Methods for administration of certain VMAT2 inhibitors

Abstract

To provide methods for administration of certain VMAT2 inhibitors.SOLUTION: Provided are methods 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]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, where digoxin is also being administered to the subject.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 diseases and disorders, such as hyperkinetic movement disorders, as well as conditions such as schizophrenia and mood disorders. The transporter protein, vesicular monoamine transporter-2 (VMAT2), plays a key role in presynaptic dopamine release, regulating the uptake of monoamines from the cytoplasm into synaptic vesicles for storage and release.

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

[0003] A formulation of valbenazine:4-toluenesulfonate (1:2) (referred to herein as "valbenazine ditosylate") is available under the FDA-approved drug designation Ingrezza. (登録商標) has been previously reported in

[0004] There is a significant unmet need for methods for 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]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof) to a patient in need thereof, where the patient is also being treated with another substance (e.g., digoxin) that may interact with the VMAT2 inhibitor. The present disclosure fulfills these and other needs, as will become apparent with reference to the disclosure below. Summary of the Invention [Means for solving the problem]

[0005] A brief summary 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]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient is also receiving digoxin, and the method comprises administering a therapeutically effective amount of the VMAT2 inhibitor to the patient.

[0006] Also provided is 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]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method comprising administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, subsequently determining that the patient should begin treatment with digoxin, and continuing to administer a therapeutically effective amount of the VMAT2 inhibitor to the patient.

[0007] Also provided is a method of 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient is also receiving digoxin, the method comprising administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, wherein the administration is in the range of 0.05 to 0.15, and more preferably 0.15 to 0.25, and more preferably 0.25 to 0.35, and more preferably 0.35 to 0.45, and more preferably 0.45 to 0.55, and more preferably 0.55 to 0.65, and more preferably 0.65 to 0.75. max Average digoxin C levels approximately 1.5 to 2.5 times higher than max and / or mean digoxin AUC in patients receiving digoxin alone 0-∞ Mean digoxin AUC is approximately 1 to 2 times higher than 0-∞ This results in:

[0008] These and other aspects of the present invention will become apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds, and / or compositions, each of which is incorporated herein by reference in its entirety. DETAILED DESCRIPTION OF THE INVENTION

[0009] Detailed Description In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context otherwise requires, throughout this specification and the claims that follow, the word "comprise" and variations thereof (e.g., "comprises" and "comprising") should be interpreted in an open-system, inclusive sense, i.e., "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0010] Throughout this specification, the terms "one embodiment" or "an embodiment" or "some embodiments" may be used. Reference to "one embodiment" or "a certain embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in one embodiment" or "in some embodiments" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0011] Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0012] As used herein, "valbenazine" may refer to (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1a]isoquinolin-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]quinolizin-2-yl ester or NBI-98854.

[0013] As used herein, "(+)-α-HTBZ" refers to a compound having the structure: [ka] (+)-α-HTBZ refers to a compound that is an active metabolite of valbenazine having the formula: (+)-α-HTBZ may also be referred to as (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]isoquinolin-2-ol; or (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or NBI-98782.

[0014] As used herein, "NBI-136110" refers to a compound having the structure: [ka] means a compound which is a metabolite of valbenazine having the formula:

[0015] As used herein, "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of 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 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( 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( 131I). In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., is non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes (hydrogen ( 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 In certain embodiments, an "isotopic variant" of a compound is one that contains unnatural proportions of one or more isotopes, including but not limited to tritium ( 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), and oxygen-15( 15 In the compounds as provided herein, any hydrogen may be, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 59, 6 2 H or any carbon, e.g. 13 C or any nitrogen, e.g. 15 N, and any oxygen, e.g. 18 It is understood that the isotopic ratio can be O. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of deuterium.

[0016] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" or "d," it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor at each designated deuterium position of, in certain embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). 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.

[0017] As used herein, "hyperkinetic disorder" or "hyperkinetic movement disorder" or "hyperkinesia" refers to a disorder or disease characterized by excessive, abnormal, involuntary movements. These neurological disorders include tremor, dystonia, myoclonus, athetosis, Huntington's disease, tardive dyskinesia, Tourette's syndrome, dystonia, hemiballismus, chorea, geriatric chorea, or tics.

[0018] 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.

[0019] 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.

[0020] As used herein, "AUC" refers to the area under the curve, or integral, of the plasma concentration of an active pharmaceutical ingredient or metabolite over time following a dosing event.

[0021] As used herein, "AUC 0-t " is the integral under the plasma concentration curve from time 0 (dosing) to time "t".

[0022] As used herein, "AUC 0-∞ " is the AUC from time 0 (dosing) to time infinity. Unless otherwise stated, AUC is the AUC 0-∞ Often drugs are packaged in a salt form (e.g., valbenazine ditosylate), and the dosage form strength refers to the mass of this salt form or the equivalent mass of its corresponding free base, valbenazine.

[0023] As used herein, C max is a pharmacokinetic parameter that indicates the maximum plasma concentration observed after delivery of the active pharmaceutical ingredient. max is the time of maximum plasma concentration, t max occurs in.

[0024] As used herein, "co-administer" and "co-administration" and variations thereof mean administering at least two drugs to a patient either subsequently, simultaneously, or so close in time to each other (e.g., within the same day, or within a one-week or 30-day period, or close enough in time that each of the at least two drugs can be detected simultaneously in plasma). When co-administered, two or more active agents are co-formulated as part of the same composition or administered as separate formulations, which may also be referred to herein as "concomitant" administration or variations thereof.

[0025] As used herein, "adjusting administration," "altering administration," "adjusting dosing," or "altering dosing" are all equivalent and mean tapering off, decreasing, or increasing the dose of the substance, discontinuing administration of the substance to the patient, or substituting a different active agent for the substance.

[0026] As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form to the patient via any art-recognized means of introduction.

[0027] As used herein, the term "disorder" is generally intended to be synonymous and is all used interchangeably with the terms "disease," "syndrome," and "condition" (as in medical condition), in that it reflects an abnormal state of the human or animal body or one of its parts that impairs normal function and typically manifests with distinguishable signs and symptoms.

[0028] As used herein, "dose" refers to a measured amount of an active agent taken by a patient at one time. In certain embodiments where the active agent is not valbenazine free base, the amount is the molar equivalent of the equivalent amount of valbenazine free base. For example, drugs are often packaged in a pharmaceutically acceptable salt form (e.g., valbenazine ditosylate), and the dosage amount in terms of strength refers to the mass of the corresponding molar equivalent of valbenazine free base. As an example, 73 mg of valbenazine tosylate is the molar equivalent of 40 mg of valbenazine free base.

[0029] As used herein, "dosing regimen" means the initial dose of an active agent taken by a patient and the interval (time or duration) between the patient's ingestion of any subsequent doses of the active agent (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). The subsequent doses of the active agent may be different from the initial dose.

[0030] As used herein, an "effective amount" and a "therapeutically effective amount" of an agent, compound, drug, composition, or combination is an amount that, upon administration to a subject or patient (e.g., a human subject or patient), is nontoxic and effective to produce some desired therapeutic effect. The precise therapeutically effective amount for a subject may depend, for example, on the subject's size and health, the nature and extent of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0031] As used herein, "informing" means referring to or providing published material, e.g., providing an active pharmaceutical agent to a user along with published material; or presenting information orally, e.g., by presentation at a seminar, conference, or other educational presentation, by conversation between a medical representative and a healthcare professional, or by conversation between a healthcare professional and a patient; or presenting information intended for a user for purposes of understanding.

[0032] As used herein, "labeling" means any label or other means of written, printed, graphic, electronic, verbal, or illustrative communication that is on or accompanies a pharmaceutical product or dosage form.

[0033] As used herein, "medical care worker" means a worker in the medical field who may need or have access to information about an active pharmaceutical agent, including its dosage forms, including information about safety, efficacy, dosing, 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.

[0034] As used herein, "Medication Guide" means the FDA-approved patient labeling for a pharmaceutical product that conforms to the specifications set forth in 21 CFR 208 and other applicable regulations and contains information about how patients can safely use the pharmaceutical product. Medication Guides are scientifically accurate and are based on and consistent with the approved professional labeling for that pharmaceutical product under 21 CFR 201.57, although their wording need not be identical to the section of the approved labeling to which they correspond. Medication Guides are typically available for pharmaceutical products that come with special risk management information.

[0035] As used herein, "patient" or "individual" or "subject" means a mammal for whom treatment is desired, including a human for whom treatment is desired, and generally refers to the recipient of that treatment.

[0036] As used herein, "patient package insert" means information about how patients can safely use a pharmaceutical product that is part of the FDA-approved labeling. It is an extension of a pharmaceutical product's technical labeling that provides consumer-oriented information about the product in layman's terms that may be distributed to patients when the product is dispensed; for example, it may describe benefits, risks, how to recognize risks, dosage, or administration.

[0037] 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 undesired biological effects or interacting 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 implies that the carrier or excipient has met the required standards of toxicology and manufacturing testing or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. As in "pharmacologically active" (or "active") derivative or analog, "pharmacologically active" (or simply "active") refers to a derivative or analog that has the same type of pharmacological activity as the parent compound, and to approximately the same extent. The term "pharmaceutically acceptable salts" includes acid addition salts formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, etc. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine, and the like.

[0038] As used herein, "product" or "pharmaceutical product" means an active agent dosage form and any published materials and packaging, if required.

[0039] As used herein, "product insert" means the pharmaceutical product's technical labeling (prescription information), the pharmaceutical product's patient package insert, or the pharmaceutical product's medication guide.

[0040] As used herein, "professional labeling" or "prescribing information" means the official description of a pharmaceutical product approved by a regulatory agency (e.g., the FDA or EMEA) that regulates the marketing of that pharmaceutical product, which includes a summary of the essential scientific information needed for the safe and effective use of the drug (e.g., indications and uses; dosage and administration; who should take the drug; adverse events (side effects); instructions for use in special populations (pregnant women, children, geriatrics, etc.); patient safety information, etc.).

[0041] As used herein, "published material" means a medium that provides information, including print, audio, visual, or electronic media (e.g., 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 recorded or electronic media).

[0042] As used herein, "risk" means the probability or likelihood of an adverse reaction, injury, or other undesirable outcome resulting from a medical procedure. "Acceptable risk" means the measure of risk of harm, injury, or illness resulting from a medical procedure that is deemed acceptable by an individual or group. Whether a risk is "acceptable" depends on the benefits that the individual or group perceives to be obtainable in exchange for taking the risk, what scientific or other advice is provided about the magnitude of the risk they are willing to accept, and many other factors (both political and societal). An "acceptable risk" of an adverse reaction means that the adverse reaction has a low probability of occurrence or its consequences are so minor, or the benefits (perceived or real) of the active agent are so great that an individual or group in society is willing to take or submit to the risk that an adverse reaction may occur. An "unacceptable risk" of an adverse reaction means that an individual or group in society is not willing to take or submit to the risk that the adverse reaction may occur when weighing the probability of the adverse reaction occurring, the consequences of the adverse reaction, and the benefits (perceived or real) of the active agent. "At risk" means a state or condition represented by a high level of risk or susceptibility. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.

