Methods for administering specific VMAT2 inhibitors

Abstract

To provide methods for administration of certain VMAT2 inhibitors.SOLUTION: Provided are methods for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, and pharmaceutically acceptable salts and / or isotopic variants thereof, to a patient in need thereof, where the patient has a mild, moderate or severe hepatic disorder.SELECTED DRAWING: None

Description

[Background technology]

[0001] Dysregulation of the dopaminergic system is essential for several central nervous system (CNS) disorders, including neurological and psychiatric illnesses and disorders. These include hypermotor movement disorders, as well as conditions such as schizophrenia and mood disorders. Its transporter protein, vesicular monoamine transporter-2 (VMAT2), plays a crucial role in presynaptic dopamine release, regulating monoamine uptake from the cytoplasm into synaptic vesicles for storage and release.

[0002] Despite the advances made in this field, there is still a need for new therapeutic products useful for treating neurological and psychiatric disorders and conditions, as well as other related diseases or conditions described herein. One such agent is valbenazine, which has the following chemical structure: [ka]

[0003] Valbenazine:4-toluenesulfonate (1:2) (hereinafter referred to as "valbenazine ditosylate") formulations are FDA-approved drug labels. (登録商標) This has been previously reported.

[0004] Liver impairment is a condition in which normal liver function is reduced. Liver impairment can be acute with a rapid onset or chronic. Chronic liver impairment, or cirrhosis, can result from many causes such as excessive alcohol consumption, hepatitis, autoimmune diseases, genetic factors, or metabolic disorders, or it can be idiopathic. Liver damage is generally irreversible, and treatment consists of preventing progression and managing symptoms. In severe cases, liver transplantation is the only option. Liver impairment may not present with significant symptoms, or it may be characterized by symptoms such as reduced ability to clot blood (coagulation disorders) and impaired brain function (encephalopathy), fluid retention in the abdominal cavity, increased risk of infection, hypogonadism, changes in liver size, jaundice, and increased sensitivity to medications.

[0005] Pharmacokinetic parameters in patients with hepatic impairment (e.g., AUC, C12C of the drug and / or its metabolites) max , t 1 / 2 Changes in the dosage can lead to many problems (including the need for dose adjustment, increased complexity for physicians when prescribing, the need for liver function tests, lack of availability of accurate dosages, lack of availability of certain drug therapies for those with liver impairment, and overdosing).

[0006] There is a significant, yet unmet, need for a method of administering a VMAT2 inhibitor (e.g., valbenazine or (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof) to a patient who requires it (where the patient has hepatic impairment). This disclosure satisfies these and other needs, as will be apparent with reference to the following disclosures. [Overview of the Initiative] [Means for solving the problem]

[0007] concise summary A method is provided for administering a vesicular monoamine transport 2 (VMAT2) inhibitor, selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has mild hepatic impairment, and the method comprises the step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient having mild hepatic impairment.

[0008] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method comprising the steps of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, later determining that the patient has mild hepatic impairment, and continuing the administration of a therapeutically effective amount of the VMAT2 inhibitor to the patient.

[0009] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor, selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method comprises the step of administering to the patient having moderate or severe hepatic impairment an amount equivalent to about 40 mg of free valbenazine base of the VMAT2 inhibitor once daily.

[0010] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor, selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method comprises the step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient having moderate or severe hepatic impairment, wherein the therapeutically effective amount of the VMAT2 inhibitor is less than the amount administered to a patient without moderate or severe hepatic impairment.

[0011] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor, selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method comprising the steps of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, later determining that the patient has moderate or severe hepatic impairment, and administering to the patient an amount of the VMAT2 inhibitor equivalent to about 40 mg of free valbenazine base once daily.

[0012] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method comprising the steps of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, later determining that the patient has moderate or severe hepatic impairment, and administering the VMAT2 inhibitor in a smaller amount than that administered to a patient without moderate or severe hepatic impairment.

[0013] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor, selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method comprises the step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient with moderate or severe hepatic impairment, wherein the administration is equivalent to the average valbenazine C of a patient without moderate or severe hepatic impairment. max Approximately 2 to 3 times higher average valvenazine C max This will result in...

[0014] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method comprises the step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient with moderate or severe hepatic impairment, wherein the administration is the mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC of a patient without moderate or severe hepatic impairment. 0-∞ (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC is approximately 3 to 4 times higher than the average (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC 0-∞ This will result in...

[0015] These and other aspects of the present invention will become apparent from the following detailed description. For this purpose, various references describing certain background information, procedures, compounds, and / or compositions in more detail are given herein and each is incorporated herein by reference in whole. [Modes for carrying out the invention]

[0016] Detailed explanation In the following description, certain specific details are provided to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention can be carried out without these details. In other cases, well-known structures are neither shown nor described in detail to avoid unnecessarily obscure descriptions of their embodiments. Unless the circumstances require otherwise, throughout this specification and the claims thereafter, the phrase “comprise” and its variations (e.g., “comprises” and “comprising”) should be interpreted in an open, comprehensive sense, that is, “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute any interpretation of the scope or meaning of the claimed invention.

[0017] Throughout this specification, the terms "one embodiment" or "an embodiment" or "some embodiments" are used interchangeably. References to “in some embodiments)” or “a certain embodiment” mean that a particular feature, structure, or characteristic described in relation to that embodiment is included in at least one embodiment. Therefore, occurrences of the phrase “in one embodiment,” “in one embodiment,” “in some embodiments,” or “in some embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, that particular feature, structure, or characteristic may be combined in any suitable manner in one or more embodiments.

[0018] Furthermore, as used in this specification and the attached claims, the singular forms "a," "an," and "the" include the plural form unless the context clearly indicates otherwise.

[0019] As used herein, “valbenazine” may be referred to as (S)-2-amino-3-methyl-butyrate (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,la]isoquinoline-2-yl ester; or L-valine,(2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinoridine-2-yl ester or NBI-98854.

[0020] As used herein, "(+)-α-HTBZ" refers to the structure: [ka] This refers to a compound that is an active metabolite of barbenadine having (+)-α-HTBZ, which may also be called (2R,3R,11bR) or (+)-α-DHTBZ, or (+)-α-HTBZ, or R,R,R-DHTBZ, or (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol; or (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or NBI-98782.

[0021] As used herein, "NBI-136110" refers to the structure: [ka] This refers to compounds that are metabolites of barbenadine and possess the characteristic [of the compound].

[0022] As used herein, "isotopic variant" means a compound that contains isotopes at a non-natural proportion in one or more of the atoms that make up such a compound. In certain embodiments, an "isotopic variant" of a compound is one or more isotopes (hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 [[ID=1-eight]]N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ([[ID=u]] 36 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-127 ( 127 I), iodine-129 ( 129 I), and iodine-131 ( 131 It should be noted that in the original text, there is an incorrect " " in the line where "nitrogen-14" is introduced, which is corrected in the translation. Also, there is an incorrect "u" in the line where "chlorine-36" is introduced in the original text, which is corrected in the translation.I) are examples, but are not limited to these. In certain embodiments, the “isotope variant” of the compound is in a stable form, i.e., non-radioactive. In certain embodiments, the “isotope variant” of the compound is one or more isotopes (hydrogen) in a non-natural proportion. 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), Nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), and oxygen-18( 18 This includes, but is not limited to, O). In certain embodiments, the “isotope variant” of the compound is in an unstable form, i.e., radioactive. In certain embodiments, the “isotope variant” of the compound is a non-natural proportion of one or more isotopes (tritium( 3 H), carbon-11 ( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), and oxygen-15( 15 Examples include, but are not limited to, O). In the compounds provided herein, where feasible according to the judgment of those skilled in the art, any hydrogen may be, for example 2 It could be H, or any carbon, for example 13 It could be C, or any nitrogen, for example. 15 It can be N, and any oxygen, for example 18 It is understood that it can be O. In certain embodiments, the "isotope variant" of the compound contains a non-natural proportion of deuterium.

[0023] With respect to the compounds provided herein, if a particular atomic position is designated to have deuterium or "D" or "d", it will be understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium (which is about 0.015%). The positions designated as containing deuterium typically have, in certain embodiments, at each designated deuterium position, the minimum isotopic enrichment coefficients (isotopic enrichment) of at least 1000 (15% deuterium incorporated), at least 2000 (30% deuterium incorporated), at least 3000 (45% deuterium incorporated), at least 3500 (52.5% deuterium incorporated), at least 4000 (60% deuterium incorporated), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium incorporated), at least 6600 (99% deuterium incorporated), or at least 6633.3 (99.5% deuterium incorporated). It has a factor. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art (including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallography).

[0024] As used herein, “hepatic impairment” means impairment of liver function.

[0025] As used herein, the “Child-Pugh Score” is a score based on five clinical measures of liver impairment (including total bilirubin, serum albumin, PT INR, ascites, and hepatic encephalopathy levels). Each measure is assigned a rank of 1, 2, or 3, and the sum of these five ranks constitutes the Child-Pugh Score. The Child-Pugh Score may be used to classify liver impairment by placing subjects into the Child-Pugh group.

[0026] As used herein, "mild hepatic impairment" refers to a ranking of liver impairment levels based on a Child-Pugh score of 5 to 6.

[0027] As used herein, "moderate hepatic impairment" refers to a ranking of liver impairment levels based on a Child-Pugh score of 7 to 9.

[0028] As used herein, "severe hepatic impairment" refers to a ranking of liver impairment levels based on a Child-Pugh score of 10 to 15.

[0029] As used herein, “hyperkinetic disorder” or “hyperkinetic movement disorder” or “hyperkinesia” means a disorder or condition characterized by excessive, abnormal, or involuntary movement. These neurological disorders include tremor, dystonia, myoclonus, athetosis, Huntington's disease, tardive dyskinesia, Tourette syndrome, dystonia, unilateral ballism, chorea, gerontological chorea, or tics.

[0030] As used herein, “tardive syndrome” includes, but is not limited to, tardive dyskinesia, tardive dystonia, tardive akathisia, tardive tics, myoclonus, tremor, and withdrawal-emergent syndrome. Tardive dyskinesia is characterized by sudden, repetitive, stereotyped, involuntary movements of the face, limbs, or trunk.

[0031] As used herein, "about" means ±20% of the stated value, and more specifically, includes values ​​of ±10%, ±5%, ±2%, and ±1% of the stated value.

[0032] As used herein, "AUC" means the area under the curve or integral of the plasma concentration of an active pharmaceutical ingredient or metabolite over time following a drug-administered event.

[0033] When used herein, "AUC" 0-t This is the integral under the plasma concentration curve from time 0 (drug administration) to time "t".

[0034] When used herein, "AUC" 0-∞ " is the AUC from time 0 (drug administration) to time infinity. Unless otherwise stated, AUC is... 0-∞ This refers to the fact that drugs are often packaged in salt form (e.g., valbenazine nitrate), and the strength of the dosage form refers to the mass of this salt form or the equivalent mass of the corresponding free base, valbenazine.

[0035] When used herein, C max C is a pharmacokinetic parameter that indicates the maximum plasma concentration observed after delivery of the active pharmaceutical component. max This is the time to the peak plasma concentration, t max It occurs in [location].

[0036] As used herein, “co-administer” and “co-administration” and their variations mean administering at least two drugs to a patient subsequently, simultaneously, or consequently in close proximity to each other in time (e.g., on the same day, or over a period of one week or 30 days, or in close enough proximity that each of the at least two drugs can be detected simultaneously in plasma). In the case of co-administration, two or more active agents are co-formulated as part of the same composition or administered as separate formulations; this may also be referred herein to as “concomitant” administration or a variation thereof.

[0037] As used herein, “adjusting administration,” “altering administration,” “adjusting dosing,” and “altering dosing” are all equivalent and mean gradually reducing, decreasing, or increasing the dose of the substance, discontinuing the administration of the substance to the patient, or using a different active agent instead of the substance.

[0038] As used herein, “administering to a patient” means the process of introducing a composition or dosage form to a patient via an introduction means recognized in the art.

[0039] As used herein, the term “disorder” is intended to be generally synonymous with the terms “disease,” “syndrome,” and “condition” (as in medical conditions), in that they reflect an abnormal condition of one of the body or parts of a human or animal that impairs normal function, and typically present with distinguishable signs and symptoms.

[0040] As used herein, “dose” means the measured amount of an active agent that a patient takes in one sitting. In certain embodiments where the active agent is not free barbenazine base, the amount is the molar equivalent to the equivalent amount of free barbenazine base. For example, drugs are often packaged in a pharmaceutically acceptable salt form (e.g., barbenazine nitrate), and the dose in terms of potency refers to the mass of the molar equivalent of the equivalent free barbenazine base. As an example, 73 mg of barbenazine nitrate is the molar equivalent of 40 mg of free barbenazine base.

[0041] As used herein, “dosing regimen” means the initial dose of the active agent taken by the patient and any subsequent doses of the active agent taken by the patient at intervals (times or symptoms) (e.g., about 20 to about 160 mg once daily, e.g., about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, or about 160 mg once daily). Further doses of the active agent may differ from the initial dose taken.

[0042] As used herein, “effective amount” and “therapeutically effective amount” of a drug, compound, medicine, composition, or combination are the amount that, when administered to a subject or patient (e.g., a human subject or patient), is non-toxic and effective in producing a desired therapeutic effect. The exact therapeutically effective amount for a subject may depend, for example, on the size and health status of the subject, the nature and degree of that status, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those skilled in the art. The effective amount for a given situation is determined by conventional experimental methods and is within the judgment of the clinician.

[0043] As used herein, “informing” means referring to or providing publicly available material, for example, providing the user with the publicly available material; or presenting information orally, for example, by a presentation at a seminar, conference, or other educational presentation, by a conversation between a medical information representative and a healthcare professional, or by a conversation between a healthcare professional and a patient; or showing the user the information intended for the purpose of understanding.

[0044] As used herein, “labeling” means all labels or other means of communication, whether written, printed, graphical, electronic, linguistic or illustrative, that are present on or accompanying a pharmaceutical product or dosage form.

[0045] As used herein, “medical care worker” means any person in the medical field who may need or have access to information about an active drug, including its dosage form, including information on safety, efficacy, administration, or pharmacokinetics. Examples of medical care workers include physicians, pharmacists, physician assistants, nurses, aides, caregivers (which may include family members or guardians), emergency medical workers, and veterinarians.

[0046] As used herein, “Medication Guide” means the FDA-approved patient labeling of a pharmaceutical product in accordance with the specifications set forth in 21 CFR 208, and other applicable regulations including information on how patients should use the pharmaceutical product safely. A medication guide is scientifically accurate and based on and consistent with the approved professional labeling of the pharmaceutical product under 21 CFR 201.57, although its wording does not need to be identical to the corresponding section of the approved labeling. Medication guides are typically available for pharmaceutical products with specific risk management information.

