block the metabolism of tasipicidine, and a suitable amount of tasipicidine or a pharmaceutically acceptable salt thereof is an amount sufficient to treat the neuropsychiatric disorder. In one embodiment, tasipicidine or a pharmaceutically acceptable salt thereof is administered to treat a neuropsychiatric disorder in an amount of no more than 600 μg per day for a patient, usually no more than 300 μg, preferably no more than 150 μg, for example, in an amount of about 5 μg-about 600 μg, typically about 5 μg-about 300 μg, preferably about 5 μg-about 200 μg, for example, about 10 μg-about 150 μg. The dose can be administered once a day, or it can be divided into several administrations per day, for example, twice a day or three times a day.

[0052] Any CYP2D6 inhibitor can be used in combination with tacitropidine or a pharmaceutically acceptable salt thereof. Examples of CYP2D6 inhibitor compounds that can be used in combination with tacitropidine or a pharmaceutically acceptable salt thereof 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 of the present disclosure is preferably a strong CYP2D6 inhibitor, for example, paroxetine, bupropion, fluoxetine, quinidine, terbinafine, dacomitinib, pridopidine, tipranavir or 3,4-methylenedioxymethamphetamine; for example, paroxetine or bupropion. In addition to the compounds listed above, there are other compounds that may effectively enhance the delivery of taciprofloxacin by inhibiting the CYP2D6 enzyme.

[0053] In one embodiment, the present disclosure relates to a combination comprising: (i) tasipilidine or a pharmaceutically acceptable salt thereof; and (ii) a CYP2D6 inhibitor.

[0054] In one embodiment, the present disclosure relates to a combination comprising tasipidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor selected from paroxetine, bupropion, fluoxetine, quinidine, terbinafine, dacomitinib, pridopidine, tipranavir and 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof. For example, the present disclosure relates to a combination comprising tasipidine or a pharmaceutically acceptable salt thereof and paroxetine, bupropion, fluoxetine, quinidine or terbinafine or a pharmaceutically acceptable salt thereof. Preferably, the present disclosure relates to a combination comprising tasipidine or a pharmaceutically acceptable salt thereof and paroxetine, bupropion or fluoxetine or a pharmaceutically acceptable salt thereof. Even more preferably, the present disclosure relates to a combination comprising tasipidine or a pharmaceutically acceptable salt thereof and paroxetine or bupropion or a pharmaceutically acceptable salt thereof; for example, the combination comprises tasipidine or a pharmaceutically acceptable salt thereof and paroxetine or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising: (i) tasipilidine or a pharmaceutically acceptable salt thereof; (ii) a CYP2D6 inhibitor; and (iii) one or more pharmaceutically acceptable excipients and / or carriers.

[0056] In one embodiment, the present disclosure relates to a pharmaceutical composition for combination therapy involving the co- or separate administration of tasipilidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor, the pharmaceutical composition comprising: (i) a therapeutically effective amount of tasipilidine or a pharmaceutically acceptable salt thereof; (ii) a CYP2D6 inhibitor; and (iii) one or more pharmaceutically acceptable excipients and / or carriers.

[0057] The pharmaceutical compositions described above can be prepared by known manufacturing methods, for example by mixing the active ingredient with conventional excipients and / or carriers well known in the art; for example fillers, binders, diluents, disintegrants, lubricants, solvents, gel formers, emulsifiers, stabilizers, colorants and / or preservatives. The pharmaceutical composition can be, for example, a tablet, capsule, granule, suppository, emulsion, suspension or solution. Depending on the route of administration and the galenic form, the amount of active ingredient in the formulation can typically vary between 0.01% and 100% by weight.

[0058] The terms used herein have the meanings indicated below.

[0059] As used herein, the term "tasipilidine" refers to 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole in free form and in pharmaceutically acceptable salt forms thereof, particularly the sulfate salt.

[0060] As used herein, the term "CYP2D6 inhibitor" refers to a drug that decreases the activity of the CYP2D6 enzyme.

[0061] As used herein, the term "strong CYP2D6 inhibitor" refers to a drug that causes at least a 5-fold increase in the plasma AUC value of a sensitive substrate metabolized by CYP2D6 or a more than 80% decrease in its clearance.