[0043] As used herein, "safety" refers to the incidence or severity of adverse events associated with the administration of an active agent, including adverse effects associated with patient-related factors (e.g., age, sex, ethnicity, race, target disease, abnormalities in renal or hepatic function, coexisting diseases, genetic characteristics (e.g., metabolic status), or environment), and active agent-related factors (e.g., dose, plasma levels, duration of exposure, or concomitant medications).

[0044] As used herein, "t max" is a pharmacokinetic parameter that defines the time to maximum plasma concentration after delivery of an active pharmaceutical ingredient.

[0045] As used herein, "t 1 / 2 " or "plasma half-life" or "elimination half-life" etc. is a pharmacokinetic parameter that defines the apparent plasma terminal phase half-life, i.e., the time it takes for the plasma concentration to decrease by half after absorption and distribution of the drug are complete.

[0046] As used herein, "treating" or "treatment" refers to therapeutic applications that slow or halt the progression of a disorder, prophylactic applications that prevent the onset of a disorder, and / or the reversal of a disorder. Reversal of a disorder differs from therapeutic applications that slow or halt a disorder in that the reversal method not only halts the progression of the disorder entirely, but also moves cellular behavior to some degree toward the normal state observed in the absence of the disorder.

[0047] As used herein, "VMAT2" refers to human vesicular monoamine transporter isoform 2, an integral membrane protein that acts to transport monoamines, particularly neurotransmitters (e.g., dopamine, norepinephrine, serotonin, and histamine), from the cytoplasm of cells to synaptic vesicles.

[0048] As used herein, the terms "VMAT2 inhibitor," "inhibiting VMAT2," or "inhibition of 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 a reversible or irreversible covalent bond between the inhibitor and VMAT2, or through the formation of a non-covalent complex. Such inhibition may only occur in certain cell types or may be dependent on specific biological events. The terms "VMAT2 inhibitor," "inhibiting VMAT2," or "inhibition of VMAT2" also refer to altering the function of VMAT2 by reducing the probability of complex formation between VMAT2 and a natural substrate.

[0049] A method of 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof is provided, wherein the patient is also receiving digoxin, and the method comprises administering to the patient a therapeutically effective amount of the VMAT2 inhibitor.

[0050] In certain embodiments, the method further comprises determining whether the patient is receiving digoxin, and monitoring the patient for signs and symptoms of digoxin toxicity and clinical response.

[0051] In certain embodiments, the method further comprises reducing the amount of digoxin administered to the patient based on the patient's ability to tolerate one or more adverse reactions associated with digoxin exposure.

[0052] Also provided is a method of 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, the method comprising: administering to the patient a therapeutically effective amount of a VMAT2 inhibitor, later determining that the patient should begin treatment with digoxin, and continuing to administer to the patient a therapeutically effective amount of a VMAT2 inhibitor; Includes.

[0053] In certain embodiments, the method further comprises monitoring the patient for signs and symptoms of digoxin toxicity and clinical response.

[0054] In certain embodiments, the method further comprises reducing the amount of digoxin administered to the patient based on the patient's ability to tolerate one or more adverse reactions associated with digoxin exposure.

[0055] Also provided is a method of 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient is also receiving digoxin, the method comprising administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, wherein the administration is in a range of 0.05 to 0.15 times the mean digoxin C of patients receiving digoxin alone. max Average digoxin C levels approximately 1.5 to 2.5 times higher than max and / or mean digoxin AUC in patients receiving digoxin alone 0-∞ Mean digoxin AUC is approximately 1 to 2 times higher than0-∞ This results in:

[0056] In certain embodiments, the method further comprises informing the patient or healthcare professional that co-administration of the VMAT2 inhibitor and digoxin may result in increased digoxin exposure.

[0057] In certain embodiments, the method further includes informing the patient or healthcare professional that co-administration of the VMAT2 inhibitor and digoxin may result in an increased risk of one or more adverse reactions associated with digoxin exposure.

[0058] In certain embodiments, monitoring for signs and symptoms of digoxin toxicity and clinical response includes monitoring the serum concentration of the digoxin.

[0059] In certain embodiments, monitoring for signs and symptoms of digoxin toxicity and clinical response includes determining whether the patient experiences one or more exposure-related adverse reactions associated with serum digoxin concentrations.

[0060] In certain embodiments, the adverse reaction associated with digoxin exposure is selected from cardiac arrhythmia and digoxin toxicity.

[0061] In certain embodiments, the adverse reaction associated with digoxin exposure is selected from nausea, vomiting, abdominal pain, intestinal ischemia, intestinal hemorrhagic necrosis, headache, weakness, dizziness, blunted affect, confusion, mental disturbance (e.g., anxiety, depression, delirium, and hallucinations), and gynecomastia.

[0062] In certain embodiments, digoxin toxicity is manifested by anorexia, nausea, vomiting, visual changes, and cardiac arrhythmias (first-, second- (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; atrioventricular dissociation; accelerated junctional (nodal) rhythm; monofocal or polymorphic ventricular premature beats (especially bigeminy or trigeminacy); ventricular tachycardia; and ventricular fibrillation). Toxicity is usually associated with digoxin levels greater than 2 ng / ml, although symptoms can occur at lower levels.

[0063] In certain embodiments, monitoring for signs and symptoms of digoxin toxicity and clinical response includes monitoring the effectiveness of the digoxin.

[0064] In certain embodiments, the method further comprises obtaining a baseline serum digoxin concentration prior to administering a therapeutically effective amount of a VMAT2 inhibitor to the patient.

[0065] In certain embodiments, the method further comprises obtaining a serum digoxin concentration after administering to the patient a therapeutically effective amount of a VMAT2 inhibitor.

[0066] In certain embodiments, the method further comprises comparing the baseline serum digoxin concentration with the serum digoxin concentration after administering a therapeutically effective amount of a VMAT2 inhibitor to the patient.

[0067] In certain embodiments, the dosage and / or frequency of administration of digoxin is reduced.

[0068] In certain embodiments, the dosage of digoxin is reduced.

[0069] In certain embodiments, the frequency of administration of digoxin is reduced.

[0070] In certain embodiments, the amount of digoxin administered is 10-90% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor.

[0071] In certain embodiments, the amount of digoxin administered is 20-80% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor.

[0072] In certain embodiments, the amount of digoxin administered is 30-70% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor.

[0073] In certain embodiments, the amount of digoxin administered is 40-60% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor.

[0074] In certain embodiments, the amount of digoxin administered is 50% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor.

[0075] In certain embodiments, the amount of digoxin administered to the patient is reduced, e.g., to 75% or less, 50% or less, or 25% or less of the amount administered to a patient who is not also receiving a VMAT2 inhibitor.

[0076] In certain embodiments, the VMAT2 inhibitor is administered to the patient to treat a neurological or psychiatric disease or disorder, such as hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, manic states in mood disorders, depressive states in mood disorders, refractory 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 choreoacanthocytosis.

[0077] In certain embodiments, the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder. In certain embodiments, the hyperkinetic movement disorder is tardive dyskinesia. In certain embodiments, the hyperkinetic movement disorder is Tourette's syndrome. In certain embodiments, the hyperkinetic movement disorder is Huntington's disease. In certain embodiments, the hyperkinetic movement disorder is tics. 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 legs syndrome, or tremor.

[0078] In certain embodiments, the VMAT2 inhibitor is administered orally.

[0079] In certain embodiments, the VMAT2 inhibitor is administered in tablet or capsule form.

[0080] In certain embodiments, the VMAT2 inhibitor is administered with or without food.

[0081] In some embodiments, the VMAT2 inhibitor is valbenazine or its pharmaceutically acceptable salt and / or isotopic variant.In some embodiments, the VMAT2 inhibitor is valbenazine or its pharmaceutically acceptable salt.In some embodiments, the VMAT2 inhibitor is valbenazine tosylate.In some embodiments, the VMAT2 inhibitor is valbenazine ditosylate.

[0082] In certain embodiments, 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]quinolizin-2-yl ester or a pharmaceutically acceptable salt thereof.

[0083] 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]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof.

[0084] 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]isoquinolin-2-ol dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.

[0085] In certain embodiments, the VMAT2 inhibitor is an isotopic variant of (+)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

[0086] In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 60 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 80 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 120 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 160 mg of valbenazine free base.

[0087] In some embodiments, the VMAT2 inhibitor is administered at a first amount for a first period of time, and then the amount is increased to a second amount. In some embodiments, the first period of time is one week. In some embodiments, the first amount is equivalent to about 40 mg of valbenazine free base. In some embodiments, the second amount is equivalent to about 80 mg of valbenazine free base.

[0088] In certain embodiments, the VMAT2 inhibitor induces a maximum plasma concentration (C) of between about 15 ng and about 60 ng of (+)-α-DHTBZ per mL of plasma. max ) and a minimum plasma concentration (C) of at least 15 ng of (+)-α-DHTBZ per mL of plasma over an 8-hour period min ) is administered in an amount sufficient to achieve

[0089] In certain embodiments, the VMAT2 inhibitor induces a maximum plasma concentration (C) of between about 15 ng and about 60 ng of (+)-α-DHTBZ per mL of plasma. max ) and approximately its C over a 12-hour period maxMinimum plasma concentration (C) between at least about 33% and 50% of min ) is administered in an amount sufficient to achieve

[0090] In certain embodiments, the VMAT2 inhibitor is administered in an amount sufficient to achieve: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (+)-α-DHTBZ per mL of plasma; and (ii) a threshold concentration of at least 15 ng of (+)-α-DHTBZ per mL of plasma over a period of about 8 hours to about 24 hours.

[0091] In certain embodiments, the C of R,R,R-DHTBZ max is about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, or about 60 ng / mL plasma. min is 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 plasma over a period of 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 28 hours, or 32 hours. In certain embodiments, the C of R,R,R-DHTBZ min is between about 15 ng / mL and about 35 ng / mL.

[0092] In certain embodiments, the pharmaceutical composition has a C of R,R,R-DHTBZ of about 15 ng / mL to about 60 ng / mL plasma. max and approximately that C over a 24-hour period max At least 33% of C min In certain embodiments, the pharmaceutical composition provides a C of R,R,R-DHTBZ of about 15 ng / mL to about 60 ng / mL plasma. max and approximately that C over a 24-hour period max At least 50% of C minIn certain embodiments, the pharmaceutical composition provides a C of R,R,R-DHTBZ of about 15 ng / mL to about 60 ng / mL plasma. max and approximately that C over a 24-hour period max At least about 33% to 50% of C min is administered in an amount sufficient to provide

[0093] In certain embodiments, the pharmaceutical composition has a C of R,R,R-DHTBZ of about 15 ng / mL to about 60 ng / mL plasma. max and approximately that C over a 12-hour period max At least 33% of C min In certain embodiments, the pharmaceutical composition provides a C of R,R,R-DHTBZ of about 15 ng / mL to about 60 ng / mL plasma. max and approximately that C over a 12-hour period max At least 50% of C min In certain embodiments, the pharmaceutical composition provides a C of R,R,R-DHTBZ of about 15 ng / mL to about 60 ng / mL plasma. max and approximately that C over a 12-hour period max At least about 33% to 50% of C min is administered in an amount sufficient to provide

[0094] In certain embodiments, the pharmaceutical composition provides to a subject about 15 ng / mL to about 60 ng / mL plasma C of R,R,R-DHTBZ. max and C between about 5 ng / mL and about 30 ng / mL plasma over a 24-hour period min In certain embodiments, the pharmaceutical composition provides a C of R,R,R-DHTBZ of about 15 ng / mL to about 60 ng / mL plasma. max and C between about 7.5 ng / mL and about 30 ng / mL plasma over a 24-hour period min The subject is administered an amount that provides

[0095] In certain embodiments, provided herein are methods for treating a neurological or psychiatric disease or disorder, the methods comprising administering to a subject a pharmaceutical composition comprising the VMAT2 inhibitor as an active pharmaceutical ingredient in an amount sufficient to provide (i) a therapeutic concentration range of about 15 ng to about 60 ng R,R,R-DHTBZ 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.