[0047] As used herein, “patient,” “individual,” or “subject” means a mammal (including a human being) that is in need of treatment, and generally refers to the recipient of such treatment.

[0048] As used herein, “patient package insert” means information on how a patient should safely use a pharmaceutical product that is part of an FDA-approved label. It is an extension of the professional label of a pharmaceutical product that provides consumer-oriented information about the product in lay-friendly language, which may be distributed to a patient when the product is administered, and may, for example, describe the benefits, risks, and how to recognize the risks, dosage, or administration.

[0049] As used herein, “pharmaceutically acceptable” refers to a substance that is not biologically or otherwise undesirable. That is, the substance can be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interactions in an adverse manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it suggests that the carrier or excipient meets the required standards of toxicology and manufacturing testing, or that it is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. “Pharmacologically active” (or “active”) derivative or analog means a derivative or analog that has the same type of pharmacological activity as the parent compound and is approximately equivalent in degree. The term "pharmaceutically acceptable salt" includes acid addition salts formed with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, and mandelic acid. Salts formed with free carboxyl groups can also be obtained from inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or iron hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, and procaine.

[0050] As used herein, “product” or “pharmaceutical product” means the dosage form of an active drug, the published documentation, and, if applicable, the packaging.

[0051] As used herein, “product insert” means the professional labeling (prescription information) of the pharmaceutical product, the patient packaging insert for the pharmaceutical product, or the drug use guide for the pharmaceutical product.

[0052] As used herein, “professional labeling” or “prescribing information” means the official description of a pharmaceutical product approved by the regulatory authority that controls the sale or purchase of that pharmaceutical product on the market (e.g., the FDA or EMEA), which includes a summary of essential scientific information necessary for the safe and effective use of the drug, such as indications and use; dosage and administration; who should take the drug; adverse events (side effects); instructions for use in special populations (e.g., pregnant women, children, the elderly); and patient safety information.

[0053] As used herein, “published material” means the medium through which the information is provided (including, but not limited to, printed, audio, visual, or electronic media such as flyers, advertisements, product inserts, printed displays, internet websites, internet web pages, internet pop-up windows, radio or television broadcasts, compact discs, DVDs, audio recordings, or other recording media or electronic media).

[0054] Or it means the probability or possibility of other undesirable outcomes arising from a medical procedure. "Acceptable risk" means a measure of the risk of harm, injury, or disease resulting from a medical procedure that an individual or group would consider acceptable. Whether a risk is "acceptable" depends on the benefits that the individual or group understands they may receive in exchange for taking the risk, whether they are willing to accept any scientific or other advice offered about the magnitude of the risk, and many other factors (both political and social). The "acceptable risk" of an adverse reaction means that the probability of the adverse reaction occurring is small, or the consequences are very minor, or the benefits (understood or actual) of the active agent are very large, so that an individual or group in society is willing to take or comply with the risk that the adverse reaction may occur. The "unacceptable risk" of an adverse reaction means that an individual or group in society is unwilling to take or comply with the risk that the adverse reaction may occur, given the proportion of the probability of the adverse reaction occurring, the consequences of the adverse reaction, and the benefits (understood or actual) of the active agent. "Being at risk" means a situation or condition characterized by a high level of risk or susceptibility. Risk assessment involves identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.

[0055] As used herein, “safety” means the incidence or severity of adverse events associated with the administration of the active agent (including adverse effects associated with patient-related factors (e.g., age, sex, ethnicity, race, target disease, abnormal renal or hepatic function, comorbidities, genetic characteristics (e.g., metabolic status), or environment) and active agent-related factors (e.g., dose, plasma levels, duration of exposure, or concomitant medications)).

[0056] When used herein, "t max " is a pharmacokinetic parameter that defines the time it takes to reach the maximum plasma concentration after delivery of the active pharmaceutical component.

[0057] When used herein, "t 1 / 2 "Plasma half-life" or "elimination half-life" are pharmacokinetic parameters that define the apparent plasma terminal phase half-life, i.e., the time it takes for the plasma concentration to be halved after the absorption and distribution of the drug is complete.

[0058] As used herein, “treating” or “treatment” means a therapeutic application that slows or halts the progression of a disorder, a preventive application that prevents the onset of a disorder, and / or reversal of a disorder. Reversal of a disorder differs from a therapeutic application that slows or halts a disorder in that, when reversed, it not only completely halts the progression of the disorder but also moves the cellular behavior to some extent toward a normal state observed in the absence of the disorder.

[0059] As used herein, "VMAT2" refers to human vesicle monoamine transporter isoform 2 (an intrinsic membrane protein that acts to transport monoamines, in particular neurotransmitters (e.g., dopamine, norepinephrine, serotonin, and histamine), from the cytoplasm of a cell to synaptic vesicles).

[0060] As used herein, the terms “VMAT2 inhibitor,” “inhibit VMAT2,” or “inhibit VMAT2” refer to the ability of the compounds disclosed herein to alter the function of VMAT2. VMAT2 inhibitors can block or reduce the activity of VMAT2 by forming reversible or irreversible covalent bonds between the inhibitor and VMAT2, or through the formation of non-covalent complexes. Such inhibition may occur only in certain cell types or may depend on certain biological events. The terms “VMAT2 inhibitor,” “inhibit VMAT2,” or “inhibit VMAT2” also refer to altering the function of VMAT2 by reducing the probability of complex formation between VMAT2 and its native substrate.

[0061] A method is provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor, selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the patient having moderate or severe hepatic impairment, the method comprising the step of administering to the patient having moderate or severe hepatic impairment an amount equivalent to about 40 mg of free valbenazine base of the VMAT2 inhibitor once daily.

[0062] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor, selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method comprises the step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient with moderate or severe hepatic impairment, wherein the therapeutically effective amount of the VMAT2 inhibitor is less than the amount administered to a patient without moderate or severe hepatic impairment.

[0063] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method comprising the steps of administering to the patient a therapeutically effective amount of the VMAT2 inhibitor, later determining that the patient has moderate or severe hepatic impairment, and administering to the patient an amount of the VMAT2 inhibitor equivalent to about 40 mg of free valbenazine base once daily.

[0064] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method comprising the steps of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, later determining that the patient has moderate or severe hepatic impairment, and administering the VMAT2 inhibitor in a smaller amount than that administered to a patient without moderate or severe hepatic impairment.

[0065] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor, selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method comprises the step of administering a therapeutically effective amount of VMAT2 inhibitor to the patient with moderate or severe hepatic impairment, wherein the administration is equivalent to the average valbenazine C of a patient without moderate or severe hepatic impairment. max Approximately 2 to 3 times higher average valvenazine C max This will result in...

[0066] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor, selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method comprises the step of administering a therapeutically effective amount of VMAT2 inhibitor to the patient with moderate or severe hepatic impairment, wherein the administration is the mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC of a patient without moderate or severe hepatic impairment. 0-∞ (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC is approximately 3 to 4 times higher than the average (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC 0-∞ This will result in...

[0067] In certain embodiments, the method further includes the step of determining whether the patient has moderate or severe liver impairment.

[0068] In certain embodiments, the method further includes a step of informing the patient or healthcare worker that administration of a VMAT2 inhibitor to a patient with moderate to severe hepatic impairment results in a higher exposure to valbenazine and / or (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol than administration of a VMAT2 inhibitor to a patient with normal hepatic function.

[0069] In certain embodiments, the method further includes a step of informing the patient or healthcare worker that administration of the VMAT2 inhibitor to a patient with moderate to severe hepatic impairment may result in one or more increased risks of exposure-related adverse reactions compared to administration of the VMAT2 inhibitor to a patient with normal hepatic function.

[0070] In certain embodiments, one or more exposure-related adverse reactions are selected from somnolence, anticholinergic effects, balance disturbance or falls, headache, akathisia, vomiting, nausea, arthralgia, QT prolongation, elevated blood glucose, weight gain, respiratory infection, salivation, dyskinesia, extrapyramidal symptoms (non-akathisia), anxiety, insomnia, elevated prolactin, elevated alkaline phosphatase, and elevated bilirubin. In certain embodiments, one or more exposure-related adverse reactions are selected from somnolence and QT prolongation.

[0071] In certain embodiments, the method further includes the step of informing the patient or healthcare professional that administration of the VMAT2 inhibitor to a patient with moderate to severe hepatic impairment may prolong the patient's QT interval more than administration of the VMAT2 inhibitor to a patient with normal hepatic function.

[0072] In certain embodiments, the patient has moderate hepatic impairment.

[0073] In certain embodiments, the patient has severe liver impairment.

[0074] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor, selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has mild hepatic impairment, and the method comprises the step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient having mild hepatic impairment.

[0075] A method is also provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method comprising the steps of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, later determining that the patient has mild hepatic impairment, and continuing the administration of a therapeutically effective amount of the VMAT2 inhibitor to the patient.

[0076] In certain embodiments, the method further includes the step of determining whether the patient has mild hepatic impairment.

[0077] In certain embodiments, the VMAT2 inhibitor is administered to a patient to treat a neurological or psychiatric disorder or condition. In certain embodiments, the neurological or psychiatric disorder or condition is hyperkinetic movement disorder, mood disorders, bipolar disorder, schizophrenia, schizoaffective disorder, manic episodes in mood disorders, depressive episodes in mood disorders, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea with acanthocyanosis.

[0078] In certain embodiments, the neurological or psychiatric disorder or disorder is hyperkinetic movement disorder. In certain embodiments, the hyperkinetic movement disorder is tardive dyskinesia. In certain embodiments, the hyperkinetic movement disorder is Tourette syndrome. In certain embodiments, the hyperkinetic movement disorder is Huntington's disease. In certain embodiments, the hyperkinetic movement disorder is a tic. In certain embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease. In certain embodiments, the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless limb syndrome, or tremor.

[0079] In certain embodiments, the VMAT2 inhibitor is administered orally.

[0080] In certain embodiments, the VMAT2 inhibitor is administered in the form of tablets or capsules.

[0081] In certain embodiments, the VMAT2 inhibitor is administered with or without food.

[0082] In certain embodiments, the VMAT2 inhibitor is a pharmaceutically acceptable salt and / or isotopic variant of valvenazine or the same. In certain embodiments, the VMAT2 inhibitor is a pharmaceutically acceptable salt of valvenazine or the same. In certain embodiments, the VMAT2 inhibitor is valvenazine tosylate. In certain embodiments, the VMAT2 inhibitor is valvenazine nitrate.

[0083] In certain embodiments, the VMAT2 inhibitor is an isotopic variant that is L-valine,(2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinoridine-2-yl ester or a pharmaceutically acceptable salt thereof.

[0084] In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg to about 160 mg of free valvebenazine base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg of free valvebenazine base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg of free valvebenazine base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 60 mg of free valvebenazine base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 80 mg of free valvebenazine base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 120 mg of free valvebenazine base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 160 mg of free valvebenazine base.

[0085] In certain embodiments, the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof.

[0086] In certain embodiments, the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt thereof.

[0087] In certain embodiments, the VMAT2 inhibitor is an isotopic variant that is (+)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol or a pharmaceutically acceptable salt thereof.

[0088] In certain embodiments, the VMAT2 inhibitor is administered in a first dose over a first period, and then the dose is increased to a second dose. In certain embodiments, the first period is one week. In certain embodiments, the first dose is equivalent to about 40 mg of free valvebenazine base. In certain embodiments, the second dose is equivalent to about 80 mg of free valvebenazine base.

[0089] In certain embodiments, the VMAT2 inhibitor reaches a maximum plasma concentration of (+)-α-DHTBZ between approximately 15 ng and 60 ng per 1 mL of plasma (C max ) and the minimum plasma concentration (C) of at least 15 ng of (+)-α-DHTBZ per 1 mL of plasma over a period of 8 hours. min It is administered in a sufficient amount to achieve the desired result.

[0090] In certain embodiments, the VMAT2 inhibitor reaches a maximum plasma concentration of (+)-α-DHTBZ between approximately 15 ng and 60 ng per 1 mL of plasma (C max ) and over a period of 12 hours, approximately its C max Minimum plasma concentration (C) between at least approximately 33% and 50% min It is administered in a sufficient amount to achieve the desired result.

[0091] In certain embodiments, the VMAT2 inhibitor is administered in an amount sufficient to achieve (i) a therapeutic concentration range of (+)-α-DHTBZ of about 15 ng to about 60 ng per mL of plasma; and (ii) a threshold concentration of at least 15 ng per mL of plasma over a period of about 8 to about 24 hours.

[0092] In certain embodiments, methods for treating neurological or psychiatric disorders or conditions are provided herein, wherein a pharmaceutical composition comprising the VMAT2 inhibitor is administered to a subject to a maximum plasma concentration (C) of R,R,R-DHTBZ between approximately 15 ng and approximately 60 ng per mL of plasma. max ) and the minimum plasma concentration (C) of at least 15 ng of R,R,R-DHTBZ per 1 mL of plasma over a period of 8 hours. min This includes the step of administering a sufficient amount to achieve the desired result.

[0093] In certain embodiments, C of R,R,R-DHTBZ max This is plasma with concentrations of approximately 15 ng / mL, 20 ng / mL, 25 ng / mL, 30 ng / mL, 35 ng / mL, 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, or 60 ng / mL. In certain embodiments, C of R,R,R-DHTBZ min This is plasma containing at least 15 ng / mL, at least 20 ng / mL, at least 25 ng / mL, at least 30 ng / mL, or at least 35 ng / mL over a period of 8, 12, 16, 20, 24, 28, or 32 hours. In certain embodiments, C of R,R,R-DHTBZ min The concentration ranges from approximately 15 ng / mL to approximately 35 ng / mL.

[0094] In certain embodiments, the pharmaceutical composition contains approximately 15 ng / mL to approximately 60 ng / mL of plasma R,R,R-DHTBZ C max and over a period of approximately 24 hours max at least 33% of C min It is administered in an amount sufficient to provide. In certain embodiments, the pharmaceutical composition is approximately 15 ng / mL to approximately 60 ng / mL of plasma R,R,R-DHTBZ C max and over a period of approximately 24 hours max at least 50% of C minIt is administered in an amount sufficient to provide. In certain embodiments, the pharmaceutical composition has a C of R,R,R-DHTBZ in plasma of about 15 ng / mL to about 60 ng / mL max and over a 24-hour period has a C max of at least about 33% to 50% of its C min and is administered in an amount sufficient to provide.