[0062] As used herein, the term "moderate CYP2D6 inhibitor" refers to a drug that causes an at least -2-fold increase in the plasma AUC value of a sensitive substrate metabolized by CYP2D6 or a 50-80% decrease in its clearance.

[0063] As used herein, the term "weak CYP2D6 inhibitor" refers to a drug that causes at least a 1.25-fold increase, but less than a 2-fold increase, in the plasma AUC value of a sensitive substrate metabolized by CYP2D6 or a 20-50% decrease in its clearance.

[0064] The "pharmaceutically acceptable salts" of the present disclosure include therapeutically active, non-toxic base and acid salt forms that tasipilidine or a CYP2D6 inhibitor is able to form with organic and inorganic bases and acids.

[0065] As used herein, the term "neuropsychiatric disorder" refers to a disorder or condition associated with challenges with sleep, eating, learning, language development, and motor skills, as well as mood instability, anxiety or obsessive-compulsive disorder, and sensory processing sensitivity. Examples of neuropsychiatric disorders include, but are not limited to, sleep disorders (e.g., insomnia with or without comorbidities), affective (emotional) disorders (e.g., depression), mental illness (e.g., eating disorders, addiction, agitation, anxiety, or psychosis), brain dysfunction, movement disorders, degenerative diseases (e.g., dementia), traumatic brain injury, chronic injury encephalopathy, neurotic disorders (e.g., post-traumatic stress disorder (PTSD)), motor neuron disease, neurodegenerative diseases, epilepsy, and headache.

[0066] As used herein, the term "Cmax" refers to the maximum concentration of a drug in plasma following administration of a dose.

[0067] As used herein, the term "AUCinf" refers to the definite integral of drug concentration in plasma as a function of time.

[0068] As used herein, the term "t1 / 2" refers to the elimination half-life.

[0069] The present disclosure will be explained in more detail by the following examples. These examples are for illustrative purposes only and do not limit the scope of the invention defined in the claims.

[0070] Example 1: In vitro studies

[0071] The purpose of these studies was to identify enzymes involved in the metabolism of tasipicidine in humans. Orion Pharma provided the test substance tasipicidine and reference compounds of the major tasipicidine 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). Tasipicidine was incubated with recombinant human (rh') cytochrome P450 (CYP) enzymes listed in Table 1. To further support the findings of the recombinant enzyme incubation, tasipicidine was incubated with human hepatocytes containing two enzyme inhibitors, namely 1-aminobenzotriazole (ABT, a non-selective CYP inhibitor) and quinidine (CYP2D6 inhibitor). In addition, the enzyme kinetics of tasipicidine metabolism were studied in rhCYP2D6.

[0072] Table 1. In vitro studies performed to identify enzymes that metabolize tasipilidine

[0073]

[0074] 1 Human in vitro enzyme preparations of commercial origin.

[0075] 2 Supersomes = recombinant enzymes produced by baculovirus-transfected insect cells.

[0076] Incubation of hepatocytes in vitro was performed as detailed in Table 2 .

[0077] Table 2. Study conditions for studying the intrinsic clearance of tasipilidine (1 μM) in human hepatocyte cultures incubated with and without inhibitors (n=2)

[0078]

[0079]

[0080] The enzyme kinetics of the metabolism of tacitropidine by rhCYP2D6 was studied by incubating the test compound containing 10 pmol / ml CYP enzyme at 0.16, 0.41, 1, 2.6, 6.4, 16, 40 and 100 μM concentrations for 0, 5, 10, 20 and 30 min. Without metabolite characterization, the CL measured for the test compound at different concentrations was int Values ​​for estimating enzyme kinetics.

[0081] The disappearance of tasipicidine was analyzed by using high-resolution liquid chromatography-mass spectrometry (UPLC-HRMS) supported by accurate mass, and the metabolites formed were identified. First, the metabolic stability of tasipicidine in different in vitro matrices was determined by monitoring the disappearance of the parent compound as a function of time. In addition, the structures of the metabolites formed were characterized based on their corresponding product ion spectra. Synthetic reference compounds of the metabolites were used to confirm the identification of those specific metabolites.