[0096] In certain embodiments, the therapeutic concentration range is from about 15 ng to about 35 ng, to about 40 ng, to about 45 ng, to about 50 ng, or to about 55 ng R,R,R-DHTBZ per mL of plasma.

[0097] In certain embodiments, the threshold concentration of R,R,R-DHTBZ is about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, or about 60 ng / mL plasma over a period of about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, or about 32 hours. In certain embodiments, the threshold concentration of R,R,R-DHTBZ is between about 15 ng / mL and about 35 ng / mL over a period of about 8 hours to about 24 hours.

[0098] Plasma concentrations may be measured by methods known in the art, and generally by tandem mass spectrometry.

[0099] Also provided is 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, for use in a method of treating neurological and psychiatric diseases and disorders in a patient in need thereof, wherein the patient is determined to have previously been administered digoxin, and the method comprises administering to the patient a therapeutically effective amount of the VMAT2 inhibitor.

[0100] Also provided is 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, for use in a method for treating neurological and psychiatric diseases and disorders in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the VMAT2 inhibitor, later determining whether the patient should begin treatment with digoxin, and continuing to administer the therapeutically effective amount of the VMAT2 inhibitor to the patient.

[0101] Also provided is 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, for use in a method for treating neurological and psychiatric diseases and disorders in a patient in need thereof, wherein the patient has been determined to have previously been administered digoxin, the method comprising administering to the patient a therapeutically effective amount of a VMAT2 inhibitor, subsequently selecting a patient who is unable to tolerate one or more adverse reactions associated with digoxin exposure, and administering a reduced amount of digoxin to the patient.

[0102] Also provided is 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, for use in a method for treating neurological and psychiatric diseases and disorders in a patient in need thereof, wherein the patient has been determined to have previously been administered digoxin, the method comprising administering to the patient a therapeutically effective amount of a VMAT2 inhibitor, subsequently selecting a patient who can tolerate one or more adverse reactions associated with digoxin exposure, and continuing to administer a therapeutically effective amount of digoxin to the patient.

[0103] Valbenazine can be prepared according to U.S. Patent Nos. 8,039,627 and 8,357,697 (the disclosures of each of which are incorporated herein by reference in their entirety). Tetrabenazine can be administered by a variety of methods, including the formulations disclosed in PCT Publications WO 2010 / 018408, WO 2011 / 019956, and WO 2014 / 047167 (the disclosures of each of which are incorporated herein by reference in their entirety). In certain embodiments, valbenazine for use in the compositions and methods provided herein is in polymorph I as disclosed in U.S. Patent Application No. 15 / 338,214 (the disclosures of which are incorporated herein by reference in their entirety).

[0104] Pharmaceutical Compositions Also provided is a composition for treating a patient in need of 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, or a pharmaceutically acceptable salt and / or isotopic variant, and who is currently receiving digoxin, the composition comprising a therapeutically effective amount of the VMAT2 inhibitor.

[0105] In certain embodiments, the patient is monitored for signs and symptoms of digoxin toxicity and clinical response.

[0106] In certain embodiments, a reduced amount of digoxin is administered to a patient based on the patient's ability to tolerate one or more adverse reactions associated with digoxin exposure after administration of a composition comprising a therapeutically effective amount of a VMAT2 inhibitor.

[0107] Also provided is a composition for treating a patient in need of 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, characterized in that the composition comprising a therapeutically effective amount of the VMAT2 inhibitor is administered to a patient who subsequently decides to begin treatment with digoxin after administration of the composition comprising a therapeutically effective amount of the VMAT2 inhibitor.

[0108] In certain embodiments, the patient is monitored for one or more exposure-related adverse events.

[0109] In certain embodiments, the reduced amount of the VMAT2 inhibitor is administered based on the patient's ability to tolerate one or more exposure-related adverse events after administration of a composition comprising a therapeutically effective amount of the VMAT2 inhibitor or a composition comprising a reduced amount of the VMAT2 inhibitor.

[0110] Also provided is a composition for treating a patient in need of 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, and who is currently receiving digoxin, the composition comprising a therapeutically effective amount of a VMAT2 inhibitor, wherein administration of the composition is effective to reduce or eliminate the mean digoxin C of a patient receiving digoxin alone. max Average digoxin C levels approximately 1.5 to 2.5 times higher than max and / or mean digoxin AUC in patients receiving digoxin alone 0-∞ Mean digoxin AUC is approximately 1 to 2 times higher than 0-∞ This results in:

[0111] In certain embodiments, the patient or healthcare professional is informed that co-administration of a VMAT2 composition and digoxin may result in increased digoxin exposure.

[0112] In certain embodiments, the patient or healthcare professional is informed that co-administration of the VMAT2 composition and digoxin may result in an increased risk of one or more adverse reactions associated with digoxin exposure.

[0113] In certain embodiments, the serum concentration of digoxin is monitored.

[0114] In certain embodiments, the dosage and / or frequency of administration of digoxin is reduced. In certain embodiments, the dosage of digoxin is reduced. In certain embodiments, the frequency of administration of digoxin is reduced.

[0115] In certain embodiments, the composition is for treating a neurological or psychiatric disease or disorder.

[0116] In certain embodiments, the composition is administered orally.

[0117] In certain embodiments, the composition is administered in tablet or capsule form.

[0118] In certain embodiments, the composition is administered with or without food.

[0119] In some embodiments, the VMAT2 inhibitor is valbenazine or its pharmaceutically acceptable salt and / or isotopic variant.In some embodiments, the VMAT2 inhibitor is valbenazine or its pharmaceutically acceptable salt.In some embodiments, the VMAT2 inhibitor is valbenazine tosylate.In some embodiments, the VMAT2 inhibitor is valbenazine ditosylate.

[0120] In certain embodiments, the isotopic variant is L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester or a pharmaceutically acceptable salt thereof.

[0121] 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]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof. 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]isoquinolin-2-ol dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.

[0122] In certain embodiments, the VMAT2 inhibitor is an isotopic variant of (+)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

[0123] In certain embodiments, the composition is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 20 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 40 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 60 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 80 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 120 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 160 mg of valbenazine free base.

[0124] In some embodiments, the composition is administered at a first amount for a first period, and then the amount of the VMAT2 inhibitor is increased to a second amount of the VMAT2 inhibitor.In some embodiments, the first period is one week.In some embodiments, the first amount is equivalent to about 40 mg of valbenazine free base.In some embodiments, the second amount is equivalent to about 80 mg of valbenazine free base.

[0125] In certain embodiments, the composition provides a maximum plasma concentration (C) of between about 15 ng and about 60 ng of (+)-α-DHTBZ per mL of plasma. max ) and a minimum plasma concentration (C) of at least 15 ng of (+)-α-DHTBZ per mL of plasma over an 8-hour period min ) is administered in an amount sufficient to achieve

[0126] In certain embodiments, the composition provides a maximum plasma concentration (C) of between about 15 ng and about 60 ng of (+)-α-DHTBZ per mL of plasma. max ) and approximately its C over a 12-hour period max Minimum plasma concentration (C) between at least about 33% and 50% of min ) is administered in an amount sufficient to achieve

[0127] In certain embodiments, the composition is administered in an amount sufficient to achieve: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (+)-α-DHTBZ per mL of plasma; and (ii) a threshold concentration of at least 15 ng of (+)-α-DHTBZ per mL of plasma over a period of about 8 hours to about 24 hours.

[0128] In certain embodiments, the amount of digoxin administered is 10-90% less than the amount administered to a patient who is not similarly receiving a VMAT2 inhibitor.

[0129] In certain embodiments, the amount of digoxin administered is 20-80% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor.

[0130] In certain embodiments, the amount of digoxin administered is 30-70% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor.

[0131] In certain embodiments, the amount of digoxin administered is 40-60% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor.

[0132] In certain embodiments, the amount of digoxin administered is 50% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor.

[0133] Also provided herein is a pharmaceutical composition for use in treating a neurological or psychiatric disease or disorder, which comprises the VMAT2 inhibitor as an active pharmaceutical ingredient in combination with one or more pharmaceutically acceptable carriers or excipients.

[0134] The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form.

[0135] The pharmaceutical compositions provided herein can be provided in unit-dosage form or multiple-dosage form. As used herein, unit-dosage form refers to a physically separate unit suitable for administration to human and animal subjects and individually packaged as known in the art. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier or excipient. Examples of unit-dosage forms include ampoules, syringes, and individually packaged tablets and capsules. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in separate unit-dosage forms. Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0136] The pharmaceutical compositions provided herein can 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 can be formulated in various dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. The pharmaceutical compositions provided herein can be administered once or multiple times at intervals. It is understood that the exact 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 testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the formulation.

[0137] Oral administration The pharmaceutical compositions provided herein can 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, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, liquids, emulsions, suspensions, solutions, 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.

[0138] Binders or granulators impart cohesion to tablets and ensure that the tablet remains intact after compression. Suitable binders or granulators include starches (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, alginates, Irish moss extract, Panwar gum, ghatti gum, mucilage of isabgol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan). Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions provided herein at from about 50% to about 99% by weight.

[0139] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Some diluents (such as mannitol, lactose, sorbitol, sucrose, and inositol) can give some compressed tablets the property of being able to disintegrate in the mouth by chewing when present in sufficient amount.Such compressed tablets can be used as chewable tablets.

[0140] 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; gums (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); polacrilin potassium; starches (e.g., corn starch, potato starch, tapioca starch, and pregelatinized starch); clays; algins; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible by one of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% by weight or from about 1 to about 5% by weight of disintegrant.

[0141] 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 (including 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 glidants include colloidal silicon dioxide, CAB-0-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Coloring agents include any of the approved, certified, water-soluble FD&C dyes, water-insoluble FD&C dyes suspended in aluminum hydroxide, and color lakes and mixtures thereof. Color lakes are combinations of water-soluble dyes adsorbed to hydrous oxides of heavy metals to produce an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants (e.g., fruits) and artificial blends of compounds that produce a pleasant taste (e.g., peppermint and methyl salicylate). Sweetening agents include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners (e.g., saccharin and aspartame).Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 10). 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0142] It should be understood that many carriers and excipients may serve 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, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. 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 compressed tablets are compressed tablets made by more than one compression cycle (including layered tablets), and press-coated or dry-coated tablets.