[0095] In certain embodiments, the pharmaceutical composition has a C of R,R,R-DHTBZ in plasma of about 15 ng / mL to about 60 ng / mL max and over a 12-hour period has a C max of at least 33% of its C min and is administered in an amount sufficient to provide. In certain embodiments, the pharmaceutical composition has a C of R,R,R-DHTBZ in plasma of about 15 ng / mL to about 60 ng / mL max and over a 12-hour period has a C max of at least 50% of its C min and is administered in an amount sufficient to provide. In certain embodiments, the pharmaceutical composition has a C of R,R,R-DHTBZ in plasma of about 15 ng / mL to about 60 ng / mL max and over a 12-hour period has a C max of at least about 33% to 50% of its C min and is administered in an amount sufficient to provide.

[0096] In certain embodiments, the pharmaceutical composition is administered to a subject in an amount sufficient to provide a C of R,R,R-DHTBZ in plasma of about 15 ng / mL to about 60 ng / mL max and over a 24-hour period a C between about 5 ng / mL and about 30 ng / mL in plasma min In certain embodiments, the pharmaceutical composition has a C of R,R,R-DHTBZ in plasma of about 15 ng / mL to about 60 ng / mL max and over a 24-hour period a C between about 7.5 ng / mL and about 30 ng / mL in plasma min and is administered to the subject in an amount sufficient to provide.

[0097] In certain embodiments, methods for treating neurological or psychiatric disorders or conditions are provided herein, the methods comprising administering to a subject in an amount sufficient to provide (i) a therapeutic concentration range of R,R,R-DHTBZ of about 15 ng to about 60 ng per mL of plasma; and (ii) a threshold concentration of at least 15 ng R,R,R-DHTBZ per mL of plasma over a period of about 8 hours to about 24 hours.

[0098] In certain embodiments, the therapeutic concentration range is R,R,R-DHTBZ from approximately 15 ng to approximately 35 ng, up to approximately 40 ng, up to approximately 45 ng, up to approximately 50 ng, or up to approximately 55 ng per 1 mL of plasma.

[0099] In certain embodiments, the threshold concentration of R,R,R-DHTBZ is approximately 15 ng / mL, 20 ng / mL, 25 ng / mL, 30 ng / mL, 35 ng / mL, 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, or 60 ng / mL of plasma over periods of approximately 8, 12, 16, 20, 24, 28, or 32 hours. In certain embodiments, the threshold concentration of R,R,R-DHTBZ is between approximately 15 ng / mL and 35 ng / mL over periods of approximately 8 to 24 hours.

[0100] Plasma concentrations can be measured by methods known in the art, and generally by tandem mass spectrometry.

[0101] In certain embodiments, the therapeutically effective dose of the VMAT2 inhibitor is 10-90% less than the dose administered to patients without moderate or severe hepatic impairment.

[0102] In certain embodiments, the therapeutically effective dose of the VMAT2 inhibitor is 20-80% less than the dose administered to patients without moderate or severe hepatic impairment.

[0103] In certain embodiments, the therapeutically effective dose of the VMAT2 inhibitor is 30-70% less than the dose administered to patients without moderate or severe hepatic impairment.

[0104] In certain embodiments, the therapeutically effective dose of the VMAT2 inhibitor is 40-60% less than the dose administered to patients without moderate or severe hepatic impairment.

[0105] In certain embodiments, the therapeutically effective dose of the VMAT2 inhibitor is about 50% less than the dose administered to patients without moderate or severe hepatic impairment.

[0106] For example, if the dose administered to a patient without moderate or severe hepatic impairment is 40 mg / day, the individual may receive a reduced dose of 4–36 mg / day, e.g., 8–32 mg / day (e.g., 12–28 mg / day), e.g., 16–24 mg / day, or in certain embodiments, about 20 mg / day. Similarly, if the dose administered to a patient without moderate or severe hepatic impairment is 80 mg / day, the individual may receive a reduced dose of 8–72 mg / day, e.g., 16–64 mg / day (e.g., 24–56 mg / day), e.g., 32–48 mg / day, or in certain embodiments, about 24 mg / day.

[0107] In certain embodiments, the dose of VMAT2 inhibitor administered to a patient is reduced to, for example, 75% or less, 50% or less, or 25% or less of the dose administered to a patient without moderate or severe hepatic impairment. For example, if the dose administered to a patient without moderate or severe hepatic impairment is 40 mg / day, the individual may receive a reduced dose of 30 mg / day, 20 mg / day, or 10 mg / day. Similarly, if the dose administered to a patient without moderate or severe hepatic impairment is 80 mg / day, the individual may receive a reduced dose of 60 mg / day, 40 mg / day, or 20 mg / day.

[0108] Also provided are vesicular monoamine transporter 2 (VMAT2) inhibitors selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or pharmaceutically acceptable salts and / or isotopic variants thereof, for use in methods for treating neurological or psychiatric disorders or disorders in patients requiring such treatment, wherein the patient has been determined to have a history of moderate or severe hepatic impairment, and the method comprises the step of administering an amount of VMAT2 inhibitor equivalent to approximately 40 mg of free valbenazine base once daily to the patient with moderate or severe hepatic impairment.

[0109] Also provided are vesicular monoamine transporter 2 (VMAT2) inhibitors selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or pharmaceutically acceptable salts and / or isotopic variants thereof, for use in methods for treating neurological or psychiatric disorders or disorders in patients requiring such treatment, the method comprising the steps of: determining the level of hepatic impairment in the patient; selecting the patient for treatment if the determined level of hepatic impairment falls within the group of hepatic impairment levels consisting of moderate and severe hepatic impairment; and administering to the selected patient an amount of VMAT2 inhibitor equivalent to about 40 mg of free valbenazine base once daily. In certain embodiments, the method further comprises the step of not selecting the patient for treatment if the determined level of hepatic impairment falls within the group of hepatic impairment levels consisting of normal and mild hepatic impairment.

[0110] Also provided are vesicular monoamine transporter 2 (VMAT2) inhibitors selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or pharmaceutically acceptable salts and / or isotopic variants thereof, for use in methods for treating neurological or psychiatric disorders or disorders in patients requiring such treatment, the method comprising the steps of: administering a therapeutically effective amount of the VMAT2 inhibitor to the patient; subsequently determining the level of hepatic impairment in the patient; selecting the patient for treatment if the determined level of hepatic impairment falls within the group of hepatic impairment levels consisting of moderate and severe hepatic impairment; and administering to the selected patient an amount of the VMAT2 inhibitor equivalent to about 40 mg of free valbenazine base once daily.

[0111] Also provided are vesicular monoamine transporter 2 (VMAT2) inhibitors selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or pharmaceutically acceptable salts and / or isotopic variants thereof, for use in methods for treating neurological or psychiatric disorders or disabilities in patients requiring such treatment, wherein the patient has been determined to have a history of mild hepatic impairment, and the method comprises the step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient with the mild hepatic impairment.

[0112] Also provided are vesicular monoamine transporter 2 (VMAT2) inhibitors selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or pharmaceutically acceptable salts and / or isotopic variants thereof, for use in methods for treating neurological or psychiatric disorders or disorders in patients requiring such treatment, the method comprising the steps of: determining the level of hepatic impairment in the patient; selecting the patient for treatment if the determined level of hepatic impairment is mild; and administering a therapeutically effective amount of the VMAT2 inhibitor. In certain embodiments, the method further comprises the step of not selecting the patient for treatment if the determined level of hepatic impairment falls within the group of moderate and severe levels of hepatic impairment.

[0113] Also provided are vesicular monoamine transporter 2 (VMAT2) inhibitors selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or pharmaceutically acceptable salts and / or isotopic variants thereof, for use in methods for treating neurological or psychiatric disorders or disorders in patients requiring such treatment, the method comprising the steps of: administering a therapeutically effective amount of the VMAT2 inhibitor to the patient; subsequently determining the level of hepatic impairment in the patient; selecting the patient for treatment if the determined level of hepatic impairment is mild; and administering a therapeutically effective amount of the VMAT2 inhibitor to the selected patient.

[0114] Also provided are vesicular monoamine transporter 2 (VMAT2) inhibitors selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or pharmaceutically acceptable salts and / or isotopic variants thereof, for use in methods for treating neurological or psychiatric disorders or disorders in patients requiring such treatment, wherein the patient has been previously determined to have moderate or severe hepatic impairment, and the method comprises the steps of administering to the patient a therapeutically effective amount of the VMAT2 inhibitor, subsequently selecting patients who cannot tolerate 1 or more exposure-related adverse reactions, and administering to the patient a reduced amount of the VMAT2 inhibitor (e.g., 40 mg once daily).

[0115] Also provided are vesicular monoamine transporter 2 (VMAT2) inhibitors selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or pharmaceutically acceptable salts and / or isotopic variants thereof, for use in methods for treating neurological or psychiatric disorders or disorders in patients requiring such treatment, wherein the patient has been previously determined to have moderate or severe hepatic impairment, and the method comprises the steps of administering a therapeutically effective amount of VMAT2 inhibitor to the patient, subsequently selecting patients who can tolerate 1 or more exposure-related adverse reactions, and continuing to administer a therapeutically effective amount of VMAT2 inhibitor to the patient.

[0116] Valbenazine may be prepared in accordance with U.S. Patent Nos. 8,039,627 and 8,357,697 (each of which disclosures are incorporated herein by reference in whole). Tetrabenazine may be administered by various methods, including formulations disclosed in PCT Publications WO 2010 / 018408, WO 2011 / 019956 and WO 2014 / 047167 (each of which disclosures are incorporated herein by reference in whole). In certain embodiments, the valvenazine for use in the compositions and methods provided herein is in polymorph I as disclosed in U.S. Patent Application No. 15 / 338,214 (each of which disclosures are incorporated herein by reference in whole).

[0117] Pharmaceutical composition Also provided is a composition for treating patients with moderate or severe hepatic impairment who require a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, the composition comprising a VMAT2 inhibitor, characterized in that the composition is administered once daily to patients with moderate or severe hepatic impairment in an amount equivalent to about 40 mg of free valbenazine base of the VMAT2 inhibitor.

[0118] Also provided is a composition for treating patients with moderate or severe hepatic impairment who require a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises a therapeutically effective amount of VMAT2 inhibitor, where the therapeutically effective amount of VMAT2 inhibitor is less than the amount administered to patients without moderate or severe hepatic impairment.

[0119] A composition is also provided for treating patients requiring a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises a VMAT2 inhibitor, and the composition comprising an amount of VMAT2 inhibitor equivalent to about 40 mg of free valbenazine base is characterized in that it is administered once daily to patients later determined to have moderate or severe hepatic impairment after administration of a composition containing a therapeutically effective amount of VMAT2 inhibitor.

[0120] Compositions are also provided for treating patients requiring a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition contains a VMAT2 inhibitor, and is characterized in that it contains a smaller amount of VMAT2 inhibitor than that administered to patients without moderate or severe hepatic impairment, and is administered to patients later determined to have moderate or severe hepatic impairment after administration of a composition containing a therapeutically effective amount of VMAT2 inhibitor.

[0121] A composition is also provided for treating patients with moderate or severe hepatic impairment who require a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises a therapeutically effective amount of VMAT2 inhibitor, wherein administration of the composition is equivalent to the average valbenazine C of patients without moderate or severe hepatic impairment. max Approximately 2 to 3 times higher average valvenazine C max This will result in...

[0122] A composition is also provided for treating patients with moderate or severe hepatic impairment who require a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises a therapeutically effective amount of VMAT2 inhibitor, wherein administration of the composition is equivalent to the average (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC of patients without moderate or severe hepatic impairment. 0-∞ (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC is approximately 3 to 4 times higher than the average (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC 0-∞ This will result in...

[0123] In certain embodiments, the patient has moderate hepatic impairment.

[0124] In certain embodiments, the patient has severe liver impairment.

[0125] In certain embodiments, the patient or healthcare worker is informed that administration of the composition to a patient with moderate to severe hepatic impairment results in a higher exposure to valbenazine and / or (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol than administration of the composition to a patient with normal hepatic function.

[0126] In certain embodiments, the patient or healthcare worker is informed that administration of the composition to a patient with moderate to severe hepatic impairment may result in one or more increased risks of exposure-related adverse reactions compared to administration of the composition to a patient with normal hepatic function.

[0127] In certain embodiments, one or more exposure-related adverse reactions are selected from somnolence, anticholinergic effects, balance disturbance or falls, headache, akathisia, vomiting, nausea, arthralgia, QT prolongation, elevated blood glucose, weight gain, respiratory infection, salivation, dyskinesia, extrapyramidal symptoms (non-akathisia), anxiety, insomnia, elevated prolactin, elevated alkaline phosphatase, and elevated bilirubin.

[0128] In certain embodiments, one or more exposure-related adverse reactions are selected from somnolence, anticholinergic effects, balance disturbance or falls, headache, akathisia, vomiting, nausea, arthralgia, and QT prolongation.

[0129] In certain embodiments, one or more exposure-related adverse reactions are selected from somnolence and QT prolongation.

[0130] In certain embodiments, the patient or healthcare professional is informed that administration of the composition to a patient with moderate to severe hepatic impairment may prolong the patient's QT interval more than administration of the composition to a patient with normal hepatic function.

[0131] A composition is also provided for treating patients with mild hepatic impairment who require a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, the composition comprising a therapeutically effective amount of the VMAT2 inhibitor.

[0132] Also provided is a composition for treating patients requiring a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises a VMAT2 inhibitor, and the composition containing a therapeutically effective amount of the VMAT2 inhibitor is administered to patients subsequently determined to have mild hepatic impairment after administration of the composition containing a therapeutically effective amount of the VMAT2 inhibitor.

[0133] In certain embodiments, the composition is intended to treat neurological or psychiatric disorders or conditions.

[0134] In certain embodiments, the composition is administered orally.

[0135] In certain embodiments, the composition is administered in the form of tablets or capsules.

[0136] In certain embodiments, the composition is administered with or without food.

[0137] In certain embodiments, the VMAT2 inhibitor is a pharmaceutically acceptable salt and / or isotopic variant of valbenazine or the same.

[0138] In certain embodiments, the VMAT2 inhibitor is a barbenazine or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, the VMAT2 inhibitor is valbenazine tosylate.

[0140] In certain embodiments, the VMAT2 inhibitor is a nitrate of valbenazine.

[0141] In certain embodiments, the VMAT2 inhibitor is an isotopic variant that is L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinoridine-2-yl ester or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments, the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof.

[0143] In certain embodiments, the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt thereof.

[0144] In certain embodiments, the VMAT2 inhibitor is an isotopic variant that is (+)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol or a pharmaceutically acceptable salt thereof.

[0145] In certain embodiments, the composition is administered in an amount equivalent to about 20 mg to about 120 mg of free valvebenazine base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 20 mg of free valvebenazine base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 40 mg of free valvebenazine base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 60 mg of free valvebenazine base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 80 mg of free valvebenazine base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 120 mg of free valvebenazine base of the VMAT2 inhibitor.

