Methods for administering certain VMAT2 inhibitors to patients with severe renal impairment

Abstract

Provided is a method for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject with severe renal impairment in need thereof.Also provided is a method for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, the method comprising: administering a VMAT2 inhibitor to the subject in need thereof, the subject having mild or moderate renal impairment, subsequently determining that the subject has severe renal impairment, and continuing to administer the VMAT2 inhibitor.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 890,697, filed August 23, 2019, and U.S. Provisional Application No. 63 / 028,754, filed May 22, 2020, which are incorporated by reference herein for all purposes. [Background technology]

[0002] Dysregulation of the dopaminergic system is essential for several central nervous system (CNS) disorders, including neurological and psychiatric diseases and disorders, including hyperkinetic disorders and conditions such as schizophrenia and mood disorders. The transport protein vesicular monoamine transporter-2 (VMAT2) plays a key role in presynaptic dopamine release and controls the uptake of monoamines from the cytoplasm into synaptic vesicles for storage and release.

[0003] Despite the advances that have been made in this field, there remains a need for new therapeutic products useful in the treatment of neurological and psychiatric diseases and disorders, and other related diseases or conditions described herein. One such agent has the following chemical structure: [ka] It is valbenazine having the formula:

[0004] A formulation of a VMAT2 inhibitor, valbenazine:4-toluenesulfonate (1:2) (referred to herein as "valbenazine ditosylate"), has previously been reported in the FDA-approved drug label INGREZZA®, which was approved in the United States on April 11, 2017, for the treatment of adults with tardive dyskinesia (TD). The prescribing information for INGREZZA indicates that INGREZZA is not recommended in patients with severe renal impairment (creatinine clearance <30 mL / min).

[0005] There is a significant unmet need for methods of administering VMAT2 inhibitors, such as valbenazine or its pharma- ceutically acceptable salts and / or isotopic variants, to patients in need thereof, particularly those with severe renal impairment.The present disclosure meets these and other needs, as will be apparent from the disclosure below. Summary of the Invention [Means for solving the problem]

[0006] overview Methods are provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, wherein the subject has severe renal impairment, comprising administering a VMAT2 inhibitor to the subject in need thereof.

[0007] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, comprising administering a VMAT2 inhibitor to a subject in need thereof, subsequently determining that the subject has severe renal impairment, and continuing administration of the VMAT2 inhibitor.

[0008] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, wherein the subject has mild or moderate renal impairment, comprising administering a VMAT2 inhibitor to the subject in need thereof, subsequently determining that the subject has severe renal impairment, and continuing administration of the VMAT2 inhibitor.

[0009] Also provided is a method for treating a disease or disorder requiring a vesicular monoamine transporter 2 (VMAT2) inhibitor in a subject in need thereof, wherein the subject has severe renal impairment, the method comprising administering a VMAT2 inhibitor to the subject in need thereof.

[0010] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, wherein the subject has severe renal impairment.

[0011] In some embodiments, the VMAT2 inhibitor is 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 its pharmaceutically acceptable salt and / or isotopic variant.In some embodiments, the VMAT2 inhibitor is 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 its pharmaceutically acceptable salt. In some embodiments, the VMAT2 inhibitor is the tosylate 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.In some embodiments, the VMAT2 inhibitor is the ditosylate 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. In some embodiments, the ditosylate 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 has crystalline form I.

[0012] In some 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 pharma- ceutically acceptable salt thereof.

[0013] In some embodiments, the VMAT2 inhibitor is tetrabenazine (9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one), or a pharma-ceutically acceptable salt and / or isotopic variant thereof. In some embodiments, the tetrabenazine is selected from the RR, SS, RS, and SR isomers of tetrabenazine, and mixtures thereof. In some embodiments, the tetrabenazine is a mixture of RR and SS isomers.

[0014] In some embodiments, the VMAT2 inhibitor is deutetrabenazine.