[0143] The tablet dosage form can be prepared from the active ingredient 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. Flavorings and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

[0144] The pharmaceutical compositions provided herein can be provided as soft and hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule (also known as dry-fill capsule (DFC)) consists of two sections, one over the other, thus completely enclosing the active ingredient. The soft gelatin capsule (SEC) is a soft, spherical shell (e.g., gelatin shell), which is plasticized by adding glycerin, sorbitol, or a similar polyol. The soft gelatin shell can contain a preservative to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben, propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. The capsules may also be coated as known by those skilled in the art to modify or sustain dissolution of the active ingredient.

[0145] The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout the other liquid and can be oil-in-water or water-in-oil. Emulsions can contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions can contain a pharmaceutically acceptable suspending agent and preservative. Hydroalcoholic solutions can contain a pharmaceutically acceptable acetal (e.g., a di(lower alkyl)acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having 1 to 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, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, a solution, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, for example, water, to be conveniently measured for administration.

[0146] Other useful liquid and semisolid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and dialkylated mono- or polyalkylene glycols (including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, 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 the polyethylene glycol). These formulations may further include 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).

[0147] The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems.

[0148] The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include organic acids and carbon dioxide sources. Coloring agents and flavoring agents can be used in all of the above dosage forms. The pharmaceutical compositions provided herein can be formulated as immediate-release or modified-release dosage forms, including delayed-, sustained-, pulsatile-, controlled-, targeted-, and programmed-release forms.

[0149] The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impair the desired therapeutic action, or with substances that supplement the desired action (e.g., antacids, proton pump inhibitors, and H2-receptor antagonists).

[0150] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation for local or systemic administration.Parenteral administration as used herein includes intravenous administration, intraarterial administration, intraperitoneal administration, intrathecal administration, intraventricular administration, intraurethral administration, intrasternal administration, intracranial administration, intramuscular administration, intrasynovial administration and subcutaneous administration.

[0151] Parenteral administration The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for dissolving or suspending in liquid before injection.Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacy.

[0152] 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, solubility enhancers, isotonic agents, etc.). The composition may contain additives such as, but not limited to, surfactants, antioxidants, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0153] Suitable aqueous vehicles include, but are not limited to, water, saline, normal saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water for injection, dextrose and lactated Ringer's injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable 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 of coconut oil, and palm kernel oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0154] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl and propylparaben, and sorbic acid. Suitable isotonicity 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, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating 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, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

[0155] The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials, or syringes. The multiple dose parenteral formulations must contain antimicrobial agents at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

[0156] In certain embodiments, the pharmaceutical compositions are provided as ready-to-use sterile solutions. In certain embodiments, the pharmaceutical compositions are provided as sterile dry soluble products (including lyophilized powders and hypodermic tablets) to be reconstituted with a vehicle before use. In certain embodiments, the pharmaceutical compositions are provided as ready-to-use sterile suspensions. In certain embodiments, the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle before use. In certain embodiments, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.

[0157] 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.

[0158] The pharmaceutical compositions can be formulated as suspensions, solids, semi-solids, or thixotropic liquids for administration as an implanted depot. In certain embodiments, the pharmaceutical compositions provided herein are dispersed in a solid inert matrix, which is insoluble in body fluids but is surrounded by an outer polymeric membrane that allows the active ingredient in the pharmaceutical composition to diffuse therethrough.

[0159] 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, hydrophilic polymers (e.g., hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate).

[0160] Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymers of ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0161] Topical administration The pharmaceutical compositions provided herein may be administered topically to the skin, orifices, or mucosa, which, as used herein, includes (intradermal), transdermal, conjunctival, intracorneal, intraocular, ocular, otic, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.

[0162] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for topical administration, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and skin patches, for local or systemic effect. Topical formulations of the pharmaceutical compositions provided herein can also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0163] Pharmaceutically acceptable carriers and excipients suitable for use in the 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, solubility enhancers, isotonicity agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0164] The pharmaceutical compositions may also be administered by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g., POWDERJECT TM (Chiron Corp., Emeryville, CA), and BIOJECT TM (Bioject Medical Technologies Inc., Tualatin, OR) can be administered topically.

[0165] The pharmaceutical compositions provided herein can be provided in the form of ointments, creams, and gels.Suitable ointment vehicles include oily or hydrocarbon bases (such as lard, benzoin lard, olive oil, cottonseed oil, and other oils, white petrolatum); emulsifiable or absorbent bases (such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin); water-removable bases (such as hydrophilic ointments); water-soluble ointment bases (including polyethylene glycols of various molecular weights); emulsion bases, either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions (including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid).These vehicles are soft on the skin, but generally require the addition of antioxidants and preservatives.

[0166] Suitable cream bases can be oil-in-water or water-in-oil. Cream vehicles can be water-washable and can include an oil phase, an emulsifier, and an aqueous phase. The oil phase, also referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol (e.g., cetyl alcohol or stearyl alcohol). The aqueous phase usually, although not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation can be a nonionic, anionic, cationic, or amphoteric surfactant.

[0167] Gels are semi-solid suspension-type systems. Single-phase gels contain organic polymers dispersed substantially uniformly throughout the liquid carrier. Suitable gelling agents include cross-linked acrylic acid 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 uniform gel, a dispersing agent (e.g., alcohol or glycerin) may be added, or the gelling agent may be dispersed by trituration, mechanical mixing, and / or stirring.

[0168] The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the form of a suppository, pessary, bougie, compress or poultice, paste, powder, dressing, cream, plaster, contraceptive, ointment, solution, emulsion, suspension, tampon, gel, foam, spray, or enema. These dosage forms can be manufactured using conventional processes.

[0169] Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body openings, which are solid at normal temperatures but melt or soften at body temperature, releasing the active ingredient into the opening. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include stiffening agents (which, when formulated with the pharmaceutical compositions provided herein, produce a melting point at about 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), spermaceti, paraffin, white wax and yellow wax, and appropriate mixtures of mono-, di-, and triglycerides of fatty acids, hydrogels (e.g., polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid); glycerinated gelatin. Combinations of various vehicles may be used. Rectal and vaginal suppositories may be prepared by the compressed method or by molding. The typical weight of a rectal and vaginal suppository is about 2 to 3 g.

[0170] The pharmaceutical compositions provided herein may be administered to the eye in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, intraocular inserts, and implants.

[0171] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract.The pharmaceutical compositions can be provided alone or in combination with suitable propellants (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) in the form of aerosol or liquid for delivery using a pressurized container, pump, spray, atomizer (e.g., atomizer that uses electrohydrodynamics to generate a fine mist), or nebulizer.The pharmaceutical compositions can also be provided as dry powders for insufflation, alone or in combination with an inert carrier (e.g., lactose or phospholipids); and as nasal drops.For intranasal use, the powder can contain a bioadhesive agent (including chitosan or cyclodextrin).

[0172] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers can be formulated to include ethanol, aqueous ethanol, or a suitable alternative agent, propellant as a solvent; and / or a surfactant, e.g., sorbitan trioleate, oleic acid, or oligolactic acid, to disperse, solubilize, or prolong the release of the active ingredients provided herein.

[0173] The pharmaceutical compositions provided herein can be micronized to a size suitable for inhalation delivery (e.g., 50 micrometers or less, or 10 micrometers or less). Particles of such sizes can be prepared using comminution 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).

[0174] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder blend of a pharmaceutical composition provided herein; a suitable powder base (e.g., lactose or starch); and a performance modifier (e.g., leucine, mannitol, or magnesium stearate). The lactose can be anhydrous or in the form of the monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled / intranasal administration can further comprise a suitable flavor (e.g., menthol and levomenthol), or a sweetener (e.g., saccharin or saccharin sodium).

[0175] The pharmaceutical compositions provided herein for topical administration may be formulated to be immediate or modified release, including delayed-, sustained-, pulsatile-, controlled-, targeted-, and programmed-release.

[0176] Modified Release The pharmaceutical compositions provided herein can be formulated as modified release dosage forms.As used herein, the term " modified release " refers to a dosage form in which the release rate or location of its active ingredient is different from that of an immediate dosage form when administered by the same route.Modified release dosage forms include delayed, prolonged, extended, sustained, pulsatile or pulsatile, controlled, accelerated and rapid, targeted, programmed release and gastric retention dosage forms.

[0177] Pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayered 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.

[0178] The pharmaceutical compositions provided herein in modified release dosage forms can be fabricated using matrix controlled release devices known to those of ordinary skill in the art.

[0179] In certain embodiments, the pharmaceutical compositions provided herein in modified release dosage forms may be formulated using erodible matrix devices, which are water-swellable, erodible, or soluble polymers, including synthetic polymers and naturally occurring polymers and derivatives such as polysaccharides and proteins.

[0180] Materials useful in forming the erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches (e.g., dextrin and maltodextrin); hydrophilic colloids (e.g., pectin); phosphatides (e.g., lecithin); alginates; propylene glycol alginate; gelatin; collagen and cellulosics (e.g., ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate ( cellulose acetate butyrate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT® (Rohm Copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; 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).

[0181] In certain embodiments, the pharmaceutical composition is formulated in a non-erodible 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. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics (e.g., polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, vinyl acetate, vinylidene chloride, vinyl chloride copolymers of ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber). Epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, and hydrophilic polymers (e.g., ethyl cellulose, cellulose acetate, crospovidone, and crosslinked partially hydrolyzed polyvinyl acetate); and fatty compounds (e.g., carnauba wax, microcrystalline wax, and triglycerides).

[0182] In a matrix controlled release system, the desired release kinetics can be controlled, for example, through the type of polymer used, the polymer viscosity, the particle size of the polymer and / or the active ingredient, the ratio of active ingredient to the polymer, and other excipients in the composition.

[0183] 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 or wet granulation followed by compression, and melt granulation followed by compression.

[0184] The pharmaceutical compositions provided herein in modified release dosage forms can be fabricated using osmotic 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 the active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water from an aqueous use environment into the core to cause drug release by extrusion through the delivery port.

[0185] In addition to the active ingredient, the core of the osmotic device contains an osmotic agent.

[0013] Optionally, the device may include a hydrophilic polymer (also referred to as "osmopolymer" and "hydrogel"), a class of osmotic agents, including, but 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, 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, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0186] Another class of osmotic agents is osmogens, which can absorb water and affect an osmotic pressure gradient across the barrier of the surrounding coating. 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.

[0187] Osmotic agents with different dissolution rates can be used to affect how rapidly the active ingredient is initially delivered from the dosage form. For example, amorphous sugars (e.g., Mannogeme EZ (SPI Pharma, Lewes, DE)) can be used to provide more rapid 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 an extended period of time. 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.

[0188] The core may also contain a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to facilitate stability or processing.

[0189] Materials useful in forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable and water-insoluble at physiologically relevant pH or that can be easily rendered water-insoluble by chemical modification (e.g., cross-linking). Examples of suitable polymers useful in forming coatings include the following: 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 acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, 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 copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0190] The semipermeable membrane can also be a hydrophobic microporous membrane, in which the pores are substantially filled with gas and not wetted by aqueous media, but are permeable to water, as disclosed in U.S. Pat. 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 halides, polyvinylidene fluorides, polyvinyl esters and ethers, natural waxes, and synthetic waxes. Delivery ports on the semipermeable membrane can be formed after coating by mechanical or laser drilling. Delivery ports can also be formed in situ by erosion of a plug of water-soluble material or by breaking a thin portion of the membrane over an indentation in the core. Furthermore, delivery ports can be formed during the coating process.