[0146] In certain embodiments, the composition is administered in a first amount of VMAT2 inhibitor over a first period, and then the amount is increased to a second amount. In certain embodiments, the first period is one week. In certain embodiments, the first amount is equivalent to about 40 mg of free valvebenazine base. In certain embodiments, the second amount is equivalent to about 80 mg of free valvebenazine base.

[0147] In certain embodiments, the composition has a maximum plasma concentration (C) of (+)-α-DHTBZ between approximately 15 ng and approximately 60 ng per 1 mL of plasma. max ) and the minimum plasma concentration (C) of at least 15 ng of (+)-α-DHTBZ per 1 mL of plasma over a period of 8 hours. min It is administered in a sufficient amount to achieve the desired result.

[0148] In certain embodiments, the composition has a maximum plasma concentration (C) of (+)-α-DHTBZ between approximately 15 ng and approximately 60 ng per 1 mL of plasma. max ) and over a period of 12 hours, approximately its C max Minimum plasma concentration (C) between at least approximately 33% and 50% minIt is administered in a sufficient amount to achieve the desired result.

[0149] In certain embodiments, the composition is administered in an amount sufficient to achieve (i) a therapeutic concentration range of (+)-α-DHTBZ of about 15 ng to about 60 ng per mL of plasma; and (ii) a threshold concentration of at least 15 ng per mL of plasma over a period of about 8 to about 24 hours.

[0150] In certain embodiments, the therapeutically effective dose of the VMAT2 inhibitor is 10-90% less than the dose administered to patients without moderate or severe hepatic impairment. In certain embodiments, the therapeutically effective dose of the VMAT2 inhibitor is 20-80% less than the dose administered to patients without moderate or severe hepatic impairment. In certain embodiments, the therapeutically effective dose of the VMAT2 inhibitor is 30-70% less than the dose administered to patients without moderate or severe hepatic impairment. In certain embodiments, the therapeutically effective dose of the VMAT2 inhibitor is 40-60% less than the dose administered to patients without moderate or severe hepatic impairment. In certain embodiments, the therapeutically effective dose of the VMAT2 inhibitor is approximately 50% less than the dose administered to patients without moderate or severe hepatic impairment.

[0151] Pharmaceutical compositions for use in treating neurological or psychiatric disorders or conditions are also provided herein, comprising its VMAT2 inhibitor as an active pharmaceutical component in combination with one or more pharmaceutically acceptable carriers or excipients.

[0152] The selection of excipients largely depends on factors such as the specific mode of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form.

[0153] The pharmaceutical compositions provided herein may be provided in unit dose forms or multiple dose forms. Unit dose forms, as used herein, refer to physically distinct units, individually packaged as known in the art, suitable for administration to human and animal subjects. Each unit dose contains a predetermined amount of the active ingredient sufficient to produce its desired therapeutic effect, in association with its required pharmaceutical carrier or excipient. Examples of unit dose forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dose forms may be administered in fractions or multiples thereof. Multiple dose forms are multiple identical unit dose forms packaged in a single container so as to be administered in separate unit dose forms. Examples of multiple unit dose forms include vials, bottles of tablets or capsules, or bottles of pints or bottles of gallons.

[0154] The pharmaceutical compositions provided herein may be administered alone or in combination with one or more other compounds provided herein, or one or more other active ingredients. The pharmaceutical compositions provided herein may be formulated in various dosage forms for oral, parenteral, and topical administration. They may also be formulated as modified release dosage forms (including delayed, extended, prolonged, sustained, pulsatile, controlled, accelerated, and fast, targeted, programmed release, and gastric retention dosage forms). These dosage forms may be prepared according to conventional methods and techniques known to those skilled in the art. The pharmaceutical compositions provided herein may be administered in a single dose or in multiple doses at time intervals. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known laboratory protocols or by extrapolation from in vivo or in vitro laboratory or diagnostic data. It is also understood that for any particular individual, a specific medication regimen should be adjusted over time in accordance with the individual's needs and the professional judgment of the person administering or supervising the administration of the formulation.

[0155] Oral administration The pharmaceutical compositions provided herein may be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes oral, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, liquids, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients (including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye-migration inhibitors, sweeteners, and flavoring agents).

[0156] A binder or granulator imparts tackiness to the tablet, ensuring that it remains intact after compression. Suitable binders or granulators include starch (e.g., corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500)); gelatin; sugars (e.g., sucrose, glucose, dextrose, molasses, and lactose); natural and synthetic gums (e.g., acacia, alginic acid, alginate, Irish moss extract, Panwar gum, ghatti gum, mucilage of isabgol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch alabogalactan) (larch). Examples of suitable fillers include, but are not limited to, arabogalactan, powdered tragacanth, and guar gum; cellulose (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); microcrystalline cellulose (e.g., AVCEL-PH-101, AVCEL-PH-103, AVCEL RC-581, AVCEL-PH-105 (FMC Corp., Marcus Hook, PA)); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions provided herein in an amount of about 50% to about 99% by weight.

[0157] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dried starch, and powdered sugar. Certain diluents (e.g., mannitol, lactose, sorbitol, sucrose, and inositol), when present in sufficient quantities, can impart properties to some compressed tablets that allow them to disintegrate in the mouth by chewing. Such compressed tablets can be used as chewable tablets.

[0158] Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose (e.g., methylcellulose and carboxymethylcellulose); wood products; natural sponges; cation exchange resins; alginic acid; gum (e.g., guar gum and Vee gum HV); citrus pulp; cross-linked cellulose (e.g., croscarmellose); cross-linked polymers (e.g., crospovidone); cross-linked starch; calcium carbonate; microcrystalline cellulose (e.g., sodium starch glycolate); potassium polaritrin; starch (e.g., corn starch, potato starch, tapioca starch, and pregelatinized starch); clay; algin (aligns); and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein will vary depending on the type of formulation and will be readily apparent to those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% by weight or about 1 to about 5% by weight of the disintegrant.

[0159] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols (e.g., glycerol behenate and polyethylene glycol (PEG)); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil); zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silica or silica gel (e.g., AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-0-SIL® (Cabot Co. of Boston, MA)); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant. Suitable flow enhancers include colloidal silicon dioxide, CAB-0-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Colorants include approved, certified, water-soluble FD&C dyes, water-insoluble FD&C dyes suspended in aluminum hydroxide, and lake colorants, as well as mixtures thereof. Lake colorants are combinations resulting from the adsorption of water-soluble dyes onto hydrated heavy metal oxides, producing an insoluble form of the dye. Flavoring and odor-modifying agents include natural flavors extracted from plants (e.g., fruits) and artificial blends of compounds that produce pleasant tastes (e.g., peppermint and methyl salicylate). Sweeteners include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners (e.g., saccharin and aspartame).Suitable emulsifiers include gelatin, acacia, tragacanth, bentonite, and surfactants (e.g., polyoxyethylene sorbitan monooleate (TWEEN®) 20), polyoxyethylene sorbitan monooleate 80 (TWEEN®) Examples include 80), and triethanolamine oleate. Examples of suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Examples of preservatives include glycerin, methylparaben and propylparaben, benzoic acid, sodium benzoate, and alcohol. Examples of humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Examples of solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of organic acids include citric acid and tartaric acid. Examples of carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0160] It should be understood that many carriers and excipients can perform several functions even within the same formulation. The pharmaceutical compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that withstands the action of stomach acid but dissolves or disintegrates in the intestines, thus protecting their active ingredients from the acidic environment of the stomach. Examples of enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammonia-treated shellac, and cellulose phthalate acetate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking unpleasant tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Examples of film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compression tablets are compression tablets produced by one or more compression cycles (such as layered tablets), and compression-coated tablets or dry-coated tablets.

[0161] The tablet dosage form may be prepared from the active ingredient, which is in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein (including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants). Flavoring agents and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

[0162] The pharmaceutical compositions provided herein may be provided as soft and hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsules (also known as dry-filled capsules (DFCs)) consist of two sections, one covering the other, thus completely enclosing the active ingredient. The soft capsules (SECs) are soft, spherical shells (e.g., gelatin shells) which are plasticized by the addition of glycerin, sorbitol, or similar polyols. The soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein (including methylparaben and propylparaben, as well as sorbic acid). The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include liquids and suspensions in propylene carbonate, vegetable oil, or triglycerides. The capsules may also be coated, as known to those skilled in the art, to modify or prolong the dissolution of the active ingredient.

[0163] The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms (emulsions, solutions, suspensions, elixirs, and syrups). Emulsions are two-layer systems in which one liquid is dispersed in the form of small spherical particles within the whole of the other liquid and may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions may contain a pharmaceutically acceptable acetal (e.g., a lower alkyl acetal (the term "lower" means an alkyl having between 1 and 6 carbon atoms) (e.g., acetaldehyde diethyl acetal)); and a water-miscible solvent having one or more hydroxyl groups (e.g., propylene glycol and ethanol). Elixirs are clear, sweet-tasting, aqueous alcoholic solutions. The syrup is a concentrated aqueous solution of sugar (e.g., sucrose) and may also contain preservatives. Regarding liquid administration forms, for example, the liquid in polyethylene glycol may be diluted with a pharmaceutically acceptable liquid carrier (e.g., water) in an amount sufficient to be conveniently measured for administration.

[0164] Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredients provided herein, and dialkylated mono or polyalkylene glycols (1,2-dimethoxymethane, diglyme, triglyceride, tetraglyceride, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol). These formulations may further contain one or more antioxidants (e.g., butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates).

[0165] The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems.

[0166] The pharmaceutical compositions provided herein may be provided as non-foaming or effervescent granules and powders, so as to be reconstituted into liquid dosage forms. Pharmacoagulable carriers and excipients used in non-foaming granules or powders may include diluents, sweeteners, and wetting agents. Pharmacoagulable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide. Colorants and flavoring agents may be used in all of the above dosage forms. The pharmaceutical compositions provided herein may be formulated as immediate-release or modified-release dosage forms (including delayed, sustained, pulsed, controlled, targeted, and programmed-release forms).

[0167] The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impair the desired therapeutic effect, or with substances that complement the desired effect (e.g., antacids, proton pump inhibitors, and H2-receptor antagonists).

[0168] The pharmaceutical compositions provided herein may be administered parenterally by injection, infusion, or implantation for topical or systemic administration. Parenteral administration methods as used herein include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, bursal, and subcutaneous administration.

[0169] Parenteral administration The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration (including liquids, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for liquids or suspensions in liquid before injection). Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceuticals.

[0170] Pharmaceutical compositions intended for parenteral administration may contain one or more pharmaceutically acceptable carriers and excipients (aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubilizers, isotonic agents). This may include, but is not limited to, an agent, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, chelating or sealing agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusters, and inert gases.

[0171] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water for injection, and Ringer's injection with dextrose and lactate. Non-aqueous vehicles include, but are not limited to, non-volatile oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain triglycerides from coconut oil, and palm kernel oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0172] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride, benzethonium chloride, methylparaben and propylparaben, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphates and citrates. Suitable antioxidants are those described herein (including bisulfite and sodium metabisulfite). Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein (including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone). Suitable emulsifiers include those described herein (such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate). Suitable chelating or sealing agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins (such as α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS)).

[0173] The pharmaceutical compositions provided herein may be formulated for single-dose or multi-dose administration. The single-dose formulations may be packaged in ampoules, vials, or syringes. The multi-dose parenteral formulations must contain an antimicrobial agent in a bacteriostatic or fungal concentration. All parenteral formulations must be sterile, as is known and practiced in the art.

[0174] In certain embodiments, the pharmaceutical composition is provided as a ready-to-use sterile solution. In certain embodiments, the pharmaceutical composition is provided as a sterile-dried soluble product (such as a lyophilized powder and a hypodermic tablet) to be reconstituted with a vehicle before use. In certain embodiments, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In certain embodiments, the pharmaceutical composition is provided as a sterile-dried insoluble product to be reconstituted with a vehicle before use. In certain embodiments, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0175] The pharmaceutical compositions provided herein may be formulated as immediate-release or modified release dosage forms (including delayed, sustained, pulsatile, controlled, targeted, and programmed release forms).

[0176] The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot. In certain embodiments, the pharmaceutical composition provided herein is dispersed in a solid inert matrix, which is insoluble in body fluids but surrounded by an outer polymer membrane that allows the active ingredients in the pharmaceutical composition to diffuse through it.

[0177] Suitable inner matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, and hydrophilic polymers (e.g., hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate).

[0178] Suitable outer polymer films include polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymer with ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol copolymer, and ethylene / vinyl oxyethanol copolymer.

[0179] Local administration The pharmaceutical compositions provided herein may be administered topically to the skin, orifices, or mucous membranes. Topical administration methods, as used herein, include (intradermal) transdermal administration, conjunctival administration, intracorneal administration, intraocular administration, ocular administration, ocular administration, transdermal administration, nasal administration, vaginal administration, urethral administration, respiratory administration, and rectal administration.

[0180] The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for topical administration for topical or systemic effects (including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, bandages, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigation, sprays, suppositories, bandages, and skin patches). Topical formulations of the pharmaceutical compositions provided herein may also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0181] Examples of pharmaceutically acceptable carriers and excipients suitable for use in topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspensions and dispersants, wetting agents or emulsifiers, complexing agents, chelating agents or sequestering agents, penetration enhancers, cryoprotective substances, freeze-drying protective substances, thickeners, and inert gases.

[0182] Pharmaceutical compositions are also used in electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g., POWDERJECT). TM (Chiron Corp., Emeryville, CA), and BIOJECT TM It can be administered topically by Bioject Medical Technologies Inc., Tualatin, OR.

[0183] The pharmaceutical compositions provided herein may be in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon bases (e.g., lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum); emulsifiable or absorbent bases (e.g., hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin); water-removable bases (e.g., hydrophilic ointments); water-soluble ointment bases (e.g., polyethylene glycol of various molecular weights); and emulsion bases, either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions (containing cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid). These vehicles soften the skin but generally require the addition of antioxidants and preservatives.

[0184] A suitable cream base may be oil-in-water or water-in-oil. The cream vehicle may be washable with water and may contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the “internal” phase and generally consists of petrolatum and fatty alcohols (e.g., cetyl alcohol or stearyl alcohol). The aqueous phase usually, though not necessarily, exceeds the volume of the oil phase and generally contains a water-retaining agent. The emulsifier in the cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.

[0185] A gel is a semi-solid suspension-type system. A single-phase gel contains an organic polymer substantially uniformly dispersed throughout a liquid carrier. Suitable gelling agents include cross-linked acrylic polymers (e.g., carbomer, carboxypolyalkylene, Carbopol®); hydrophilic polymers (e.g., polyethylene oxide, polyoxyethylene-polyoxypropylene copolymer, and polyvinyl alcohol); cellulose polymers (e.g., hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose); gums (e.g., tragacanth and xanthan gum); sodium alginate, and gelatin. To prepare a homogeneous gel, a dispersant (e.g., alcohol or glycerin) may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and / or stirring.