[0082] In vitro results

[0083] In the human in vitro system, tacitropidine is metabolized primarily by CYP enzymes, particularly CYP2D6. 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.

[0084] The intrinsic clearance (CL) of tacitropidine (1 μM) was determined in rhCYP2D6. int ) was 1.75 μl / min / pmol CYP, and the apparent enzyme kinetic parameters Km and Vmax were 0.53 μM and 3.1 pmol / min / pmol CYP, respectively.

[0085] CYP1A1, CYP1A2, and CYP2C19 were identified as minor contributors to the metabolism of tasipilidine.

[0086] The following metabolic pathways were found in the tasipidine metabolic preparation:

[0087] O-dealkylation to metabolite 1 followed by further oxidation (N- or O-) and dehydrogenation to metabolite 2 (catalyzed by CYP2D6>>CYP1A1, CYP1A2, CYP2C19)

[0088] Oxidation (N- or O-) and dehydrogenation to produce metabolite 2 (catalyzed by CYP2D6>>CYP2C19)

[0089] CYP2D6 catalyzes the formation of all metabolites detected

[0090] In conclusion, CYP2D6 was identified as the major enzyme catalyzing the metabolism of tasipilidine in humans.

[0091] Example 2: First Human Study

[0092] The first-in-human study was a randomized, double-blind, placebo-controlled, single ascending dose study in healthy women and men aged 18-44 years. Subjects were assigned to groups of 8 subjects, 6 of whom received the active ingredient treatment and 2 received the placebo treatment. During this study, each subject took 1 dose of tasipicidine oral solution or 1 dose of placebo oral solution. The study doses of tasipicidine were 10, 25, 50, 100 and 150 μg as an oral solution.

[0093] Subjects were genotyped for CYP2D6 at screening. Conversion of CYP2D6 genotype to CYP2D6 phenotype was performed according to the national consensus published by the Dutch Pharmacogenetics Working Group from KNMP (https: / / www.knmp.nl / index.php / media / 113). Subjects with CYP2D6 poor metabolizer genotypes were excluded from this study. CYP2D6 genotypes were converted to activity scores according to the CYP2D6 allele function table from PharmGKB (https: / / www.pharmgkb.org / page / cyp2d6RefMaterials).

[0094] Blood samples were collected frequently via an intravenous cannula to assess plasma concentrations of tasipilidine and its metabolite 1. The sampling times were before (0 h) and 15 min, 30 min, 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 plasma concentration-time data by non-compartmental methods using commercial Phoenix WinNonlin software version 8.3.

[0095] The pharmacokinetic data from the single-dose portion of this study provide strong support for the role of CYP2D6 as the major elimination pathway of tasipicidine, as shown by the correlation of tasipicidine AUCinf and Cmax with the CYP2D6 activity score ( Figure 1 Furthermore, the reduction in variability (CV%) of tasipilidine AUCinf after correction for CYP2D6 activity score supported this finding (Table 3).

[0096] Table 3. AUCinf of tasipilidine from the single-dose portion of the first-in-human study [mean (CV%), n=6] (AS, activity score based on CYP2D6 genotype)

[0097] Dosage (μg) AUCinf(h*pg / ml) AUCinf*AS(h*pg / m1) 10 52(46) 90(34) 25 186(61) 254(15) 50 360(71) 475(40) 100 1028(63) 1026(12) 150 1741(46) 2033(39)

[0098] Example 3: PK simulation using PBPK model

[0099] Physiologically based pharmacokinetic (PBPK) models were used to simulate plasma exposure of tadalafil in fasting, 70 kg, healthy, 30-year-old men with different CYP2D6 phenotypes. 9.8.2 software for simulation. The input parameters of the model are shown in Table 4.