[0191] The total amount and release rate of the active ingredient released can be substantially controlled via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0192] The pharmaceutical composition in an osmotic controlled release dosage form may further comprise additional conventional excipients as described herein to facilitate performance or processing of the formulation.

[0193] The osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art.

[0194] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage forms, which comprise an asymmetric osmotic membrane coating a core containing the active ingredient and other pharmaceutically acceptable excipients. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip-coating.

[0195] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage forms, which comprise an osmotic membrane coating a core containing the active ingredient(s), hydroxyethyl cellulose, and other pharmaceutically acceptable excipients.

[0196] The pharmaceutical compositions provided herein in modified release dosage forms can be fabricated as multiparticulate controlled release devices, which contain multiple particles, granules, or pellets ranging in diameter from about 10 pm to about 3 mm, from about 50 pm to about 2.5 mm, or from about 100 pm to 1 mm. Such multiparticulates can be made by processes known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt-congealing, and by spray coating seed cores.

[0197] Other excipients, as described herein, can be blended with the pharmaceutical composition to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated with various film-forming materials (e.g., enteric polymers, water-swellable polymers, and water-soluble polymers). The multiparticulates can be further processed as capsules or tablets.

[0198] 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 a subject to be treated, including liposome-based, resealed erythrocyte-based, and antibody-based delivery systems.

[0199] Dosage For 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 of 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 in single 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.

[0200] 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, and in certain embodiments, the dosage level is about 1 to about 25 mg / kg / day.

[0201] In certain embodiments, the dosage level is about 5.0-150 mg / day, and in certain embodiments, 10-100 mg / day. In certain embodiments, the dosage level is about 80 mg / day. In certain embodiments, the dosage level is about 40 mg / day.

[0202] For oral administration, the pharmaceutical composition may be provided in the form of a tablet containing 1.0 to 1,000 mg of 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, for symptomatic adjustment of the dosage to the patient being treated. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 100 mg of active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 80 mg of active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 75 mg of active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 50 mg of active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 40 mg of active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 25 mg of active ingredient. The composition may be administered on a regimen of 1 to 4 times per day, including 1, 2, 3, and 4 times per day.

[0203] It will be understood, however, that the specific dosage level and frequency for any particular patient may vary and will depend upon a variety of factors including the activity of the specific compound used, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host being treated.

[0204] The compounds provided herein may also be combined or used in combination with other agents useful in the treatment, prevention, or amelioration of one or more symptoms of the diseases or conditions for which the compounds provided herein are useful, including tic disorders and other conditions commonly treated with antipsychotic medications.

[0205] In certain embodiments, the compounds provided herein can also be combined or used in combination with typical antipsychotic drugs. In certain embodiments, the typical antipsychotic drug is fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine, or trifluoperazine. In certain embodiments, the antipsychotic drug is an atypical antipsychotic drug. In certain embodiments, the atypical antipsychotic drug is aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone. In certain embodiments, the atypical antipsychotic drug is clozapine.

[0206] Such other agents or drugs can be administered simultaneously or sequentially with the compounds provided herein by their commonly used route and amount.When the compounds provided herein are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds provided herein can be used, but are not required.Therefore, the pharmaceutical compositions provided herein include those that contain one or more other active ingredients or therapeutic agents in addition to the compounds provided herein.

[0207] The weight ratio of the compound provided herein to the second active ingredient can vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when the compound provided herein is used in combination with the second drug or a pharmaceutical composition containing such other drug, the weight ratio of the particulate matter to the second drug can range from about 1,000:1 to about 1:1,000, or from about 200:1 to about 1:200.

[0208] Combinations of particulates provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0209] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented merely by way of illustration and to assist those of ordinary skill in the art in using the present disclosure. The examples are not intended to limit the scope of the present disclosure in any way. [Example]

[0210] Example 1 A Phase 1, Open-Label, Single-Series Crossover Study Evaluating the Effect of NBI-98854 on the Pharmacokinetics of Digoxin in Healthy Subjects This was a phase 1, open-label, single-sequence crossover drug-drug interaction study of NBI-98854 in a total of 24 healthy adult subjects (12 men and 12 women). At screening, subjects were genotyped to determine their cytochrome P450 2D6 (CYP2D6) status. Subjects who were poor metabolizers were excluded from study participation. After providing informed consent, subjects were screened for eligibility to participate in the study within 28 days prior to Day 1 (the first day of study drug administration). Subjects who met the eligibility criteria entered the study site on the morning of Day -1 (the day before dosing) and remained at the study site until the end of the study (Day 17). Subjects received digoxin 0.5 mg (administered as two 0.25 mg immediate-release [IR] tablets) once daily at approximately 08:00 on Days 1 and 14. Additionally, subjects received 80 mg of NBI-98854 once daily (administered as two 40 mg capsules) at approximately 0800 hours on days 10 through 16. On day 14, digoxin was administered concurrently with the NBI-98854 dose.

[0211] Subjects were required to fast overnight from midnight until 4 hours after dosing on Days 1 and 14. In addition, clinical laboratory evaluations were performed under fasting conditions. On each dosing day, study medication was administered with 240 mL of water. Subjects were provided with standard meals at regular mealtimes during their stay at the study site once study evaluations / dosing were completed. Subjects were released from the study site on Day 17 (final study day or early termination) after all safety and study evaluations were completed.

[0212] Blood samples were collected for PK analysis of NBI-98854 and its metabolites, NBI-98782 and NBI-136110, as well as for digoxin at scheduled times during the study. Safety was assessed throughout the study.

[0213] NBI-98854 40 mg capsules were administered orally. The dose of NBI-98854 was based on the ditosylate salt (dose expressed as the free base). Subjects received a single dose of 80 mg of NBI-98854 (as two 40 mg capsules) twice during the study at approximately 08:00 on days 10 through 16.

[0214] Pharmacokinetics Blood samples for determination of digoxin plasma concentrations were collected on days 1 and 14 approximately 30 minutes before digoxin administration, and 15, 30, and 45 minutes, as well as 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours after digoxin administration.

[0215] The following PK parameters were evaluated for digoxin: Area under the plasma concentration versus time curve (AUC) from 0 to 24 hours 0-24 ) Area under the plasma concentration versus time curve (AUC) from 0 to 4 hours 0-4 ) Area under the plasma concentration versus time curve (AUC) from time 0 to the last measurable concentration 0-tlast ) Area under the plasma concentration versus time curve (AUC) extrapolated from time 0 to infinity 0-∞ ) · Maximum plasma concentration (C max ) Time to maximum plasma concentration (t max ) Time before first measurable concentration (T lag ) Apparent terminal half-life (t 1 / 2 )

[0216] Blood samples for determining plasma concentrations of NBI-98854 and its metabolites NBI-98782 and NBI-136110 were collected at the following times: approximately 30 minutes prior to NBI-98854 dosing on days 10-13; approximately 30 minutes prior to NBI-98854 dosing and 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 12 hours after NBI-98854 dosing on day 14; approximately 30 minutes prior to NBI-98854 dosing on days 15 and 16; and approximately 24 hours after NBI-98854 dosing on day 16 and prior to release on day 17 (or early termination). The following plasma PK parameters were assessed for NBI-98854, NBI-98782, and NBI-136110: AUC 0-24 , C max , and t max .

[0217] During review of the PK data, three subjects (subjects 1011008, 1011016, and 1011018) were identified as having abnormally low plasma concentrations of NBI-98854, NBI-98782, and NBI-136110 on day 14 after receiving the fifth dose of NBI-98854 coadministered with digoxin. As a result, peak and total exposure (C) of all three analytes were observed. max and AUC 0-24 ) were significantly lower than the predicted range and the mean values observed on Day 14 (except for these three subjects). These low values were not consistent with the predicted drug concentrations after daily administration of NBI-98854. The predicted NBI-98854 concentrations on Day 14 were within the C range, excluding the three outliers. max and AUC 0-24 The PK data are expressed by values. Because the purpose of this study was to evaluate NBI-98854 as a Pgp inhibitor at its steady-state exposure, and the Day 14 data for these three subjects were likely exceptions, the PK data were also analyzed excluding the data for these three subjects. This analysis is referred to in this report as the PK analysis subset. The results of this PK analysis subset are presented in this section and provide a more conservative prediction of the drug interaction between digoxin and NBI-98854. Low C on day 14 max and AUC 0-24 Subjects with [Table 1]

[0218] PK parameters for digoxin alone and in combination with NBI-98854 are summarized below (excluding subjects 1011008, 1011016, and 1011018).

[0219] Digoxin was readily absorbed after oral administration alone or in combination with NBI-98854. Mean digoxin C max and AUC 0-∞) were approximately 1.9-fold and 1.4-fold higher, respectively, when digoxin was administered in combination with NBI-98854 than after treatment with digoxin alone. max was 0.25 hours shorter after digoxin in combination with NBI-98854 than after digoxin alone (0.75 hours vs. 1.0 hours). 1 / 2 were similar with and without NBI-98854 administration (35 and 36 hours, respectively).

[0220] t max , T lag , t 1 / 2 PK data for , MRT, and Vz / F were rounded to two significant figures, and all other parameters (AUC 0-24 , AUC 0-tlast , AUC 0-∞ , C max , and CL / F) were rounded to three significant figures. The last significant figure was rounded up if the number to the right was ≥ 5 and rounded down if the number to the right was ≤ 4. Summary of Pharmacokinetic Parameters for Digoxin Alone vs. Digoxin in Combination with NBI-98854 (PK Analysis Subset) [Table 2] Data excludes subjects 1011008, 1011016, and 1011018. max , T [ag , and t 1 / 2 PK data for all other parameters (AUC 0-4 , AUC 0-24 , AUC 0-tlast , AUC 0-∞ and C max ) was rounded to three significant figures. The last significant figure was rounded up if the number to the right was >5, and rounded down if the number to the right was <4.

[0221] Its digoxin geometric mean ratio and AUC after treatment with digoxin in combination with NBI-98854 or digoxin alone 0-∞ , AUC 0-tlast , and C max The 90% CIs of the associations are summarized below: AUC after treatment with digoxin in combination with NBI-98854 or digoxin alone 0-∞ , AUC 0-tlast , and C max The geometric mean ratios of AUC were 136.4%, 138.5%, and 191.7%, respectively. 0-∞ (126.0%-147.6%), AUC 0-tlast (127.0%~151.1%), and C max The upper and lower limits of its corresponding 90% CI (166.4%-220.8%) are outside the "no effect" range of 80%-125%, which is the AUC 0-∞ , AUC 0-tlast , and C max 1 shows the effect of treatment with NBI-98854 on Geometric mean ratios of digoxin for pharmacokinetic exposure parameters (PK analysis subset) [Table 3] aGeometric least squares mean ratios were based on a mixture model using log-transformed (base 10) data. b The 90% confidence intervals for the geometric mean ratios were based on least squares means using log-transformed (base 10) data. NOTE: Data excludes subjects 1011008, 1011016, and 1011018.