[0186] The pharmaceutical compositions provided herein may be administered rectally, urethra, vagina, or perianally in the form of suppositories, pessaries, bougies, patches or poultices, pastes, powders, bandages, creams, ointments, contraceptives, ointments, liquids, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms may be manufactured using conventional processes.

[0187] Rectal, urethral, ​​and vaginal suppositories are solid bodies for insertion into bodily orifices, which are solid at normal temperatures but melt or soften at body temperature to release their active ingredients into the orifice. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include stiffening agents (which, when formulated with the pharmaceutical compositions provided herein, have a melting point near body temperature) and vehicles such as antioxidants (including bisulfite and sodium metabisulfite) as described herein. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), whale wax, paraffin, white wax and yellow wax, as well as suitable mixtures of monoglycerides, diglycerides and triglycerides of fatty acids, hydrogels (e.g., polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid); and glycerinated gelatin. Various combinations of vehicles may be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2-3 g.

[0188] The pharmaceutical compositions provided herein may be administered to the eye in the form of liquids, suspensions, ointments, emulsions, gel-forming solutions, powders for liquids, gels, intraocular implants, and implants.

[0189] The pharmaceutical compositions provided herein may be administered intranasally or by inhalation into the airways. These pharmaceutical compositions may be provided alone or in combination with a suitable spray (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) in the form of aerosols or liquids for delivery using pressurized vessels, pumps, sprays, atomizers (e.g., atomizers that use electrohydrodynamics to produce a fine mist), or nebulizers. The pharmaceutical compositions may also be provided alone or in combination with an inert carrier (e.g., lactose or phospholipids) as dry powders for blowing; and as nasal drops. For intranasal use, the powders may contain a bioadhesive (such as chitosan or cyclodextrin).

[0190] Liquids or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers may be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent or solvent for dispersing, solubilizing, or prolonging the release of the active ingredients provided herein; and / or surfactants, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0191] The pharmaceutical compositions provided herein can be atomized to a size suitable for inhalation delivery (e.g., 50 micrometers or less, or 10 micrometers or less). Particles of such size can be prepared using pulverization methods known to those skilled in the art (e.g., spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high-pressure homogenization, or spray drying).

[0192] Capsules, blisters, and cartridges for use in inhalers or injectors may be formulated to contain the pharmaceutical compositions provided herein; a suitable powder base (e.g., lactose or starch); and a powder mixture of a performance modifier (e.g., / -leucine, mannitol, or magnesium stearate). The lactose may be anhydrous or in monohydrate form. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhalation / intranasal administration may further contain a suitable flavor (e.g., menthol and levomenthol) or a sweetener (e.g., saccharin or sodium saccharin).

[0193] The pharmaceutical compositions provided herein for topical administration may be formulated to be immediate-release or modified-release (including delayed, sustained, pulsatile, controlled, targeted, and programmed release).

[0194] Modified emission The pharmaceutical compositions provided herein may be formulated as modified release dosage forms. As used herein, the term “modified release” refers to a dosage form in which the rate or location of release of the active ingredient differs from that of the immediate-dose dosage form when administered via the same route. Modified release dosage forms include delayed, prolonged, extended, sustained, pulsatile or pulsatile-type, controlled, accelerated, and rapid, targeted, programmed release, as well as gastric retention dosage forms.

[0195] Pharmaceutical compositions in modified release formulations can be prepared using various modified release devices and methods known to those skilled in the art (including, but not limited to, matrix-controlled release devices, osmotically controlled release devices, multiparticulate-controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof). The release rate of the active ingredient can also be modified by varying the particle size and polymorphism of the active ingredient.

[0196] The pharmaceutical compositions provided herein in modified release dosage forms may be fabricated using matrix-controlled release devices known to those skilled in the art.

[0197] In certain embodiments, the pharmaceutical compositions provided herein in modified release dosage forms may be formulated using an erosive matrix device (which is a polymer that is swellable in water, erosive, or soluble, and includes synthetic polymers as well as naturally occurring polymers and derivatives (e.g., polysaccharides and proteins)).

[0198] Useful materials for forming an erosive matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gums such as agar, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan; starch (e.g., dextrin and maltodextrin); hydrophilic colloids (e.g., pectin); phosphatides (e.g., lecithin); alginates; propylene glycol alginate; gelatin; collagen and cellulosic materials (e.g., ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate) CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose trimellitate acetate (HPMCAT), and ethyl hydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT® (Rohm) America, Inc., Piscataway, NJ); poly(2-hydroxyethyl methacrylate); polylactide; copolymers of L-glutamic acid and ethyl-L-glutamate; copolymers of biodegradable glycolic acid lactate; poly-D-(-)-3-hydroxybutyrate; and other acrylic acid derivatives (e.g., homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride).

[0199] In certain embodiments, the pharmaceutical composition is formulated in a non-erosive matrix device. The active ingredient is dissolved or dispersed in an inert matrix and, once administered, is released primarily by diffusion throughout the inert matrix. Suitable materials for use as a non-erosive matrix device include, but are not limited to, the following: insoluble plastics (e.g., polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl acetate, vinylidene chloride, vinyl chloride copolymer with ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber) Epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyl oxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, and hydrophilic polymers (e.g., ethylcellulose, cellulose acetate, crospovidone, and crosslinked partially hydrolyzed polyvinyl acetate); and fatty compounds (e.g., carnauba wax, microcrystalline wax, and triglycerides).

[0200] In a matrix-controlled release system, the desired release dynamics can be controlled, for example, by the type of polymer used, the polymer viscosity, the particle size of the polymer and / or its active components, the ratio of the active components to the polymer, and other excipients in the composition.

[0201] The pharmaceutical compositions provided herein in modified release dosage forms may be prepared by methods known to those skilled in the art (including direct compression, dry granulation or wet granulation followed by compression, and melt granulation followed by compression).

[0202] The pharmaceutical compositions provided herein in modified release dosage forms may be fabricated using osmotically controlled release devices (including one-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extruding core systems (ECS)). Generally, such devices have at least two components: (a) a core containing its active ingredient; and (b) a semipermeable membrane (which encloses its core) having at least one delivery port. The semipermeable membrane controls the inflow of water from an aqueous environment into its core to cause drug release by extrusion through its delivery port.

[0203] In addition to its active ingredient, the core of its penetration device is an osmotic substance. This may include, as needed, an agent (which creates the driving force for the transport of water from its operating environment to the core of the device). Examples of water-swellable hydrophilic polymers (also known as "osmopolymers" and "hydrogels"), which are a class of osmotic agents, include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides (e.g., calcium alginate), polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, and polyvinyl alcohol. PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers (e.g., methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0204] Another class of osmogenic substances are osmogens, which can absorb water and influence the osmotic gradient across the surrounding coating barrier. Suitable osmogens include, but are not limited to, inorganic salts (e.g., magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate); sugars (e.g., dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol); organic acids (e.g., ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid); urea; and mixtures thereof.

[0205] Osmotic agents with different dissolution rates can be used to influence how quickly their active ingredient is initially delivered from its dosage form. For example, amorphous sugars (e.g., Mannogeme EZ (SPI Pharma, Lewes, DE)) can be used to provide faster delivery during the first 2-3 hours to adequately produce the desired therapeutic effect, and then gradually and continuously release the remaining amount to maintain the desired level of therapeutic or prophylactic effect over a longer period. In this case, the active ingredient is released at such a rate to replace the amount of active ingredient that has been metabolized and excreted.

[0206] The core may also contain a wide variety of other excipients and carriers, as described herein, to enhance the performance of its dosage form or to facilitate stability or processing.

[0207] Useful materials for forming semipermeable membranes include various grades of acrylic substances, vinyl, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable and water-insoluble at physiologically relevant pH levels, or that are easily made water-insoluble by chemical changes (e.g., crosslinking). Examples of suitable polymers useful for forming coatings include: plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose trimellitate acetate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, β-glucan acetate, β-glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halide, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0208] Semipermeable membranes can also be hydrophobic microporous membranes, where the pores are substantially filled with gas and not moistened with an aqueous medium, but are permeable to water as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water-permeable membranes are typically composed of hydrophobic polymers, such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halide, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes. Delivery ports on the semipermeable membrane may be formed after coating by mechanical or laser perforation. Delivery ports may also be formed in situ by erosion of a plug of water-soluble material or by rupturing a thin portion of the membrane over an indentation in the core. Furthermore, delivery ports may be formed during the coating process.

[0209] The total amount and rate of release of the active ingredient can be substantially controlled through the thickness and porosity of the semipermeable membrane, the composition of its core, and the number, size, and location of its delivery ports.

[0210] The pharmaceutical composition in an osmotically controlled release dosage form may further contain additional conventional excipients as described herein to enhance the performance or processing of the formulation.

[0211] The osmotically controlled release dosage form can be prepared according to conventional methods and techniques known to those skilled in the art.

[0212] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release formulations, which include an asymmetric permeable membrane coating a core containing its active ingredient and other pharmaceutically acceptable excipients. These AMT controlled-release formulations can be prepared according to conventional methods and techniques known to those skilled in the art, such as direct compression, dry granulation, wet granulation, and immersion coating.

[0213] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled release dosage forms, which include an osmotic membrane coating a core containing its active ingredient, hydroxyethyl cellulose, and other pharmaceutically acceptable excipients.

[0214] The pharmaceutical compositions provided herein in modified release dosage forms can be fabricated as multiple microparticle controlled release devices, which include a number of particles, granules, or pellets ranging in diameter from about 10 pm to about 3 mm, about 50 pm to about 2.5 mm, or about 100 pm to 1 mm. Such multiple microparticles can be made by processes known to those skilled in the art (including wet and dry granulation, extrusion / spheronization, roller compaction, melt-solidification), and by spray coating a seed core.

[0215] Other excipients as described herein can be blended with the pharmaceutical composition to assist in processing and forming the multiple microparticles. The resulting particles can themselves constitute a multiple microparticle device or can be coated with various film-forming materials (such as enteric polymers, water-swellable polymers, and water-soluble polymers). The multiple microparticles can be further processed as capsules or tablets.

[0216] Targeted delivery The pharmaceutical compositions provided herein can also be formulated to be targeted to specific tissues, receptors, or other areas of the body of the subject to be treated (including liposome-based, resealed red blood cell-based, and antibody-based delivery systems).

[0217] Dosage In the treatment, prevention, or amelioration of one or more symptoms of tic disorders or other conditions, disorders, or diseases associated with VMAT2 inhibition, appropriate dosage levels are generally about 0.001 to 100 mg / kg patient body weight per day (mg / kg / day), about 0.01 to about 80 mg / kg / day, about 0.1 to about 50 mg / kg / day, about 0.5 to about 25 mg / kg / day, or about 1 to about 20 mg / kg / day, which can be administered as a single dose or multiple doses. Within this range, the dosage can be 0.005 to 0.05 mg / kg / day, 0.05 to 0.5 mg / kg / day, or 0.5 to 5.0 mg / kg / day, 1 to 15 mg / kg / day, 1 to 20 mg / kg / day, or 1 to 50 mg / kg / day. In certain embodiments, the dosage level is about 0.001 to 100 mg / kg / day.

[0218] In certain embodiments, the dosage level is about 25 to 100 mg / kg / day. In certain embodiments, the dosage level is about 0.01 to about 40 mg / kg / day. In certain embodiments, the dosage level is about 0.1 to about 80 mg / kg / day. In certain embodiments, the dosage level is about 0.1 to about 50 mg / kg / day. In certain embodiments, the dosage level is about 0.1 to about 40 mg / kg / day. In certain embodiments, the dosage level is about 0.5 to about 80 mg / kg / day. In certain embodiments, the dosage level is about 0.5 to about 40 mg / kg / day. In certain embodiments, the dosage level is about 0.5 to about 25 mg / kg / day. In certain embodiments, the dosage level is about 1 to about 80 mg / kg / day. In certain embodiments, the dosage level is about 1 to about 75 mg / kg / day. In certain embodiments, the dosage level is about 1 to about 50 mg / kg / day. In certain embodiments, the dosage level is about 1 to about 40 mg / kg / day. In certain embodiments, the dosage level is about 1 to about 25 mg / kg / day.

[0219] In certain embodiments, the dosage level is approximately 5.0 to 150 mg / day, and in certain embodiments, it is 10 to 100 mg / day. In certain embodiments, the dosage level is approximately 80 mg / day. In certain embodiments, the dosage level is approximately 40 mg / day.

[0220] With regard to oral administration, the pharmaceutical composition may be provided in the form of tablets containing 1.0 to 1,000 mg of the active ingredient, particularly about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 750 mg, about 800 mg, about 900 mg, and about 1,000 mg of the active ingredient, for symptomatic adjustment of the dosage for the patient to be treated. In certain embodiments, the pharmaceutical composition may be provided in the form of tablets containing about 100 mg of the active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of tablets containing about 80 mg of the active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 75 mg of the active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 50 mg of the active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 40 mg of the active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 25 mg of the active ingredient. The composition may be administered in a regimen of 1 to 4 times per day (including 1, 2, 3, and 4 times per day).

[0221] However, it is understood that the specific dose levels and frequencies for any particular patient may vary and depend on various factors, including the activity of the specific compound used, its metabolic stability and duration of action, age, weight, overall health, sex, diet, mode and timing of administration, elimination rate, drug combinations, the severity of the particular condition, and the host being treated.

[0222] The compounds provided herein may also be combined with or used in combination with other agents that are useful in treating, preventing, or improving one or more symptoms of a disease or condition (generally including tic disorders and other conditions treated with antipsychotic drug applications) in which the compounds provided herein are useful.

[0223] In certain embodiments, the compounds provided herein may also be combined with or used in combination with representative antipsychotics. In certain embodiments, the representative antipsychotics may be fluphenazine, haloperidol, roxapine, morindone, perphenazine, pimozide, sulpiride, thioridazine, or trifluoperazine. In certain embodiments, the antipsychotic is an atypical antipsychotic. In certain embodiments, the atypical antipsychotic is aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone. In certain embodiments, the atypical antipsychotic is clozapine.

[0224] Such other agents or drugs may be administered concurrently or sequentially with the compounds provided herein, depending on their commonly used route and dosage. If the compounds provided herein are used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compounds provided herein may be used, but is not required. Therefore, the pharmaceutical compositions provided herein include those containing one or more other active ingredients or therapeutic agents in addition to the compounds provided herein.