[0015] In some embodiments, the VMAT2 inhibitor is selected from dihydrotetrabenazine (2-hydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine), or a pharmaceutically acceptable salt and / or isotopic variant thereof. In some embodiments, the dihydrotetrabenazine is selected from the RRR, SSS, SSRR, RSS, SSR, RRS, RSR, and SRS isomers of dihydrotetrabenazine, and mixtures thereof. In some embodiments, the VMAT2 inhibitor is the RRR isomer ((+)-alpha-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.

[0016] These and other aspects of the present invention will become apparent upon reference to the following detailed description, to which various references are set forth herein which describe in more detail certain background information, procedures, compounds, and / or compositions, and each of which is hereby incorporated by reference in its entirety. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 shows the effect of hepatic impairment and severe renal impairment on valbenazine pharmacokinetics. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Detailed Description In the following description, specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will appreciate 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 the description of the embodiments. Unless otherwise required by context, throughout this specification and the claims that follow, the word "comprise" and variations thereof, such as "comprises" and "comprising", are to be interpreted in an inclusive and open-ended sense, i.e., "including but not limited to". Additionally, the headings provided herein are merely for convenience and are not to be interpreted as to the scope or meaning of the invention as set forth in the claims.

[0019] References throughout this specification to "one embodiment" or "an embodiment" or "some embodiments" or "a particular embodiment" mean that a particular feature, structure, or feature described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in some embodiments" or "in a particular embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or features may be combined in any suitable manner in one or more embodiments.

[0020] Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0021] As used herein, "valbenazine" refers 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 the compound of the structure: [ka] It may also be referred to as NBI-98854. INGREZZA contains valbenazine present as valbenazine ditosylate, whose chemical name is 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, 4-methylbenzenesulfonate (1:2). Valbenazine ditosylate is slightly water soluble. Its molecular formula is C38H54N2O10S2, its molecular weight is 762.97 / mol (ditosylate), and it has the following structure: [ka] has.

[0022] Valbenazine ditosylate may exist as an amorphous form and crystalline forms I-VI. The synthesis and characterization of valbenazine ditosylate amorphous form and crystalline forms I-IV are described in U.S. Patent No. 10,065,952, the entirety of which is incorporated herein by reference for all purposes. Valbenazine ditosylate crystalline form I has an X-ray diffraction pattern. The X-ray diffraction pattern of valbenazine ditosylate crystalline form I may include peaks at 2-theta angles of about 6.3, 17.9, and 19.7°. The X-ray diffraction pattern of valbenazine ditosylate crystalline form I may include peaks at 2-theta angles of about 6.3, 17.9, or 19.7°. The X-ray diffraction pattern of valbenazine ditosylate crystalline form I may include peaks at 2-theta angles of about 6.3 and 17.9°. The X-ray diffraction pattern of valbenazine ditosylate crystalline form I may include a peak at a 2-theta angle of about 6.3°. Valbenazine ditosylate crystalline form I has an endothermic differential scanning calorimetry (DSC) thermogram. In some embodiments, crystalline form I has a DSC thermogram that includes an endothermic event with an onset temperature of about 240° C. and a peak at about 250° C.

[0023] As used herein, "tetrabenazine" may also be referred to as 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinolizin-2-one. The compound has chiral centers at the 3 and 11b carbon atoms and therefore, theoretically, can be represented as follows: [ka] It can exist in a total of four isomeric forms, as shown in Commercially available tetrabenazine is a racemic mixture of RR and SS isomers. See, e.g., XENAZINE (tetrabenazine) US Prescribing Information, September 13, 2017, which is incorporated herein by reference in its entirety for all purposes.

[0024] As used herein, "deutetrabenazine" may also be referred to as (RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxyd3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one. Deutetrabenazine is the compound shown below: [ka] It is a racemic mixture containing See, e.g., AUSTEDO (deutetrabenazine) US Prescribing Information, June 6, 2018, which is incorporated by reference herein in its entirety for all purposes.

[0025] As used herein, dihydrotetrabenazine may also be referred to as 2-hydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine. The compound has three chiral centers and therefore theoretically exists in a total of eight isomeric forms, as shown below: [ka] The synthesis and characterization of the eight isomers are described in Sun et al. (2011) Eur. J. Med. Chem. 1841-1848, which is incorporated by reference in its entirety for all purposes.