[0222] PK data for NBI-98854, NBI-98782, and NBI-136110 were compiled for the safety analysis set (excluding the three subjects). PK parameters for NBI-98854, NBI-98782, and NBI-136110 are summarized below. NBI-98854 was readily absorbed following oral administration of NBI-98854. Summary of Pharmacokinetic Parameters for NBI-98854, NBI-98782, and NBI-136110 for Day 14 Doses (Safety Analysis Set) [Table 4-1] [Table 4-2] Data reflect subjects in the safety analysis with PK parameters for the analytes at Day 14, except for subjects 1011008, 1011016, and 1011018.

[0223] The results of this study showed that NBI-98854 80 mg co-administered with 0.5 mg digoxin significantly increased the C max Digoxin AUC 0-∞ The effect of NBI-98854 on digoxin was modest (1.4-fold increase), with a mean t 1 / 2 were similar with and without NBI-98854 administration. 90% CI for geometric mean ratios (C max Regarding the AUC, it was 166.4% to 220.8%. 0-∞The C of digoxin (126.0%-147.6%) is outside the "no effect" range of 80%-125%. max and AUC 0-∞ These data show the effect of treatment with NBI-98854 on digoxin absorption in the intestinal tract. Thus, these data are consistent with inhibition of the efflux pump Pgp by NBI-98854 in the intestinal tract, which results in increased absorption of digoxin.

[0224] This study was designed to evaluate the PK of digoxin when administered alone and concomitantly with NBI-98854, and the safety and tolerability of NBI-98854 when administered alone and concomitantly with digoxin.

[0225] NBI-98854 was found to be a weak inhibitor of the efflux transporter Pgp. The efficacy of Pgp inhibition (IC of 23.8 pM) 50 ) and systemic plasma concentrations of NBI-98854 (in this study, the C of NBI-98854 after an 80 mg dose of 916 ng / mL or 2.19 pM) max Based on a comparison of the observed steady-state concentrations of NBI-98854 (the molecular weight of NBI-98854 is 418.578 g / mol) with the observed steady-state concentrations of NBI-98854 in the gastrointestinal tract, systemic interactions with the transporter were unlikely. However, concentrations of NBI-98854 in the gastrointestinal tract were likely to be much higher. Therefore, it was possible that NBI-98854 could alter digoxin PK by inhibiting intestinal Pgp.

[0226] The results of this study showed that NBI-98854 80 mg co-administered with 0.5 mg digoxin significantly increased the C max The results showed that digoxin AUC increased approximately 1.9-fold. 0-∞ The effect of NBI-98854 on digoxin was modest (1.4-fold increase) and 1 / 2 were similar with and without NBI-98854 administration. Thus, these data are consistent with inhibition of the efflux pump Pgp by NBI-98854 in the intestine, which results in increased absorption of digoxin.

[0227] Based on a review of all study records, the abnormally low plasma concentrations of NBI-98854, NBI-98782, and NBI-136110 observed in subjects 1011008, 1011016, and 1011018 were likely due to subject noncompliance. Exposure measures for NBI-98854 and its metabolites NBI-98782 and NBI-136110 (excluding those three subjects) at Day 14 were generally consistent with previous studies.

[0228] safety Safety was assessed based on adverse events (AEs), clinical laboratory results, vital signs, physical examination, and electrocardiogram (ECG).

[0229] safety results There were no pre-treatment AEs in the study. TEAEs were assigned to treatment based on the time of the last treatment administered before the onset of the AE.

[0230] There were no deaths or SAEs reported in this study. AEs leading to discontinuation of the study were reported in three subjects (one due to insomnia and anxiety, one due to anxiety and nausea, and one due to anxiety). Overall, 20 subjects (83.3%) experienced AEs during the study. By treatment group, 41.7% (10 subjects) of subjects experienced AEs after treatment with digoxin (until subjects received NBI-98854 on Day 10), 65.2% of subjects experienced AEs after initiating NBI-98854 on Day 10 (until subjects received both study drugs on Day 14), and 65.0% experienced AEs after coadministration of digoxin and NBI-98854 on Day 14.

[0231] Somnolence and anxiety were the most common AEs reported after administration of NBI-98854 alone, reported by 39.1% (9 subjects) and 17.4% (4 subjects), respectively, and considered by the investigators to be probably or definitely related to the study drug. Diarrhea was the most common AE after coadministration of digoxin and NBI-98854, reported in 20.0% (4 subjects) of subjects and considered by the investigators to be unrelated to the study drug. Headache was also common; it occurred after digoxin administration alone (20.8%; 5 subjects) and after administration of digoxin and NBI-98854 (15.0%; 3 subjects). The majority of AEs were considered mild to moderate in intensity. The number and percentage of subjects who experienced TEAEs are summarized below by treatment: Treatment-emergent adverse events reported in >1 subject in any treatment group (safety analysis set) [Table 5-1] [Table 5-2] a Started after the first dose of digoxin (Day 1) but before the first dose of NBI-98854 (Day 10) b Starting after the first dose of NBI-98854 (day 10) but before the day 14 dose of digoxin and NBI-98854 c Starting after the 14th dose of digoxin and NBI-98854

[0232] Three subjects experienced AEs that led to study discontinuation. These AEs included anxiety, insomnia, and nausea. The most common AE reported for study discontinuation was anxiety, reported in all three subjects. One anxiety event was considered serious.

[0233] conclusion Coadministration of digoxin and NBI-98854 results in increased absorption of digoxin, consistent with inhibition of the efflux pump P-glycoprotein (Pgp) by NBI-98854 in the intestinal tract.

[0234] Coadministration of digoxin and NBI-98854 significantly increased C max Approximately 1.9-fold increase in and AUC 0-∞ The 90% CI for the geometric mean ratio (C max Regarding the AUC, it was 166.4% to 220.8%. 0-∞ The C of digoxin (126.0%-147.6%) is outside the "no effect" range of 80%-125%. max and AUC 0-∞ The effect of treatment with NBI-98854 on digoxin t was similar with and without NBI-98854 administration (35 and 36 hours, respectively). max was 0.25 hours shorter after administration of digoxin in combination with NBI-98854 than after administration of digoxin alone (0.75 hours vs. 1.0 hours).

[0235] NBI-98854 80 mg was well tolerated in healthy subjects when administered alone or concomitantly with digoxin. No deaths or serious adverse events (SAEs) were reported in this study. AEs leading to study discontinuation were reported in three subjects (one due to insomnia and anxiety, one due to anxiety and nausea, and one due to anxiety). The most common AEs were somnolence (9 subjects, 39.1%) and anxiety (4 subjects; 17.4%) after initiating NBI-98854 administration and were considered by the investigator to be probably or definitely related to the study drug. Diarrhea was the most common AE after coadministration of digoxin and NBI-98854 (4 subjects; 20.0%) and was considered by the investigator to be unrelated to the study drug. The majority of AEs were considered mild to moderate in intensity. There were no clinically significant changes in laboratory test results, vital signs, physical examination, or ECG parameters during the study. No subjects had a corrected QT (QTcF) interval using the Fridericia formula >450 msec or a maximum increase from baseline >30 msec.

[0236] Example 2: Pharmacological characterization of valbenazine, tetrabenazine, and their metabolites Upon oral administration, TBZ is reduced to form four distinct isomeric secondary alcohol metabolites (collectively referred to as dihydrotetrabenazine (DHTBZ)). TBZ contains three asymmetric carbon centers (C-2, C-3, and C-11β), hypothetically giving rise to eight stereoisomers. However, because the C-3 and C-11β carbons are fixed in relative configuration, 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).

[0237] The affinity of each compound to rat forebrain membranes was determined by [ 3 H]-DHTBZ binding was measured by inhibition of DHTBZ binding. Affinity relative to R,R,R-DHTBZ was also calculated and shown. Data are reported as the negative logarithm of the Ki (pKi) for statistical calculations, with normally distributed binding parameters used to determine both the mean and SEM. The Ki values were determined as 10 (-pKi) from the mean pKi. The R,R,R-DHTBZ stereoisomer binds to both rat and human VMAT2 with the highest affinity (Ki = 1.0-4.2 nM). In comparison, the remaining three DHTBZ stereoisomers (S,R,R-DHTBZ, S,S,S-DHTBZ, and 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 the rat forebrain [Table 6] a The affinity for R,R,R-DHTBZ was determined in the same assay. i was calculated using the values.

[0238] The primary metabolic clearance pathways of valbenazine (VBZ, NBI-98854) are hydrolysis (to form R,R,R-DHTBZ) and mono-oxidation (to form 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 decline with half-lives similar to those of VBZ.

[0239] VBZ and its metabolites R,R,R-DHTBZ and NBI-136110 were tested for their ability to inhibit [H]-DHTBZ binding to VMAT2 in cell lines or native tissues. The affinity of each compound was determined by [H]-DHTBZ binding to either human platelets or rat striatal membranes. 3The affinities relative to R,R,R-DHTBZ were also calculated and shown. Data were both expressed as K for statistical calculations with normally distributed binding parameters used to determine the mean and SEM (n=4 for each compound in each tissue). i Report the K as the negative logarithm of (pKi). i Values are calculated from the mean pKi to 10 (-pKi) Its primary metabolite, R,R,R-DHTBZ, 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 7]

[0240] VBZ and NBI-136110 had similar effects on VMAT2 inhibition, but the K values were approximately 40-65 times lower than that 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 showed that R,R,R-DHTBZ was the most potent inhibitor of VMAT2, followed by S,R,R-DHTBZ. By comparison, S,S,S-DHTBZ and R,S,S-DHTBZ, two other primary metabolites of TBZ, were found to be poor VMAT2 inhibitors, with affinities approximately 60- and 160-fold weaker than R,R,R-DHTBZ.

[0241] The affinity of VBZ and its metabolites R,R,R-DHTBZ and NBI-136110 for other targets beyond VMAT2 was investigated, including GPCRs, cell surface monoamine transporters, and cardiac potassium channels, as well as human ether-a-go-go-related genes. Multiple classes of protein targets, including ion channels containing the gene (HERG), were evaluated in a broad Cerep screen.

[0242] A multitarget activity screen (Cerep screen) of these compounds against over 80 targets showed that VBZ and its metabolites, R,R,R-DHTBZ and NBI-136110, did not inhibit the binding of their cognate ligands to any of their targets by more than 50% at concentrations between 1 and 10 μM. In contrast, the other three DHTBZ stereoisomers (S,R,R-DHTBZ, S,S,S-DHTBZ, and R,S,S-DHTBZ, which are metabolites of TBZ but not VBZ) showed >50% inhibition of ligand binding to many receptor subtypes, including serotonin, dopamine, and adrenergic receptors. Results were expressed as percent specific binding of the control: (specific binding of the tested compound / specific binding of the control) × 100. All compounds were tested at final concentrations of 1 μM or 10 μM. Results are a selection of a larger 80 target panel (n=2 for each compound at each target) performed as an initial screen in Cerep. Results in bold (>50%) indicate activity at the target receptor. In vitro activity of valbenazine and DHTBZ stereoisomers at dopamine, serotonin, and adrenergic receptors. [Table 8] a For the purpose of a broad panel screen, its S,S,S- and R,S,S-metabolites were tested as a 50 / 50 mixture.