[0225] The weight ratio of the compound provided herein to its second active ingredient may vary and depend on the effective dose of each ingredient. Generally, the effective dose of each is used. For example, when the compound provided herein is used in combination with its second drug or a pharmaceutical composition containing such other drugs, the weight ratio of particulate matter to its second drug may range from about 1,000:1 to about 1:1,000, or from about 200:1 to about 1:200.

[0226] The combinations of particulate matter and other active ingredients provided herein may also generally fall within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0227] Examples of embodiments of the present disclosure are provided in the following embodiments. The following embodiments are presented solely for illustrative purposes and to assist those skilled in the art in using the present disclosure. The embodiments are not intended in any way to limit the scope of the present disclosure. [Examples]

[0228] Example 1 A Phase 1 study to evaluate the safety, tolerability, and pharmacokinetics of a single dose of NBI-98854 in subjects with mild, moderate, or severe hepatic failure. This was a Phase I single-dose open-label study to evaluate the safety, tolerability, and pharmacokinetics (PK) of NBI-98854 50 mg single dose and its metabolites in subjects with mild, moderate, and severe hepatic impairment compared to subjects with normal liver function. A total of 24 male and female subjects were enrolled (including 6 subjects with normal liver function (Group I), 6 subjects with mild stable hepatic impairment (Group II), 6 subjects with moderate stable hepatic impairment (Group III), and 6 subjects with severe stable hepatic impairment (Group IV)). Subjects enrolled with normal liver function were assumed to be similar in age, sex, race, and weight to the approximately 18 subjects with hepatic impairment. All subjects were genotyped to determine their cytochrome P450 2D6 (CYP2D6) status.

[0229] The Child-Pugh scale was used to classify the severity of liver impairment into three groups: mild (score of 5–6), moderate (score of 7–9), and severe (score of 10–15).

[0230] After providing informed consent, subjects were screened on day 1 for eligibility for a 28-day course of the study drug. Eligible subjects were admitted to the facility on the morning before the administration day (-day 1) and remained there for 4 days. Subjects were released on day 4 after 72 hours of PK sample collection and safety evaluation. On the mornings of days 5 and 6, subjects returned to the facility for PK sample collection and safety evaluation; the final study visit was on day 8 (7 days post-administration).

[0231] On day 1, a single dose of NBI-98854 50 mg was administered at approximately 08:00. Blood samples for PK analysis of NBI-98854 and its metabolites were collected approximately 45 minutes before administration and up to 120 hours after administration. Safety assessments were performed at scheduled times throughout the study.

[0232] NBI-98854 50 mg capsules were administered orally. Each capsule contained 50 mg of NBI-98854 free base as nitrosylate. Lot number 1560.002 of NBI-98854 was used in this study.

[0233] Pharmacokinetics On day 1, blood samples for PK analysis of NBI-98854 and its metabolites were collected approximately 45 minutes before administration, and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, and 120 hours after administration. The following PK parameters were calculated: • Area under the time curve (AUC) of plasma concentration from 0 to 24 hours. 0-24 ) · The area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration 0-tlast ) · The area under the plasma concentration-time curve (AUC) from time 0 to infinity 0-∞ ) · AUC 0-tlast from AUC 0-∞ to the percentage of extrapolated AUC up to AUC extr ) · The maximum plasma concentration (C max ) · The time to reach the maximum plasma concentration (t max ) · The lag time (T lag ) from dosing to the appearance time of the measurable test substance · The apparent terminal half-life (t 1 / 2 ) · The apparent terminal rate constant (λ z ) · The apparent mean residence time (MRT) and · The molar AUC of metabolites NBI-98782 and NBI-136110 relative to the parent drug NBI-98854 0-∞ ratio.

[0234] The following PK parameters were calculated only for NBI-98854: · The apparent total body clearance (CL / F) after oral administration · The apparent volume of distribution during the terminal phase (Vz / F) after oral administration

[0235] The plasma PK parameters for NBI-98854, NBI-98782, and NBI-136110 in the liver impairment group are summarized below.

[0236] t max 、T lag 、t 1 / 2 、MRT, and the PK data for Vz / F were rounded to 2 significant figures, and all other parameters (AUC 0-24 、AUC0-tlast AUC 0-∞ , C max The terms , and CL / F) were rounded to three significant figures. The last significant figure was rounded up if the digit to its right was ≥ 5, and rounded down if the digit to its right was ≤ 4.

[0237] Pharmacokinetic results NBI-98854 has an average T time of 0.17 to 0.38 hours. lag As indicated by the values, it appeared in the plasma shortly after oral administration in all groups. Compared to the normal group with liver impairment (233 ng / mL), the mean C max The values ​​were higher across the mild (384 ng / mL), moderate (556 ng / mL), and severe (631 ng / mL) liver impairment groups. 1 / 2 The MRT time was longer in the severe group (28 hours) than in the mild, moderate, or normal groups (range: 21-22 hours). The MRT time ranged from 23 to 30 hours, with the longest duration observed in the severe liver group. Mean AUC 0-∞ The values ​​were higher in the mild (3510 ng × hour / mL), moderate (5550 ng × hour / mL), and severe (6430 ng × hour / mL) liver groups compared to the normal liver group (2680 ng × hour / mL).

[0238] NBI-98782 has an average T time of 0.42 to 0.67 hours. lag As indicated by the values, NBI-98854 appeared in plasma shortly after oral administration across all groups. max The values ​​were higher in the moderate (20.0 ng / mL) and severe (19.2 ng / mL) liver groups than in the mild (10.6 ng / mL) or normal (8.61 ng / mL) liver groups. (Median t for NBI-98782) max The mean t was longer in the moderate (16 hours) and severe (14 hours) liver impairment groups than in the mild liver impairment and normal groups (both 6.0 hours). 1 / 2The MRT time was longer in the severe group (32 hours) than in the moderate (24 hours), mild (23 hours), or normal (23 hours) groups. The MRT time ranged from 36 to 53 hours, with the longest duration observed in the severe liver impairment group.

[0239] NBI-136110 has an average T time of 0.33 to 0.54 hours. lag As indicated by the values, across all groups, NBI-98854 appeared in plasma shortly after oral administration. The median t of NBI-136110 max The results were similar across the groups (range: 2.5–4.0 hours). Average C max The mean apparent terminal half-life (t) was higher in the moderate (32.5 ng / mL) and severe (36.5 ng / mL) groups than in the mild (25.0 ng / mL) or normal (23.1 ng / mL) groups. 1 / 2 The MRT time was longer in the severe group (57 hours) than in the mild, moderate, or normal groups (range: 33-36 hours). The MRT time ranged from 51 to 81 hours, with the longest duration observed in the severe liver impairment group.

[0240] Plasma AUC for NBI-98782 vs. NBI-98854 0-∞ The mean molar ratio ranged from 16.5% to 27.8%, with the highest levels observed in the moderate liver group. Plasma AUC for NBI-136110 vs. NBI-98854 0-∞ The average molar ratio ranged from 28.3% to 37.3%, and was highest in the normal functioning group. NBI-98854 plasma pharmacokinetic parameters in the liver impairment group [Table 1-1] [Table 1-2] NBI-98782 plasma pharmacokinetic parameters and parameter ratios in the liver impairment group [Table 2-1] [Table 2-2] NBI-136110 plasma pharmacokinetic parameters and parameter ratios in the liver impairment group [Table 3]

[0241] PK exposure parameters, AUC 0-∞ and C max The geometric mean ratios for NBI-98854, NBI-98782, and NBI-136110 are provided below.

[0242] NBI-98854: Average AUC of NBI-98854 0-∞ The values ​​were higher in the mild (1.23 times higher), moderate (1.88 times higher), and severe (2.37 times higher) liver groups compared to the normal liver group; the mean LS difference was statistically significant in the moderate (p=0.026) and severe (p<0.001) liver groups compared to the normal group.

[0243] Average C of NBI-98854 max The values ​​were higher in the mild (1.44 times higher), moderate (1.99 times higher), and severe (2.50 times higher) groups compared to the normal liver group, and the mean difference in LS was statistically significant in the severe liver group (p=0.005) compared to the normal group.

[0244] NBI-98782: Average AUC of NBI-98782 0-∞ The values ​​were higher in the mild (1.23 times higher), moderate (2.77 times higher), and severe (3.43 times higher) groups compared to the normal liver group; the mean LS difference was statistically significant in the moderate (p=0.013) and severe (p<0.001) groups compared to the normal group.

[0245] Average C of NBI-98782 maxThe values ​​were higher in the mild (1.20 times higher), moderate (2.09 times higher), and severe (2.17 times higher) groups compared to the normal liver group; the mean LS difference was statistically significant in the moderate (p=0.014) and severe (p<0.001) liver groups compared to the normal group.

[0246] NBI-136110: Average AUC of NBI-136110 0-∞ The values ​​were higher in the mild (1.08 times higher), moderate (1.41 times higher), and severe (1.87 times higher) groups compared to the normal liver group; the mean difference in LS was statistically significant in the severe (p<0.001) group compared to the normal group.

[0247] Average C of NBI-136110 max The values ​​were higher in the mild (1.07 times higher), moderate (1.32 times higher), and severe (1.58 times higher) groups compared to the normal liver group; the mean difference in LS was statistically significant in the severe liver group (p=0.002) compared to the normal group. AUC 0-∞ and C max Geometric mean ratios of the liver injury groups in NBI-98854, NBI-98782, and NBI-136110. [Table 4-1] [Table 4-2] a. The geometric least squares (LS) mean ratio was based on an analysis of variance model using logarithmically transformed (base 10) data. b. The 90% confidence interval (CI) for the geometric mean ratio was based on the LS mean using logarithmically transformed (base 10) data. The cP value was derived from a two-tailed test comparing the mean treatment LS values.

[0248] Half-life and t maxThe mean group differences in LS for NBI-98854, NBI-98782, and NBI-136110 are provided below. Regarding NBI-98854, NBI-98782, and NBI-136110, t 1 / 2 The mean difference in LS was statistically significant in the severe liver group compared to the normal liver group.

[0249] Regarding NBI-98854, NBI-98782, and NBI-136110, max The mean difference in LS was not statistically significant compared to the normal liver group in any of the liver impairment groups (mild, moderate, and severe). Half-lives and t of NBI-98854, NBI-98782, and NBI-136110 in the liver impairment group. max LS average difference [Table 5-1] [Table 5-2] at 1 / 2 Regarding this, the least squares mean difference from the analysis of variance model; t max Regarding this, we use the Hodges-Lehmann estimator. bt / 2 Regarding the least squares mean difference and t max For this, the 90% confidence interval is the Hodges-Lehmann estimator. ct 1 / 2 Regarding the least squares mean and t max This refers to the two-sided p-value of the test for differences between groups, based on the Wilcoxon rank-sum test.

[0250] Liver damage was observed in NBI-98854 and its metabolites, NBI-98782, and NBI-136110, with a peak (C max ) and increased total exposure (AUC) were associated with this. max and AUC 0-∞A modest increase (<2x) was observed in the mild liver impairment group for NBI-98854 and NBI-98782. NBI-98854 C max (Approximately 2-3 times) and NBI-98782 AUC 0-∞ A significant increase (approximately 3.5 times) was observed in the moderate and severe liver impairment groups. NBI-136110 C max and AUC 0-∞ A modest increase (<2x) was observed in the mild, moderate, and severe liver impairment groups.

[0251] Regarding liver damage, NBI-98854, NBI-98782, and NBI-136110, t max and t 1 / 2 It did not significantly affect the (<2x increase) result.

[0252] safety Safety was assessed based on adverse events (AEs), clinical laboratory tests (including blood, serum chemistry, and urine analysis), vital signs (including blood pressure and pulse measured while standing), physical examination, and 12-lead electrocardiogram (ECG) recordings.

[0253] safety results NBI-98854 50 mg administered on day 1 was well tolerated by all subjects. No deaths, serious or severe treatment-induced adverse events (TEAEs) were reported, and no subjects discontinued the study due to TEAEs. Two subjects (33.3%) in each liver impairment group experienced at least one TEAE, while >1 subject experienced no events. There were no clinically significant changes in laboratory measurements, vital signs, or ECG parameters during the study, and no clinically significant differences were noted across the groups.

[0254] In each group, two subjects (33.3%) experienced at least one TEAE. A summary of the TEAEs reported by each group is provided below. Summary of adverse events [Table 6-1] [Table 6-2]

[0255] All TEAEs during this study were judged by the investigators to be mild in intensity. Treatment-related AEs (those thought to be likely or certainly related to the study drug) were reported in four subjects (including abdominal discomfort (normal liver function), headache (mild liver impairment), constipation (moderate liver impairment), and indigestion (severe liver impairment)). All of these AEs were judged to be likely related to the study drug.

[0256] No deaths, serious TEAEs, or discontinuations due to AEs were reported in this study.

[0257] conclusion Liver damage was observed in NBI-98854 and its metabolites, NBI-98782, and NBI-136110, with a peak (C max This was associated with increased exposure and overall exposure (AUC).

[0258] C max and AUC 0-∞ A modest increase (<2x) was observed in subjects with mild hepatic impairment with respect to NBI-98854 and NBI-98782, and NBI-98854 C max (Approximately 2-3 times) and NBI-98782 AUC 0-∞ A significant increase (approximately 3.5 times) was observed in subjects with moderate or severe liver impairment. NBI-136110 C max and AUC 0-∞ A modest increase (<2x) was observed in the mild, moderate, and severe liver impairment groups.

[0259] NBI-98854 50 mg was well tolerated in both normal subjects and subjects with liver impairment.

[0260] Liver damage was observed in NBI-98854 and its metabolites, NBI-98782, and NBI-136110, with a peak (C max ) and increased total exposure (AUC) were associated with this. max and AUC 0-∞ A modest increase (<2x) was observed in the mild liver impairment group for NBI-98854 and NBI-98782. NBI-98854 C max (Approximately 2-3 times) and NBI-98782 AUC 0-∞ A significant increase (approximately 3.5 times) was observed in the moderate and severe liver impairment groups. NBI-136110 C max and AUC 0-∞ A modest increase (<2x) was observed in the mild, moderate, and severe liver impairment groups.

[0261] Regarding liver damage, NBI-98854, NBI-98782, and NBI-136110, t max and t 1 / 2 It did not have a significant impact.

[0262] Example 2: Pharmacological characterization of barbenazine, tetrabenazine, and their metabolites Upon oral administration, TBZ is reduced to form four distinct isomeric secondary alcohol metabolites (collectively called dihydrotetrabenazine (DHTBZ)). TBZ contains three chiral carbon centers (C-2, C-3, and C-11β), and hypothetically, eight stereoisomers could be produced. However, since the relative configurations of the C-3 and C-11β carbons are fixed, only four stereoisomers are possible: (R,R,R-DHTBZ or (+)-α-DHTBZ (alternative nomenclature) or NBI-98782 (laboratory nomenclature)). S,S,S-DHTBZ or (-)-α-DHTBZ or NBI-98771; S,R,R-DHTBZ or (+)-β-DHTBZ or NBI-98795; and R,S,S-DHTBZ or (-)-β-DHTBZ or NBI-98772.