[0026] As used herein, "(+)-α-HTBZ" refers to a compound having the structure: [ka] wherein (+)-α-HTBZ is the RRR isomer of dihydrotetrabenazine and may also be referred to as (2R,3R,11bR) or [+]-α-HTBZ 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.

[0027] As used herein, "NBI-136110" refers to a compound having the structure: [ka] The present invention refers to a compound which is a metabolite of valbenazine having the formula:

[0028] 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 is an isotope of 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( 31P), 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( 131 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 is in a stable form, i.e., is non-radioactive. In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., is non-radioactive. 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 in an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound is in an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound is in an unstable form, i.e., radioactive. 3 H), Carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), and oxygen-15 ( 15In the compounds 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, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 2 H or any carbon can be e.g. 13 C or any nitrogen can be used as an example 15 N, and any oxygen, for example 18 It will be understood that the isotopic proportion of deuterium can be O. In certain embodiments, "isotopic variants" of a compound contain unnatural proportions of deuterium.

[0029] With reference 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%. In certain embodiments, positions designated as having deuterium typically have a minimum isotopic enrichment factor at each designated deuterium position of 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 may be determined using conventional analytical methods known to those of skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy and crystallography.

[0030] 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.

[0031] 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. 0~∞ The term "AUC" refers to the AUC from time 0 (dosing) to time infinity.

[0032] As used herein, C max C is a pharmacokinetic parameter that indicates the maximum observed plasma concentration following delivery of the active pharmaceutical ingredient. max is the time of maximum plasma concentration t max This occurs.

[0033] As used herein, "renal clearance" is used in its normal sense to refer to any clearance caused by the kidney, for example, by glomerular filtration, tubular excretion, or degradation in tubular cells. "Primary renal clearance" means that renal clearance is one of the major clearance pathways for a drug. Within the meaning of this application, "primary renal clearance" means that renal clearance accounts for at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% of the total clearance of the drug. In some embodiments, valbenazine does not undergo primary renal clearance.

[0034] As used herein, "substantially similar" means that the two values ​​are within a 0.5 to 2-fold difference. For example, valbenazine or a pharmaceutical salt thereof can be administered to a patient with normal renal function, and then the exposure of valbenazine and its active metabolite (+)-α-HTBZ can be measured. In some embodiments, the exposure is measured by the C max In some embodiments, exposure is measured by AUC 0~∞Similarly, the exposure of valbenazine and its active metabolite (+)-α-HTBZ can be determined in patients with mild, moderate, or severe renal impairment. The fold change in exposure of valbenazine and its active metabolite (+)-α-HTBZ in patients with mild, moderate, or severe renal impairment relative to exposure in patients with normal renal function as a reference can then be determined.

[0035] As used herein, "co-administer" and "co-administration" and variations thereof refer to the administration of at least two drugs to a subject subsequent to, simultaneously, or resulting in close temporal proximity to one another (e.g., on the same day or week or within a 30 day period, or close enough that each of the at least two drugs can be detected simultaneously in plasma). When co-administered, the two or more active agents may be formulated together as part of the same composition, or may be administered as separate formulations. This is sometimes referred to herein as "concomitant" administration or variations thereof.

[0036] As used herein, "adjusting administration," "altering administration," "adjusting dosing," or "altering dosing" are all equivalent and mean tapering, reducing, or increasing the dose of a substance, ceasing administration of a substance to a subject, or substituting a substance with a different active agent.

[0037] As used herein, "administering to a subject" refers to the process of introducing a composition or dosage form into a subject using art-recognized means of introduction.

[0038] As used herein, "clinically stable" means that the subject is healthy or in a disease state where little immediate change, if any, is expected.For example, if the subject has been receiving a constant dose of drug treatment for at least one month, the subject is considered clinically stable.A clinically stable subject may be symptomatic.However, symptoms should be at a certain level in terms of type and severity.

[0039] As used herein, "clinically significant" is used herein to refer to a change in a subject's clinical condition, such as the level of side effects, that is deemed important by the physician treating the subject.