[0100] Table 4. Input parameter values ​​of the PBPK model

[0101] parameter value MW 232.28g / mol logP 1.66 pKa 9.24 Caco-2Papp <![CDATA[1.54x10 -5 cm / s]]> Blood to plasma ratio 1.13 Unbound fraction in plasma 86％ Km of CYP2D6 0.106mg / l Vmax of CYP2D6 0.000043mg / s Inter-system extrapolation factor 0.2 Renal clearance 6.3l / h

[0102] PBPK simulations predicted that AUCinf, Cmax, and tmax of tasipilidine in subjects with a poor CYP2D6 metabolizer phenotype (CYP2D6 activity = 0) would be lower than in subjects with average CYP2D6 activity. 1 / 2 increased significantly (Table 5).

[0103] Table 5. Simulated effects of CYP2D6 activity on PK parameters of 10 μg oral tadalafil

[0104] CYP2D6 activity AUCinf(h*pg / ml) Cmax(pg / ml) t1 / 2(h) average value 69 17 3.4 Poor metabolism 616 43 11.5 Weak / Average Ratio 8.9 2.5 3.4

[0105] Example 4: Observed Effects of Paroxetine (Strong CYP2D6 Inhibitor) Combination Therapy on Tamiflu PK

[0106] The effect of co-treatment with paroxetine, a strong CYP2D6 inhibitor, on the PK of tasipicridine was investigated. This study was an open-label, crossover study involving 5 healthy female and / or male subjects aged 26-51 years. The study started with 8 days of treatment with paroxetine 20 mg tablets once daily. On the last day of paroxetine treatment, a single dose of 10 μg of tasipicridine was administered as an oral solution 1 h after taking paroxetine after an overnight fast.

[0107] Subjects were genotyped for CYP2D6 at screening. Conversion of CYP2D6 genotype to CYP2D6 phenotype was performed according to the national consensus published by the Dutch Pharmacogenetics Working Group from KNMP (https: / / www.knmp.nl / index.php / media / 113). Subjects with a CYP2D6 poor metabolizer genotype were excluded from this study. CYP2D6 genotype was converted to activity score according to the CYP2D6 allele function table from PharmGKB (https: / / www.pharmgkb.org / page / cyp2d6RefMaterials).

[0108] Blood samples were collected frequently via an intravenous cannula to assess plasma concentrations of tasipilidine and its metabolite 1. The sampling times were before (0 h) and 20 min, 40 min, 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 plasma concentration-time data by non-compartmental methods using commercial Phoenix WinNonlin software version 8.3.

[0109] When paroxetine was co-administered, the AUCinf, Cmax, and t1 / 2 of tasipilidine were significantly increased ( Figure 2 , Table 6).

[0110] Table 6. Mean (CV%) PK parameters of 10 μg oral tasipilidine with and without co-administration of paroxetine (n=5, mean CYP2D6 activity score=1.2)

[0111] AUCinf(h*pg / ml) Cmax(pg / ml) t1 / 2(h) Not using paroxetine 106(47) 26(26) 2.6(26) Use of paroxetine 281(14) 47(13) 4.3(15) Use / non-use ratio 3.1(44) 1.9(23) 1.7(13)

[0112] Those skilled in the art will appreciate that the embodiments described herein may be modified without departing from the inventive concept. Those skilled in the art will also appreciate that the present disclosure is not limited to the specific embodiments disclosed, but is intended to also cover variations of the embodiments within the scope of the present disclosure.

Claims

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

2. A combination product according to claim 1 for use in the treatment of a neuropsychiatric disorder in a human in need thereof.

3. A combination product according to any one of claims 1 or 2, wherein the neuropsychiatric disorder is anxiety, depression, agitation, insomnia disorder or insomnia disorder associated with depression, anxiety or pain.

4. A combination product according to claim 1 for use in increasing the plasma level of tasipicidine in a human being in need of treatment with tasipicidine.

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

6. A combination product according to 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. A combination product according to any one of claims 1 to 6, wherein the CYP2D6 inhibitor is paroxetine or bupropion.

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

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

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

11. A method for treating a neuropsychiatric disorder comprising administering tasipilidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor to a human in need of such treatment.

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

13. The method according to any one of claims 11 or 12, wherein the neuropsychiatric disorder is anxiety, depression, agitation, insomnia disorder or insomnia disorder with depression, anxiety or pain.

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

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

16. 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. A pharmaceutical composition according to claim 16 for use in the treatment of neuropsychiatric disorders.

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