[0263] The affinity of each compound to the rat forebrain membrane [ 3 The affinity was measured by inhibition of [H]-DHTBZ binding. Affinity compared to R,R,R-DHTBZ is also calculated and shown. Both data are reported as the negative logarithm of Ki (pKi) for statistical calculations on the normally distributed binding parameters used to determine the mean and SEM. The Ki value was determined as 10(-pKi) from the mean pKi. The R,R,R-DHTBZ stereoisomer binds to VMAT2 with the highest affinity in both rat and human (Ki = 1.0~4.2 nM). In comparison, the remaining three DHTBZ stereoisomers (S,R,R-DHTBZ, S,S,S-DHTBZ, R,S,S-DHTBZ) bind to VMAT2 with Ki values ​​of 9.7 nM, 250 nM, and 690 nM, respectively. In vitro VMAT2 binding affinity in rat forebrain [Table 7] a The affinity for R,R,R-DHTBZ was determined in the same study by K i The calculation was performed using the values.

[0264] The primary metabolic clearance pathways for valbenazine (VBZ, NBI-98854) are hydrolysis (forming R,R,R-DHTBZ) and monooxidation (forming the metabolite NBI-136110). R,R,R-DHTBZ and NBI-136110 (the two most abundant circulating metabolites of VBZ) are formed gradually, and their plasma concentrations decrease with half-lives similar to those of VBZ.

[0265] VBZ and its metabolites R,R,R-DHTBZ and NBI-136110 were tested for their ability to inhibit the binding of [3H]-DHTBZ to VMAT2 in cell lines or native tissues. The affinity of each compound was tested for its ability to bind to either human platelets or rat striatal membrane. 3The inhibition of H]-DHTBZ binding was measured. Affinity compared to R,R,R-DHTBZ was also calculated and is shown. The data were both statistically calculated using normally distributed binding parameters, which were used to determine the mean and SEM (n=4 for each compound in each tissue). i Report the negative logarithm of (pKi). i The value is 10 from the mean pKi. (-pKi) It was determined that VMAT2 was the most potent inhibitor of VMAT2 in rat striatum and human platelet homogenates. In vitro VMAT2 binding affinity of valbenazine and its metabolites [Table 8]

[0266] VBZ and NBI-136110 exhibited similar effects in inhibiting VMAT2, but their Ki values ​​were approximately 40–65 times higher than those of R,R,R-DHTBZ (lower affinity). These results were confirmed by radioligand binding assays of DHTBZ stereoisomers (i.e., TBZ metabolites) in rat forebrain, which also indicated that R,R,R-DHTBZ was the most potent inhibitor of VMAT2, followed by S,R,R-DHTBZ. In comparison, S,S,S-DHTBZ and R,S,S-DHTBZ, the other two primary metabolites of TBZ, were found to be insufficient VMAT2 inhibitors with affinity approximately 60 and 160 times weaker than R,R,R-DHTBZ, respectively.

[0267] Beyond VMAT2, the affinity of VBZ and its metabolites R,R,R-DHTBZ and NBI-136110 to other targets was investigated for GPCRs, cell surface monoamine transporters, cardiac potassium channels, and human ether-α-go-go related compounds. We evaluated a wide range of protein targets, including ion channels containing gene receptors (HERGs), in extensive Cerep screening.

[0268] Multi-target activity screening (Cerep screening) of over 80 targets for these compounds showed that VBZ and its metabolites, R,R,R-DHTBZ and NBI-136110, did not inhibit the binding of congeneral ligands to any of their targets by more than 50% at concentrations of 1–10 μM. In contrast, three other DHTBZ stereoisomers (S,R,R-DHTBZ, S,S,S-DHTBZ, and R,S,S-DHTBZ (these are metabolites of TBZ but not of VBZ)) showed >50% inhibition of ligand binding to many receptor subtypes, including serotonin, dopamine, and adrenergic receptors. Results were expressed as the percentage of specific binding of the control: (specific binding of the tested compound / specific binding of the control) × 100. All compounds were tested at a final concentration of 1 μM or 10 μM. The results are an excerpt from a larger panel of 80 targets performed as the initial screening at Cerep (n=2 for each compound at each target). Results in bold (>50%) indicate activity at the target receptor. In vitro activity of valvenazine and DHTBZ stereoisomers at dopamine, serotonin, and adrenergic receptors. [Table 9] a For the purpose of creating a large panel screen, the S,S,S-metabolites and R,S,S-metabolites were tested as a 50 / 50 mixture.

[0269] To describe the monoamine system in more detail, detailed radioligand binding assays were performed on a common metabolite of TBZ and VBZ (R,R,R-DHTBZ) as well as other related metabolites specific to TBZ and VBZ, for dopamine, serotonin, and adrenergic receptor subtypes, and for transporters of dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Detailed analysis revealed the high specificity of R,R,R-DHTBZ for the VMAT2 transporter and the nonspecific activity of other TBZ metabolites (including relatively high affinity for dopamine and serotonin receptor subtypes). Interestingly, the R,R,R-DHTBZ metabolite showed the greatest nonselectivity with respect to monoamine receptors. Neither TBZ nor VBZ metabolites had any affinity for the monoamine transporters DAT, SERT, or NET. To complete the selectivity profile for VMAT2, the functional activity of these compounds against the human VMAT1 transporter was tested in VMAT1-expressing cells. Reserpine, a non-selective, irreversible, high-affinity uptake inhibitor of VMAT1, substantially inhibited uptake via VMAT1, but TBZ, VBZ, or their metabolites R,R,R-DHTBZ or NBI-136110 showed no significant inhibitory activity at concentrations up to 10 μM. Uptake for both VMAT1 and VMAT2, measured in untransfected host cells, was found to be similar to that in cells transfected in the presence of excess reserpine.

[0270] Radioligand binding assays and broad panel screenings demonstrate that, in addition to various potencies in the VMAT2 transporter, two of DHTBZ metabolites of TBZ (S,S,S-DHTBZ and R,S,S-DHTBZ) interact with D1 and D2 receptors. Since VBZ is not metabolized into any of these DHTBZ stereoisomers, it does not have any direct or indirect effect on postsynaptic dopamine receptors through its metabolites.

[0271] Furthermore, results from a broad panel screening indicate that VBZ and its major metabolites (R,R,R-DHTBZ and NBI-136110) have little to no affinity for over 80 binding sites, including receptors, monoamine transporters, and ion channels. This profile suggests a low likelihood of pharmacological off-target effects. In addition, uptake studies using TBZ, VBZ, and their metabolites R,R,R-DHTBZ and NBI-136110 confirmed the selectivity of these compounds for VMAT2, as they did not significantly affect monoamine uptake via VMAT1 compared to reserpine (a known VMAT1 / VMAT2 inhibitor).

[0272] The selectivity and specificity of VBZ were distinguished using two in vivo surrogate measures of pharmacological effect. Ptosis (known to occur via adrenergic activation and prolactin release from the pituitary gland, regulated via the D2 dopamine receptor) showed differences between treatment with TBZ and VBZ. TBZ, VBZ, and R,R,R-DHTBZ all induced ptosis in the same manner. This confirms that the administration of metabolites formed by administering TBZ or VBZ, or their active metabolites themselves (R,R,R-DHTBZ), all have activity related to norepinephrine release in VMAT2, which affects presynaptic monoamine release, and in this case specifically to induce ptosis. Following similar treatments (but this time using prolactin release as an alternative for dopaminergic modulation), R,R,R-DHTBZ and VBZ (to a lower degree) induced increases in serum prolactin levels similar to those of TBZ.

[0273] The various embodiments described above may be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and / or listed in the application data sheet are incorporated herein by reference in their entirety. Aspects of the embodiments may be modified if it is necessary to use concepts from various patents, applications, and publications to provide further embodiments.