[0040] As used herein, "dose" refers to the measured amount of active agent taken by a subject at one time.In certain embodiments where the active agent is not valbenazine free base, the amount is the molar equivalent to the corresponding amount of valbenazine free base.For example, drugs are often packaged in the form of pharmaceutically acceptable salts, such as valbenazine ditosylate, and dosages of strength refer to the molar equivalent mass of the corresponding organic base valbenazine.For example, 73mg of valbenazine tosylate is the molar equivalent of 40mg of valbenazine free base.

[0041] As used herein, "dosing regimen" means the dose of active agent initially taken by a subject, and the interval (time or symptomatic) at which any subsequent doses of active agent are taken by the subject, e.g., about 20 to about 160 mg once daily, e.g., about 20, about 40, about 60, about 80, about 100, about 120 or about 160 mg once daily. Additional doses of active agent may be different from the dose initially taken.

[0042] As used herein, an "effective amount" and a "therapeutically effective amount" of an agent, compound, drug, composition or combination is an amount that is non-toxic, tolerable, and effective to produce some desired therapeutic effect upon administration to a subject or subjects (e.g., human subjects or patients). The precise therapeutically effective amount for a subject may depend, for example, on the size and health of the subject, the nature and extent of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those skilled in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0043] As used herein, "informing" means referring to or providing publicly available material, e.g., providing an active agent along with publicly available material to a user, or presenting information verbally, e.g., by a seminar, conference presentation, or other educational presentation, by a dialogue between a pharmaceutical salesperson and a medical professional, or by a dialogue between a medical professional and a subject, or presenting intended information to a user for understanding.

[0044] As used herein, "labeling" means any labeling or other written, printed, graphic, electronic, verbal, or demonstrative means of communication on or accompanying a pharmaceutical product or dosage form.

[0045] As used herein, "healthcare practitioner" refers to a health care practitioner who may need or have access to information regarding active agents, including their dosage forms, including information regarding safety, efficacy, dosing, administration, or pharmacokinetics. Examples of healthcare practitioners include physicians, pharmacists, physician assistants, nurses, aides, caregivers (which may include family members or guardians), emergency medical personnel, and veterinarians.

[0046] As used herein, "level of renal sufficiency" refers to the level of renal (kidney) function in an individual. As used herein, levels of renal sufficiency in an individual include: no renal impairment, mild renal impairment, moderate renal impairment, severe renal impairment, and end-stage renal disease (ESRD). The term renal impairment includes mild renal impairment, moderate renal impairment, severe renal impairment, and end-stage renal disease (ESRD).

[0047] Various thresholds or cutoffs can be used to determine the renal function sufficiency level in an individual depending on the technique used and the interpretation of the healthcare provider. Several variables can be considered when determining the renal function sufficiency level in an individual, including, for example, whether the individual is obese, the race of the individual, the sex of the individual, and the age of the individual. Recommendations for classification of renal function sufficiency are known in the art. These recommendations may change over time as newer techniques or better equivalents are used to more accurately determine renal function in an individual. For example, a patient with mild to moderate renal impairment may have a creatine clearance rate of 30-90 mL / min. On the other hand, a patient with severe renal impairment may have a creatine clearance rate of <30 mL / min.

[0048] As used herein, "pharmaceutical treatment guide" means the patient labeling of a drug approved by FDA that meets the standards set forth in 21 CFR 208 and other applicable regulations, including patient information on how to use the drug safely. A pharmaceutical treatment guide is scientifically accurate and is based on and does not contradict the professional labeling of the drug approved under 21 CFR 201.57, although the wording need not be identical to the section of the approved labeling to which it corresponds. Pharmaceutical treatment guides are typically available for drugs with special risk management information.

[0049] As used herein, "parkinsonian signs or symptoms" or "parkinsonism" is a collective term referring to a group of neurological conditions or disorders related to motor function similar to those seen in Parkinson's disease, but which may be caused by conditions other than Parkinson's disease. To assess parkinsonism, the Simpson-Angus Rating Scale (SAS) may be utilized. See Simpson et al. (1970) Acta Psychiatry Scand Suppl 212:11-19. This rating scale includes 10 items: gait, arm dropping, shoulder shaking, elbow stiffness, wrist stiffness, leg pendulousness, head dropping, glabella tap, tremor, and salivation. Each item is rated between 0 and 4. A total score is obtained by adding the items and dividing by 10. Scores up to 0.3 are considered within the normal range.