[0243] To describe the monoamine system in more detail, detailed radioligand binding assays were performed on the common metabolite of TBZ and VBZ (R,R,R-DHTBZ) as well as other related metabolites unique to TBZ and VBZ at dopamine, serotonin, and adrenergic receptor subtypes, as well as transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Detailed analysis revealed high specificity of R,R,R-DHTBZ for the VMAT2 transporter and 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 for 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 cells expressing VMAT1. Reserpine, a nonselective, irreversible, high-affinity uptake inhibitor of VMAT1, substantially inhibited uptake through VMAT1, whereas there was no significant inhibitory activity of TBZ, VBZ, or their metabolites R,R,R-DHTBZ or NBI-136110 at concentrations up to 10 μM. For both VMAT1 and VMAT2, uptake was measured in untransfected host cells and found to be similar to that in transfected cells in the presence of excess reserpine.

[0244] Radioligand binding assays and broad panel screening indicate that, in addition to varying potencies at the VMAT2 transporter, two of TBZ's other DHTBZ metabolites (S,S,S-DHTBZ and R,S,S-DHTBZ) interact with D1 and D2 receptors. Because VBZ is not metabolized to any of these DHTBZ stereoisomers, its effects on postsynaptic dopamine receptors, either directly or indirectly through its metabolites, are absent.

[0245] Furthermore, results from a broad panel screen 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 potential for pharmacological off-target effects. Furthermore, uptake studies using TBZ, VBZ, and its metabolites R,R,R-DHTBZ and NBI-136110 confirmed the selectivity of these compounds for VMAT2, as they had no significant effect on monoamine uptake through VMAT1 compared with reserpine (a known VMAT1 / VMAT2 inhibitor).

[0246] The selectivity and specificity of VBZ were demonstrated using two in vivo surrogate measures of pharmacological effect. Ptosis (known to occur via adrenergic activation and prolactin release from the pituitary gland and regulated through D2 dopamine receptors) showed differences between treatment with TBZ and VBZ. TBZ, VBZ, and R,R,R-DHTBZ induced ptosis in an equivalent manner. This confirms that the metabolites formed by administration of TBZ or VBZ, or the active metabolite itself (R,R,R-DHTBZ), all have activity at VMAT2, which affects presynaptic monoamine release, in this case specifically norepinephrine release, to induce ptosis. After similar treatment (but this time using prolactin release as a surrogate for dopaminergic regulation), R,R,R-DHTBZ and VBZ (to a lesser extent) induced similar increases in serum prolactin levels as TBZ.

[0247] The various embodiments described above can 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 in this specification and / or listed in the application data sheet are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, if necessary, to use the concepts of various patents, applications, and publications to provide still further embodiments.

[0248] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the language used should not be construed to limit the scope of the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments, along with the full range of equivalents to which such claims are entitled. Thus, the scope of the claims is not limited by the disclosure. The present invention provides, for example, the following items. (Item 1) 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]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient is also receiving digoxin, the method comprising: administering to the patient a therapeutically effective amount of the VMAT2 inhibitor; The method includes: (Item 2) 10. The method of claim 1, further comprising monitoring the patient for signs and symptoms of digoxin toxicity and clinical response. (Item 3) 3. The method of claim 1 or 2, further comprising reducing the amount of digoxin administered to the patient based on the patient's ability to tolerate one or more adverse reactions associated with digoxin exposure. (Item 4) 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]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, said method comprising: administering to said patient a therapeutically effective amount of said VMAT2 inhibitor; later determining that the patient should begin treatment with digoxin; and continuing to administer the therapeutically effective amount of the VMAT2 inhibitor to the patient; The method includes: (Item 5) 5. The method of claim 4, further comprising monitoring the patient for signs and symptoms of digoxin toxicity and clinical response. (Item 6) 6. The method of claim 4 or 5, further comprising reducing the amount of digoxin administered to the patient based on the patient's ability to tolerate one or more adverse reactions associated with digoxin exposure. (Item 7) 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]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof, to a patient in need thereof, wherein the patient is also receiving digoxin, the method comprising: administering to the patient a therapeutically effective amount of the VMAT2 inhibitor; wherein the administration is greater than or equal to the mean digoxin C of patients receiving digoxin alone. max Average digoxin C levels approximately 1.5 to 2.5 times higher than max and / or mean digoxin AUC in patients receiving digoxin alone 0-∞ Mean digoxin AUC is approximately 1 to 2 times higher than 0-∞ A method for producing (Item 8) 8. The method of any one of items 1 to 7, further comprising informing the patient or healthcare professional that co-administration of the VMAT2 inhibitor and digoxin may result in increased digoxin exposure. (Item 9) 9. The method of any one of items 1 to 8, further comprising informing the patient or a healthcare professional that co-administration of the VMAT2 inhibitor and digoxin may result in an increased risk of one or more adverse reactions associated with digoxin exposure. (Item 10) 10. The method according to any one of items 1 to 9, wherein monitoring the signs and symptoms of digoxin toxicity and clinical response comprises monitoring the serum concentration of the digoxin. (Item 11) 10. The method of any one of items 1 to 9, wherein monitoring the signs and symptoms of digoxin toxicity and clinical response comprises determining whether the patient experiences one or more exposure-related adverse events associated with serum digoxin concentrations. (Item 12) The method according to any one of Items 1 to 9, wherein the step of monitoring signs and symptoms of digoxin toxicity and clinical response comprises the step of monitoring the effectiveness of the digoxin. (Item 13) 13. The method of any one of items 1 to 3, or 7 to 12, further comprising obtaining a baseline serum digoxin concentration prior to administering to the patient the therapeutically effective amount of the VMAT2 inhibitor. (Item 14) 14. The method of claim 13, further comprising obtaining a serum digoxin concentration after administering to the patient the therapeutically effective amount of the VMAT2 inhibitor. (Item 15) 15. The method of claim 14, further comprising comparing the baseline serum digoxin concentration with the serum digoxin concentration after administering the therapeutically effective amount of the VMAT2 inhibitor to the patient. (Item 16) 16. The method according to any one of items 1 to 15, wherein the dosage and / or frequency of administration of digoxin is reduced. (Item 17) 17. The method of claim 16, wherein the dosage of digoxin is reduced. (Item 18) 18. The method of claim 16 or 17, wherein the administration frequency of the digoxin is reduced. (Item 19) 19. The method of any one of items 1 to 18, wherein the VMAT2 inhibitor is administered to the patient to treat neurological and psychiatric diseases and disorders. (Item 20) 20. The method of item 19, wherein the neurological or psychiatric disease or disorder is hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, manic states in mood disorders, depressive states in mood disorders, refractory 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 choreoacanthocytosis. (Item 21) 21. The method of item 20, wherein the neurological and psychiatric disease and disorder is hyperkinetic movement disorder. (Item 22) 22. The method of claim 21, wherein the hyperkinetic movement disorder is tardive dyskinesia. (Item 23) 22. The method of claim 21, wherein the hyperkinetic movement disorder is Tourette's syndrome. (Item 24) 22. The method of claim 21, wherein the hyperkinetic movement disorder is Huntington's disease. (Item 25) 22. The method of claim 21, wherein the hyperkinetic movement disorder is a tic. (Item 26) 22. The method of claim 21, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease. (Item 27) 22. The method of item 21, wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome, or tremor. (Item 28) 28. The method of any one of items 1 to 27, wherein the VMAT2 inhibitor is administered orally. (Item 29) 29. The method of any one of items 1 to 28, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. (Item 30) 30. The method of any one of items 1 to 29, wherein the VMAT2 inhibitor is administered with or without food. (Item 31) 31. The method of any one of items 1 to 30, wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt and / or isotopic variant thereof. (Item 32) 32. The method of claim 31, wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt thereof. (Item 33) 33. The method of claim 32, wherein the VMAT2 inhibitor is valbenazine tosylate. (Item 34) 34. The method of claim 33, wherein the VMAT2 inhibitor is valbenazine ditosylate. (Item 35) 32. The method of claim 31, 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]quinolizin-2-yl ester or a pharmaceutically acceptable salt thereof. (Item 36) 36. The method of any one of items 1 to 35, wherein the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base. (Item 37) 37. The method of claim 36, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg of valbenazine free base. (Item 38) 37. The method of claim 36, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg of valbenazine free base. (Item 39) 37. The method of claim 36, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 60 mg of valbenazine free base. (Item 40) 37. The method of claim 36, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 80 mg of valbenazine free base. (Item 41) 37. The method of claim 36, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 120 mg of valbenazine free base. (Item 42) 36. The method of any one of items 1 to 35, wherein the VMAT2 inhibitor is administered in a first amount for a first period of time, and then the amount is increased to a second amount. (Item 43) Item 43. The method of item 42, wherein the first period of time is one week. (Item 44) 44. The method of claim 42 or 43, wherein the first amount is equivalent to about 40 mg of valbenazine free base. (Item 45) 45. The method of any one of items 42 to 44, wherein the second amount is equivalent to about 80 mg of valbenazine free base. (Item 46) The VMAT2 inhibitors have a maximum plasma concentration (C) of between about 15 ng and about 60 ng of (+)-α-DHTBZ per mL of plasma. max ) and a minimum plasma concentration (C) of at least 15 ng of (+)-α-DHTBZ per mL of plasma over an 8-hour period min 36. The method of any one of items 1 to 35, wherein the compound is administered in an amount sufficient to achieve the desired effect. (Item 47) The VMAT2 inhibitors have a maximum plasma concentration (C) of between about 15 ng and about 60 ng of (+)-α-DHTBZ per mL of plasma. max ) and approximately C over a 12 hour period max Minimum plasma concentration (C) between at least about 33% and 50% of min 36. The method of any one of items 1 to 35, wherein the compound is administered in an amount sufficient to achieve the desired effect. (Item 48) 36. The method of any one of items 1 to 35, wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (+)-α-DHTBZ per mL of plasma; and (ii) a threshold concentration of at least 15 ng of (+)-α-DHTBZ per mL of plasma over a period of about 8 hours to about 24 hours. (Item 49) 36. The method according to any one of items 1 to 35, wherein the amount of digoxin administered is 10 to 90% less than the amount administered to a patient who is not similarly administered a VMAT2 inhibitor. (Item 50) 36. The method according to any one of items 1 to 35, wherein the amount of digoxin administered is 20 to 80% less than the amount administered to a patient who is not similarly administered a VMAT2 inhibitor. (Item 51) 36. The method according to any one of items 1 to 35, wherein the amount of digoxin administered is 30 to 70% less than the amount administered to a patient who is not similarly administered a VMAT2 inhibitor. (Item 52) 36. The method according to any one of items 1 to 35, wherein the amount of digoxin administered is 40-60% less than the amount administered to a patient who is not similarly administered a VMAT2 inhibitor. (Item 53) The method according to any one of items 1 to 35, wherein the amount of digoxin administered is 50% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor. (Item 54) 31. The method of any one of items 1 to 30, wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof. (Item 55) 55. The method of item 54, wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol dihydrotetrabenazine or a pharmaceutically acceptable salt thereof. (Item 56) 55. The method of item 54, wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof isotopic variant. (Item 57) A composition for treating a patient in need of 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, or a pharmaceutically acceptable salt and / or isotopic variant, and who is currently receiving digoxin, wherein the composition comprises a therapeutically effective amount of the VMAT2 inhibitor. (Item 58) 58. The composition of item 57, wherein the patient is monitored for signs and symptoms of digoxin toxicity and clinical response. (Item 59) 59. The composition of item 57 or 58, wherein the composition comprising the reduced amount of digoxin is administered to the patient based on the patient's ability to tolerate one or more adverse reactions associated with digoxin exposure after administration of the composition comprising the therapeutically effective amount of the VMAT2 inhibitor. (Item 60) 1. A composition for treating a patient in need of 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, wherein the composition comprises said VMAT2 inhibitor; The composition comprising a therapeutically effective amount of the VMAT2 inhibitor is characterized in that the composition is administered to the patient who is subsequently determined to start treatment with digoxin after administration of the composition comprising the therapeutically effective amount of the VMAT2 inhibitor. (Item 61) 61. The composition of item 60, wherein the patient is monitored for one or more exposure-related adverse reactions. (Item 62) 62. The composition of any one of items 60 and 61, wherein the composition comprising the reduced amount of the VMAT2 inhibitor is characterized in that it is administered based on the ability of the patient to tolerate one or more exposure-related adverse reactions after administration of a composition comprising a therapeutically effective amount of the VMAT2 inhibitor as defined in item 4 or a composition comprising a reduced amount of the VMAT2 inhibitor as defined in item 5. (Item 63) 1. A composition for treating a patient in need of 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, or a pharmaceutically acceptable salt and / or isotopic variant thereof, and who is currently being treated with digoxin, the composition comprising a therapeutically effective amount of the VMAT2 inhibitor; wherein administration of the composition is more effective than the mean digoxin C max Average digoxin C levels approximately 1.5 to 2.5 times higher than max and / or mean digoxin AUC in patients receiving digoxin alone 0-∞ Mean digoxin AUC is approximately 1 to 2 times higher than 0-∞ A composition that produces (Item 64) 64. The composition of any one of items 57 to 63, wherein the patient or healthcare professional is informed that co-administration of the composition and digoxin may result in increased digoxin exposure. (Item 65) 65. The composition of any one of items 57-64, wherein the patient or healthcare professional is informed that co-administration of the composition and digoxin may result in an increased risk of one or more adverse reactions associated with digoxin exposure. (Item 66) 66. The composition of any one of items 57 to 65, wherein the serum concentration of digoxin is monitored. (Item 67) 67. The composition according to any one of items 57 to 66, wherein the dosage and / or frequency of administration of the digoxin is reduced. (Item 68) 68. The composition of claim 67, wherein the dosage of digoxin is reduced. (Item 69) 69. The composition of item 67 or 68, wherein the administration frequency of the digoxin is reduced. (Item 70) 70. The composition according to any one of items 57 to 69, wherein the composition is for treating neurological and psychiatric diseases and disorders. (Item 71) 71. The composition of item 70, wherein the neurological and psychiatric disease and disorder is hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, manic states in mood disorders, depressive states in mood disorders, refractory 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 choreoacanthocytosis. (Item 72) 72. The composition of item 71, wherein the neurological and psychiatric disease and disorder is hyperkinetic movement disorder. (Item 73) 73. The composition of item 72, wherein the hyperkinetic movement disorder is tardive dyskinesia. (Item 74) 73. The composition of item 72, wherein the hyperkinetic movement disorder is Tourette's syndrome. (Item 75) 73. The composition of item 72, wherein the hyperkinetic movement disorder is Huntington's disease. (Item 76) 73. The composition of item 72, wherein the hyperkinetic movement disorder is a tic. (Item 77) 73. The composition of item 72, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease. (Item 78) 73. The composition of item 72, wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome, or tremor. (Item 79) 79. The composition according to any one of items 57 to 78, characterized in that the composition is administered orally. (Item 80) 80. The composition according to any one of items 57 to 79, characterized in that the composition is administered in the form of a tablet or capsule. (Item 81) 81. The composition according to any one of items 57 to 80, characterized in that the composition is administered with or without food. (Item 82) 82. The composition of any one of items 57 to 81, wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt and / or isotopic variant thereof. (Item 83) 83. The composition of item 82, wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt thereof. (Item 84) 84. The composition of item 83, wherein the VMAT2 inhibitor is valbenazine tosylate. (Item 85) 85. The composition of item 84, wherein the VMAT2 inhibitor is valbenazine ditosylate. (Item 86) 83. The composition of item 82, 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]quinolizin-2-yl ester or a pharmaceutically acceptable salt thereof. (Item 87) 87. The composition according to any one of items 57 to 86, wherein the composition is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base of the VMAT2 inhibitor. (Item 88) 88. The composition according to item 87, wherein the composition is administered in an amount equivalent to about 20 mg of valbenazine free base of the VMAT2 inhibitor. (Item 89) 88. The composition according to item 87, wherein the composition is administered in an amount equivalent to about 40 mg of valbenazine free base of the VMAT2 inhibitor. (Item 90) 88. The composition according to item 87, wherein the composition is administered in an amount equivalent to about 60 mg of valbenazine free base of the VMAT2 inhibitor. (Item 91) 88. The composition according to item 87, wherein the composition is administered in an amount equivalent to about 80 mg of valbenazine free base of the VMAT2 inhibitor. (Item 92) 88. The composition according to item 87, wherein the composition is administered in an amount equivalent to about 120 mg of valbenazine free base of the VMAT2 inhibitor. (Item 93) 87. The composition of any one of items 57 to 86, wherein the composition is administered at a first amount of the VMAT2 inhibitor for a first period of time, and then the amount is increased to a second amount of the VMAT2 inhibitor. (Item 94) Item 94. The composition of item 93, wherein the first period of time is one week. (Item 95) 95. The composition of claim 93 or 94, wherein the first amount is equivalent to about 40 mg of valbenazine free base. (Item 96) 96. The composition of any one of items 93 to 95, wherein the second amount is equivalent to about 80 mg of valbenazine free base. (Item 97) The composition provides a maximum plasma concentration (C) of (+)-α-DHTBZ of between about 15 ng and about 60 ng per mL of plasma. max ) and a minimum plasma concentration (C) of at least 15 ng of (+)-α-DHTBZ per mL of plasma over an 8-hour period min 87. The composition according to any one of items 57 to 86, characterized in that it is administered in an amount sufficient to achieve (Item 98) The composition provides a maximum plasma concentration (C) of (+)-α-DHTBZ of between about 15 ng and about 60 ng per mL of plasma. max ) and approximately C over a 12 hour period max Minimum plasma concentration (C) between at least about 33% and 50% of min 87. The composition according to any one of items 57 to 86, characterized in that it is administered in an amount sufficient to achieve (Item 99) 87. The composition of any one of items 57 to 86, characterized in that the composition is administered in an amount sufficient to achieve: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (+)-α-DHTBZ per mL of plasma; and (ii) a threshold concentration of at least 15 ng of (+)-α-DHTBZ per mL of plasma over a period of about 8 hours to about 24 hours. (Item 100) 87. The composition of any one of items 57 to 86, wherein the amount of digoxin administered is 10 to 90% less than the amount administered to a patient who is not similarly administered a VMAT2 inhibitor. (Item 101) 87. The composition of any one of items 57 to 86, wherein the amount of digoxin administered is 20 to 80% less than the amount administered to a patient who is not similarly administered a VMAT2 inhibitor. (Item 102) 87. The composition of any one of items 57 to 86, wherein the amount of digoxin administered is 30 to 70% less than the amount administered to a patient who is not similarly administered a VMAT2 inhibitor. (Item 103) 87. The composition of any one of items 57 to 86, wherein the amount of digoxin administered is 40 to 60% less than the amount administered to a patient who is not also receiving a VMAT2 inhibitor. (Item 104) 87. The composition of any one of items 57 to 86, wherein the amount of digoxin administered is 50% less than the amount administered to a patient who is not also administered a VMAT2 inhibitor. (Item 105) 82. The composition according to any one of items 57 to 81, wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and / or isotopic variant thereof. (Item 106) 106. The composition of claim 105, wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol dihydrotetrabenazine or a pharmaceutically acceptable salt thereof. (Item 107) 106. The composition of claim 105, wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof isotopic variant.