[0274] These and other modifications may be made to the embodiments in light of the detailed description above. In general, the language used in the following claims should not be construed as limiting the claims to the specific embodiments disclosed herein and therein, but rather as encompassing all possible embodiments, along with the entire scope of equivalents to which such claims are granted. Thus, the claims are not limited by the disclosure. The present invention provides, for example, the following items. (Item 1) A method for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method is A step of administering an amount of the VMAT2 inhibitor equivalent to approximately 40 mg of free valvenazine base to the patient having moderate or severe hepatic impairment once daily. A method that includes (Item 2) A method for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method is A step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient having moderate or severe hepatic impairment. A method comprising, wherein the therapeutically effective dose of the VMAT2 inhibitor is less than the dose administered to a patient without moderate or severe hepatic impairment. (Item 3) A method for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method being: A step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient. The process of later determining that the patient has moderate or severe liver impairment, A step of administering to the patient once a day an amount of the VMAT2 inhibitor equivalent to approximately 40 mg of free valvenazine base, A method that includes (Item 4) A method for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method being: A step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, A step of later determining that the patient has moderate or severe liver impairment, The process of administering the VMAT2 inhibitor in a smaller dose than that administered to patients without moderate or severe hepatic impairment, A method that includes (Item 5) A method for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method is A step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient having moderate or severe hepatic impairment. This includes, where the said administration is the average valbenazine C in patients without moderate or severe hepatic impairment. max Approximately 2 to 3 times higher average valvenazine C max A method of producing something. (Item 6) A method for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient has moderate or severe hepatic impairment, and the method is A step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient having moderate or severe hepatic impairment. This includes, where the dose is the mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC in patients without moderate or severe hepatic impairment. 0-∞ (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC is approximately 3 to 4 times higher than the average (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC 0-∞ A method of producing something. (Item 7) The patient has moderate hepatic impairment, as described in any one of items 1 to 6. (Item 8) The patient has severe liver impairment, as described in any one of items 1 to 6. (Item 9) The method according to any one of items 1 to 8, further comprising the step of informing the patient or healthcare worker that administration of the VMAT2 inhibitor to a patient with moderate to severe hepatic impairment results in a higher exposure to valbenazine and / or (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol than administration of the VMAT2 inhibitor to a patient with normal hepatic function. (Item 10) The method according to any one of items 1 to 9, further comprising the step of informing the patient or healthcare worker that administration of the VMAT2 inhibitor to a patient with moderate to severe hepatic impairment may result in an increased risk of 1 or more exposure-related adverse reactions compared to administration of the VMAT2 inhibitor to a patient with normal hepatic function. (Item 11) The method according to item 10, wherein the above 1 or more exposure-related adverse reactions are selected from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, QT prolongation, elevated blood glucose, weight gain, respiratory infection, salivation, dyskinesia, extrapyramidal symptoms (non-akathisia), anxiety, insomnia, elevated prolactin, elevated alkaline phosphatase, and elevated bilirubin. (Item 12) The method according to item 11, wherein the exposure-related adverse reactions described in item 1 or more are selected from somnolence, anticholinergic effects, balance disturbance or falls, headache, akathisia, vomiting, nausea, arthralgia, and QT prolongation. (Item 13) The method described in item 12, wherein the above 1 or more exposure-related adverse reactions are selected from somnolence and QT prolongation. (Item 14) The method according to any one of items 1 to 13, further comprising the step of informing the patient or healthcare professional that administration of the VMAT2 inhibitor to a patient with moderate to severe hepatic impairment may prolong the patient's QT interval more than administration of the VMAT2 inhibitor to a patient with normal hepatic function. (Item 15) A method for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient requiring such inhibitor, wherein the patient has mild hepatic impairment, and the method is as follows: A step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient having mild hepatic impairment. A method that includes (Item 16) A method for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method being: A step of administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, The process of later determining that the patient has mild hepatic impairment, and The process of continuing to administer the therapeutically effective amount of the VMAT2 inhibitor to the patient, A method that includes (Item 17) The method according to any one of items 1 to 16, wherein the VMAT2 inhibitor is administered to the patient to treat a neurological or psychiatric disorder or condition. (Item 18) The neurological or psychiatric disorder or disorder is hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, manic episodes in mood disorders, depressive episodes in mood disorders, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea with acanthocyanosis, as described in item 17. (Item 19) The neurological or psychiatric disorder or disorder is hyperkinetic movement disorder, as described in item 18. (Item 20) The hyperkinetic movement disorder is tardive dyskinesia, as described in item 19. (Item 21) The hyperkinetic movement disorder is Tourette's syndrome, as described in item 19. (Item 22) The aforementioned hyperkinetic movement disorder is Huntington's disease, as described in item 19. (Item 23) The hyperkinetic movement disorder is a tic, as described in item 19. (Item 24) The hyperkinetic disorder is chorea associated with Huntington's disease, as described in item 19. (Item 25) The hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless limb syndrome, or tremor, as described in item 19. (Item 26) The VMAT2 inhibitor is administered orally according to the method described in any one of items 1 to 25. (Item 27) The VMAT2 inhibitor is administered in the form of a tablet or capsule, according to any one of items 1 to 26. (Item 28) The VMAT2 inhibitor is administered with or without food, according to any one of items 1 to 27. (Item 29) The method according to any one of items 1 to 28, wherein the VMAT2 inhibitor is a pharmaceutically acceptable salt and / or isotopic variant thereof. (Item 30) The method according to item 29, wherein the VMAT2 inhibitor is barbenazine or a pharmaceutically acceptable salt thereof. (Item 31) The method according to item 30, wherein the VMAT2 inhibitor is valbenazine tosylate. (Item 32) The method according to item 31, wherein the VMAT2 inhibitor is valbenazine nitrate. (Item 33) The method according to item 29, wherein the VMAT2 inhibitor is an isotopic variant of L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinoridine-2-yl ester or a pharmaceutically acceptable salt thereof. (Item 34) The method according to any one of items 1 to 33, wherein the VMAT2 inhibitor is administered in an amount equivalent to free valvebenazine base between approximately 20 mg and approximately 160 mg. (Item 35) The method according to item 34, wherein the VMAT2 inhibitor is administered in an amount equivalent to approximately 20 mg of free valvenazine base. (Item 36) The method according to item 34, wherein the VMAT2 inhibitor is administered in an amount equivalent to approximately 40 mg of free valvenazine base. (Item 37) The method according to item 34, wherein the VMAT2 inhibitor is administered in an amount equivalent to approximately 60 mg of free valvenazine base. (Item 38) The method according to item 34, wherein the VMAT2 inhibitor is administered in an amount equivalent to approximately 80 mg of free valvenazine base. (Item 39) The method according to item 34, wherein the VMAT2 inhibitor is administered in an amount equivalent to approximately 120 mg of free valvenazine base. (Item 40) The method according to any one of items 1 to 33, wherein the VMAT2 inhibitor is administered in a first amount over a first period, and then the amount is increased to a second amount. (Item 41) The first period is one week, as described in item 38. (Item 42) The first amount is equivalent to approximately 40 mg of free valvenazine base, as described in item 38 or 39. (Item 43) The method according to any one of items 38-40, wherein the second amount is equivalent to approximately 80 mg of free valvenazine base. (Item 44) The VMAT2 inhibitor reaches a maximum plasma concentration of (+)-α-DHTBZ between approximately 15 ng and 60 ng per 1 mL of plasma (C max ) and the minimum plasma concentration (C) of at least 15 ng of (+)-α-DHTBZ per 1 mL of plasma over a period of 8 hours. min The method described in any one of items 1 to 33, administered in an amount sufficient to achieve ) (Item 45) The VMAT2 inhibitor reaches a maximum plasma concentration of (+)-α-DHTBZ between approximately 15 ng and 60 ng per 1 mL of plasma (C max ) and over a period of approximately 12 hours, C max Minimum plasma concentration (C) between at least approximately 33% and 50% min The method described in any one of items 1 to 33, administered in an amount sufficient to achieve ) (Item 46) The VMAT2 inhibitor is administered in an amount sufficient to achieve (i) a therapeutic concentration range of (+)-α-DHTBZ of about 15 ng to about 60 ng per mL of plasma; and (ii) a threshold concentration of at least 15 ng per mL of plasma over a period of about 8 hours to about 24 hours, as described in any one of items 1 to 33. (Item 47) The method according to any one of items 1 to 33, wherein the therapeutically effective dose of the VMAT2 inhibitor is 10 to 90 percent less than the dose administered to patients without moderate or severe hepatic impairment. (Item 48) The method according to any one of items 1 to 33, wherein the therapeutically effective dose of the VMAT2 inhibitor is 20 to 80% less than the dose administered to patients without moderate or severe hepatic impairment. (Item 49) The method according to any one of items 1 to 33, wherein the therapeutically effective dose of the VMAT2 inhibitor is 30 to 70 percent less than the dose administered to patients without moderate or severe hepatic impairment. (Item 50) The method according to any one of items 1 to 33, wherein the therapeutically effective dose of the VMAT2 inhibitor is 40-60% less than the dose administered to patients without moderate or severe hepatic impairment. (Item 51) The therapeutically effective dose of the VMAT2 inhibitor is approximately 50% less than the dose administered to patients without moderate or severe hepatic impairment, as described in any one of items 1 to 33. (Item 52) The method according to any one of items 1 to 28, wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof. (Item 53) The method according to item 52, wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol or a pharmaceutically acceptable salt thereof. (Item 54) The method according to item 52, wherein the VMAT2 inhibitor is an isotopic variant which is (+)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol or a pharmaceutically acceptable salt thereof. (Item 55) A composition for treating patients with moderate or severe hepatic impairment who require a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises the VMAT2 inhibitor, and the composition is characterized in that the composition is administered once daily to the patient with moderate or severe hepatic impairment in an amount equivalent to about 40 mg of free valbenazine base of the VMAT2 inhibitor. (Item 56) A composition for treating patients with moderate or severe hepatic impairment who require a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises a therapeutically effective amount of the VMAT2 inhibitor. The composition wherein the therapeutically effective amount of the VMAT2 inhibitor is less than the amount administered to a patient without moderate or severe hepatic impairment. (Item 57) A composition for treating patients requiring a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises the VMAT2 inhibitor, The composition comprising an amount of the VMAT2 inhibitor equivalent to approximately 40 mg of free valbenazine base is characterized in that it is administered once daily to the patient who is later determined to have moderate or severe hepatic impairment after administration of the composition comprising a therapeutically effective amount of the VMAT2 inhibitor. (Item 58) A composition for treating patients requiring a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises the VMAT2 inhibitor, The composition is characterized in that it contains less of the VMAT2 inhibitor than would be administered to a patient without moderate or severe hepatic impairment, and is administered to the patient who is later determined to have moderate or severe hepatic impairment after administration of the composition containing a therapeutically effective amount of the VMAT2 inhibitor. (Item 59) A composition for treating patients with moderate or severe hepatic impairment who require a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises a therapeutically effective amount of the VMAT2 inhibitor. Here, the administration of the composition is measured in patients without moderate or severe hepatic impairment, and the average valbenazine C max Approximately 2 to 3 times higher average valvenazine C max A composition that produces [a certain result]. (Item 60) A composition for treating patients with moderate or severe hepatic impairment who require a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises a therapeutically effective amount of the VMAT2 inhibitor. Here, the administration of the composition is measured in patients without moderate or severe hepatic impairment. (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC 0-∞ (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC is approximately 3 to 4 times higher than the average (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol AUC 0-∞ A composition that produces [a certain result]. (Item 61) The patient has moderate hepatic impairment, and the composition according to any one of items 55 to 61. (Item 62) The patient has severe hepatic impairment, and the composition is as described in any one of items 55 to 61. (Item 63) The composition according to any one of items 55 to 62, wherein the patient or healthcare worker is informed that administration of the composition to a patient with moderate to severe hepatic impairment results in a higher exposure to valbenazine and / or (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol than administration of the composition to a patient with normal hepatic function. (Item 64) The composition according to any one of items 55 to 63, wherein the patient or healthcare worker is informed that administration of the composition to a patient with moderate to severe hepatic impairment may result in an increased risk of one or more exposure-related adverse reactions compared to administration of the composition to a patient with normal hepatic function. (Item 65) The composition according to item 64, wherein the one or more exposure-related adverse reactions described above are selected from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, QT prolongation, elevated blood glucose, weight gain, respiratory infection, salivation, dyskinesia, extrapyramidal symptoms (non-akathisia), anxiety, insomnia, elevated prolactin, elevated alkaline phosphatase, and elevated bilirubin. (Item 66) The composition according to item 65, wherein the one or more exposure-related adverse reactions are selected from somnolence, anticholinergic effects, balance disturbance or falls, headache, akathisia, vomiting, nausea, arthralgia, and QT prolongation. (Item 67) The composition according to item 66, wherein the one or more exposure-related adverse reactions are selected from somnolence and QT prolongation. (Item 68) The composition according to any one of items 55 to 67, wherein the patient or healthcare professional is informed that administration of the composition to a patient with moderate to severe hepatic impairment may prolong the patient's QT interval more than administration of the composition to a patient with normal hepatic function. (Item 69) A composition for treating patients with mild hepatic impairment who require a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises a therapeutically effective amount of the VMAT2 inhibitor. (Item 70) A composition for treating patients requiring a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises the VMAT2 inhibitor, The composition comprising a therapeutically effective amount of the VMAT2 inhibitor is characterized in that it is administered to the patient who is later determined to have mild hepatic impairment after administration of the composition comprising the therapeutically effective amount of the VMAT2 inhibitor. (Item 71) The composition described above is for treating neurological or psychiatric disorders or disorders, as described in any one of items 55 to 70. (Item 72) The composition according to item 71, wherein the neurological or psychiatric disorder or disorder is hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, manic episodes in mood disorders, depressive episodes in mood disorders, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea with acanthocyanosis. (Item 73) The composition according to item 72, wherein the neurological or psychiatric disorder or disorder is hyperkinetic movement disorder. (Item 74) The composition according to item 73, wherein the hyperkinetic movement disorder is tardive dyskinesia. (Item 75) The composition described in item 73, wherein the hyperkinetic movement disorder is Tourette syndrome. (Item 76) The composition described in item 73, wherein the hyperkinetic disorder is Huntington's disease. (Item 77) The composition according to item 73, wherein the hyperkinetic movement disorder is a tic. (Item 78) The composition according to item 73, wherein the hyperkinetic disorder is chorea associated with Huntington's disease. (Item 79) The composition according to item 73, wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless limb syndrome, or tremor. (Item 80) The composition described above is characterized in that it is administered orally, as described in any one of items 55 to 79. (Item 81) The composition according to any one of items 55 to 80, characterized in that it is administered in the form of a tablet or a capsule. (Item 82) The composition described in any one of items 55 to 81 is characterized in that it is administered with or without food. (Item 83) The composition according to any one of items 55 to 82, wherein the VMAT2 inhibitor is a pharmaceutically acceptable salt and / or isotopic variant thereof. (Item 84) The composition according to item 83, wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt thereof. (Item 85) The composition according to item 84, wherein the VMAT2 inhibitor is valbenazine tosylate. (Item 86) The composition according to item 85, wherein the VMAT2 inhibitor is a nitrate of valbenazine. (Item 87) The composition according to any one of items 55 to 86, characterized in that it is administered in an amount equivalent to about 20 mg to about 120 mg of free valvebenazine base of the VMAT2 inhibitor. (Item 88) The composition according to item 87, characterized in that it is administered in an amount equivalent to about 20 mg of free valvenazine base of the VMAT2 inhibitor. (Item 89) The composition according to item 87, characterized in that it is administered in an amount equivalent to about 40 mg of free valvenazine base of the VMAT2 inhibitor. (Item 90) The composition according to item 87, characterized in that it is administered in an amount equivalent to about 60 mg of free valvenazine base of the VMAT2 inhibitor. (Item 91) The composition according to item 87, characterized in that it is administered in an amount equivalent to about 80 mg of free valvebenazine base of the VMAT2 inhibitor. (Item 92) The composition according to item 87, characterized in that it is administered in an amount equivalent to about 120 mg of free valvenazine base of the VMAT2 inhibitor. (Item 93) The composition according to any one of items 55 to 86, characterized in that the composition is administered in a first amount of the VMAT2 inhibitor over a first period, and then the amount is increased to a second amount. (Item 94) The composition according to item 93, wherein the first period is one week. (Item 95) The composition according to item 93 or 94, wherein the first amount is equivalent to about 40 mg of free valvenazine base. (Item 96) The composition according to any one of items 93 to 95, wherein the second amount is equivalent to approximately 80 mg of free valvenazine base. (Item 97) The composition has a maximum plasma concentration (C) of (+)-α-DHTBZ between approximately 15 ng and approximately 60 ng per 1 mL of plasma. max ) and the minimum plasma concentration (C) of at least 15 ng of (+)-α-DHTBZ per 1 mL of plasma over a period of 8 hours.min A composition according to any one of items 55 to 86, characterized in that it is administered in an amount sufficient to achieve ). (Item 98) The composition has a maximum plasma concentration (C) of (+)-α-DHTBZ between approximately 15 ng and approximately 60 ng per 1 mL of plasma. max ) and over a period of approximately 12 hours, C max Minimum plasma concentration (C) between at least approximately 33% and 50% min A composition according to any one of items 55 to 86, characterized in that it is administered in an amount sufficient to achieve (item 99). The composition described in any one of items 55 to 86 is characterized in that it is administered in an amount sufficient to achieve (i) a therapeutic concentration range of (+)-α-DHTBZ of about 15 ng to about 60 ng per mL of plasma; and (ii) a threshold concentration of at least 15 ng per mL of plasma over a period of about 8 hours to about 24 hours. (Item 100) The composition according to any one of items 55 to 86, characterized in that the therapeutically effective amount of the VMAT2 inhibitor is 10 to 90 percent less than the amount administered to a patient without moderate or severe hepatic impairment. (Item 101) The composition according to any one of items 55 to 86, characterized in that the therapeutically effective amount of the VMAT2 inhibitor is 20 to 80 percent less than the amount administered to a patient without moderate or severe hepatic impairment. (Item 102) The composition according to any one of items 55 to 86, characterized in that the therapeutically effective amount of the VMAT2 inhibitor is 30 to 70 percent less than the amount administered to a patient without moderate or severe hepatic impairment. (Item 103) The composition according to any one of items 55 to 86, characterized in that the therapeutically effective amount of the VMAT2 inhibitor is 40 to 60 percent less than the amount administered to a patient without moderate or severe hepatic impairment. (Item 104) The composition according to any one of items 55 to 86, characterized in that the therapeutically effective amount of the VMAT2 inhibitor is about 50% less than the amount administered to a patient without moderate or severe hepatic impairment. (Item 105) The composition according to item 83, wherein the VMAT2 inhibitor is an isotopic variant of L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinoridine-2-yl ester or a pharmaceutically acceptable salt thereof. (Item 106) The composition according to any one of items 55 to 82, wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof. (Item 107) The composition according to item 106, wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol, or a pharmaceutically acceptable salt thereof. (Item 108) The composition according to item 106, wherein the VMAT2 inhibitor is an isotopic variant which is (+)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol or a pharmaceutically acceptable salt thereof.

Claims

1. A composition for treating patients with neurological or psychiatric disorders or conditions, comprising (S)-2-amino-3-methyl-butyrate (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-yl ester and a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from pharmaceutically acceptable salts thereof, The aforementioned patient has severe liver dysfunction, The aforementioned composition is administered orally to the patient, A composition wherein the therapeutically effective amount is equivalent to approximately 20 mg of (S)-2-amino-3-methyl-butyrate (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-yl ester, measured by its free base, once daily.

2. The composition according to claim 1, wherein the composition is administered in the form of a tablet or a capsule.

3. The composition according to claim 1 or 2, wherein the VMAT2 inhibitor is a salt of (S)-2-amino-3-methyl-butyrate (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-yl ester.

4. The composition according to any one of claims 1 to 3, wherein the VMAT2 inhibitor is a ditosylate of (S)-2-amino-3-methyl-butyrate (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-yl ester.

5. The composition according to any one of claims 1 to 4, wherein the patient has a Child-Pugh score of 10 to 15.

6. The composition according to any one of claims 1 to 4, wherein the patient has a higher exposure to (S)-2-amino-3-methylbutyrate (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-yl ester and its metabolite (+)-α-HTBZ compared to the exposure in a patient with normal liver function who has been administered the same amount of the VMAT2 inhibitor.

7. The aforementioned exposure, C ｍａｘ or AUC ０－∞ The composition according to claim 6, measured by [method].

8. The composition according to any one of claims 1 to 7, wherein the neurological or psychiatric disorder or disorder is hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, manic episodes in mood disorders, depressive episodes in mood disorders, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea with acanthocyanosis.

9. The composition according to any one of claims 1 to 8, wherein the neurological or psychiatric disorder or disorder is hyperkinetic dyskinetics.

10. The composition according to claim 9, wherein the hyperkinetic movement disorder is tardive dyskinesia.

11. The composition according to claim 9, wherein the hyperkinetic movement disorder is Tourette syndrome.

12. The composition according to claim 9, wherein the hyperkinetic movement disorder is Huntington's disease.

13. The composition according to claim 9, wherein the hyperkinetic movement disorder is a tic.

14. The composition according to claim 9, wherein the hyperkinetic disorder is chorea associated with Huntington's disease.

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