[0050] As used herein, "patient" or "individual" or "subject" means a mammal, including a human, for whom treatment is desired, and generally refers to the recipient of the treatment.

[0051] As used herein, "patient package insert" means information for patients about how to use a drug safely that is part of the labeling approved by the FDA. It is an extension of the drug's technical labeling that provides consumer information about the product in non-technical terms and may be distributed to patients when the product is dispensed, and may describe, for example, benefits, risks, how to recognize risks, dosage, or administration.

[0052] As used herein, "pharmacologically acceptable" refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a subject without producing undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmacologically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the necessary standards of toxicological and manufacturing testing, or that the carrier or excipient is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. "Pharmacologically active" (or "active") "Pharmacologically active" (or simply "active") as in derivative or analog refers to a derivative or analog that has the same type of pharmacological activity as the parent compound, and approximately the same degree.

[0053] As used herein, "pharmaceutically acceptable salt" refers to any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counterions well known in the art.Such salts include, but are not limited to, (1) hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2 -ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid and similar. or (2) salts formed when an acidic proton present in the parent compound is either (a) replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or an alkali or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) coordinated with an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.Pharmaceutically acceptable salts include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, as well as, if the compound contains a basic functional group, hydrohalides, such as hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate, picrates, cinnamates, mandeates, and the like. and the like. In some embodiments, the salts may be of a non-toxic organic or inorganic acid, such as phosphate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, or the like.

[0054] As used herein, "crystalline" refers to a solid in which the constituent atoms, molecules or ions are packed in a regularly ordered, repeating three-dimensional pattern. In particular, a crystalline compound or salt may be produced in one or more crystal forms. Different crystal forms may be distinguished by X-ray powder diffraction (XRPD) patterns.

[0055] As used herein, "substantially crystalline" refers to a compound or salt that is at least a particular weight percent crystalline. In some embodiments, the compound or salt is substantially crystalline. Examples of crystalline or substantially crystalline forms include a single crystalline form or a mixture of different crystalline forms. Particular weight percentages include 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%. In some embodiments, substantially crystalline refers to a compound or salt that is at least 70% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 80% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 85% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 90% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 95% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 98% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 99% crystalline.

[0056] As used herein, "product" or "pharmaceutical product" means a dosage form of an active agent together with disclosure materials and, optionally, packaging.

[0057] As used herein, "product insert" means the technical labeling (prescribing information) of a drug, the patient insert for a drug, or the medication guide for a drug.

[0058] As used herein, "technical labeling" or "prescribing information" means the formal description of a drug approved by a regulatory agency that regulates the sale of medicines (e.g., the FDA or EMEA) that contains a summary of the essential scientific information needed for the safe and effective use of the drug, such as indications and usage, dosage and administration, who should take it, adverse events (side effects), instructions for use in special populations (pregnant women, children, geriatrics, etc.), patient safety information, etc.

[0059] As used herein, "publication material" means any medium that provides information, including print, audio, visual, or electronic media, such as a flyer, advertisement, product insert, printed display, Internet website, Internet web page, Internet pop-up window, radio or television broadcast, compact disc, DVD, audio recording or other recording or electronic media.

[0060] As used herein, "risk" refers to the probability or likelihood of an adverse reaction, injury or other undesirable outcome resulting from a medical procedure. "Acceptable risk" refers to a measure of risk of harm, injury or disease resulting from a medical procedure that an individual or group is willing to tolerate. Whether a risk is "acceptable" depends on the benefit that an individual or group perceives to be obtained in exchange for taking the risk, whether the individual or group accepts any scientific and other advice given regarding the magnitude of the risk, and a number of other factors, political and social. An "acceptable risk" of an adverse reaction means that the adverse reaction is so unlikely or so unlikely to occur, or the benefit (perceived or actual) of the active agent is so great that an individual or group in society is willing to take or subject the risk that the adverse reaction may occur. An "unacceptable risk" of an adverse reaction means that an individual or group in society has considered the probability of the adverse reaction, the consequences of the adverse reaction, and the benefit (perceived or actual) of the active agent, and is not willing to take or subject the risk that the adverse reaction may occur. "At risk" means to be in a situation or condition characterized 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.