Claims

1. 1. A composition for use in a method of treating a patient having a neurological or psychiatric disease or disorder, comprising a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, and pharmaceutically acceptable salts thereof, the patient is also co-administered digoxin; The method comprises: (a) orally administering said composition to said patient; (b) monitoring the exposure of the digoxin in the patient's blood; and (c) adjusting the dose of digoxin if the exposure of the digoxin in the patient's blood increases. and wherein the digoxin exposure is expressed as the area under the plasma concentration versus time curve (AUC) extrapolated from time 0 to infinity. ０－∞ ) or as the time of maximum plasma concentration (t ｍａｘ The maximum observed plasma concentration (C ｍａｘ ) the composition.

2. 10. The method of claim 1, wherein adjusting the dose of digoxin comprises reducing the dose of digoxin.

3. 3. The composition of any one of claims 1 to 2, wherein the increased exposure to digoxin increases the risk of one or more exposure-related adverse reactions.

4. 4. The composition of claim 3, wherein the method further comprises monitoring the patient for one or more exposure-related adverse reactions.

5. 5. The composition of claim 3 or 4, wherein the one or more exposure-related adverse reactions are selected from headache, anxiety, insomnia, diarrhea, restlessness, and abnormal dreams.

6. 6. The composition of any one of claims 1 to 5, wherein the method further comprises obtaining a baseline serum digoxin concentration prior to administering the composition to the patient.

7. 7. The composition of claim 1, wherein the dosage and / or frequency of administration of the digoxin is reduced.

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

9. 9. The composition of any one of claims 1 to 8, wherein the VMAT2 inhibitor is a salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

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

11. 11. The composition of claim 10, wherein the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is in polymorphic Form I.

12. 12. The composition of any one of claims 1 to 11, wherein the neurological or psychiatric disease or disorder is hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, manic states in mood disorders, depressive states in mood disorders, refractory 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 choreoacanthocytosis.

13. 13. The composition of any one of claims 1 to 12, wherein the neurological or psychiatric disease or disorder is hyperkinetic movement disorder.

14. 14. The composition of claim 13, wherein the hyperkinetic movement disorder is tardive dyskinesia.

15. 14. The composition of claim 13, wherein the hyperkinetic movement disorder is Tourette's syndrome.

16. 14. The composition of claim 13, wherein the hyperkinetic movement disorder is Huntington's disease.

17. 14. The composition of claim 13, wherein the hyperkinetic movement disorder is a tic.

18. 14. The composition of claim 13, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

19. 19. The composition of any one of claims 1 to 18, wherein the therapeutically effective amount is an amount equivalent to about 40 mg, as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base, taken once daily for one week, and an amount equivalent to about 80 mg, as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base, taken once daily after one week.

20. 19. The composition of any one of claims 1 to 18, wherein the therapeutically effective amount is an amount equivalent to about 40 mg, as measured as (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base, once daily.

21. 19. The composition of any one of claims 1 to 18, wherein the therapeutically effective amount is an amount equivalent to about 60 mg, as measured as (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base, once daily.

22. 19. The composition of any one of claims 1 to 18, wherein the therapeutically effective amount is an amount equivalent to about 80 mg, as measured as (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base, once daily.

23. 19. The composition of any one of claims 1 to 18, wherein the therapeutically effective amount is an amount equivalent to about 20 mg, as measured as (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base, once daily.