[0061] As used herein, "safety" refers to the incidence or severity of adverse events associated with administration of an active agent, including adverse effects related to factors related to the patient (e.g., age, sex, ethnicity, race, target disease, genetic characteristics such as abnormalities in renal or hepatic function, comorbid diseases, metabolic status, or environment) and factors related to the active agent (e.g., dose, plasma levels, duration of exposure, or concomitant drug therapy).

[0062] As used herein, "treating" or "treatment" refers to therapeutic applications to slow or stop the progression of a disorder, prophylactic applications to prevent the onset of a disorder, and / or reversal of a disorder. Reversal of a disorder differs from therapeutic applications that slow or stop the disorder in that the method of reversal not only stops the progression of the disorder completely, but also causes cellular behavior to move to some degree toward the normal state observed in the absence of the disorder.

[0063] As used herein, "VMAT2" refers to human vesicular monoamine transporter isoform 2, an integral membrane protein that acts to transport neurotransmitters such as monoamines, particularly dopamine, norepinephrine, serotonin and histamine, from the cytosol of cells to synaptic vesicles.

[0064] As used herein, the term "VMAT2 inhibitor", "inhibits VMAT2" or "inhibition of VMAT2" refers 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 be evident in certain cell types or may be associated with certain biological events. The term "VMAT2 inhibitor", "inhibits VMAT2" or "inhibition of VMAT2" also refers to altering the function of VMAT2 by decreasing the probability of complex formation between VMAT2 and a natural substrate.

[0065] In some embodiments, the VMAT2 inhibitor is 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 its pharmaceutically acceptable salt and / or isotopic variant.In some embodiments, the VMAT2 inhibitor is 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 its pharmaceutically acceptable salt. In some embodiments, the VMAT2 inhibitor is the tosylate 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. In some embodiments, the VMAT2 inhibitor is the ditosylate 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. In some embodiments, the ditosylate of valbenazine is substantially crystalline. In some embodiments, the crystalline ditosylate of valbenazine is form I. In some embodiments, the crystalline ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 2-theta angles of 6.3, 17.9, and 19.7°±0.2°.

[0066] In some embodiments, the VMAT2 inhibitor is selected from dihydrotetrabenazine (2-hydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine) or a pharmaceutically acceptable salt and / or isotopic variant thereof. In some embodiments, the dihydrotetrabenazine is selected from the RRR, SSS, SSRR, RSS, SSR, RRS, RSR, and SRS isomers of dihydrotetrabenazine, and mixtures thereof. In some embodiments, the VMAT2 inhibitor is the RRR isomer ((+)-alpha-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 some embodiments, the VMAT2 inhibitor is (+)-alpha-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 thereof.In some embodiments, the VMAT2 inhibitor is (+)-alpha-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.

[0067] As used herein, "hypersensitivity" or "hypersensitivity reaction" refers to immunological sensitization by a drug and / or its metabolites. Generally, there are four types of hypersensitivity: Type I, IgE-mediated - immediate hypersensitivity, including systemic hypersensitivity (e.g., anaphylaxis and urticaria) and respiratory hypersensitivity (e.g., asthma); Type II, IgG or IgM mediated - antibody-mediated cytotoxicity reactions, and Type III, IgG mediated - immune complex reactions that often occur simultaneously and are generally associated with systemic or organ hypersensitivity reactions. Types II and III immune disorders include anemia, leukopenia, thrombocytopenia, interstitial pneumonitis, vasculitis, lupus-like reactions or glomeronephritis; and Type IV, T-lymphocyte-mediated - A delayed-type hypersensitivity response that occurs most commonly as a delayed-type hypersensitivity skin reaction.

[0068] Methods are provided for administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, wherein the subject has severe renal impairment, comprising: administering a VMAT inhibitor to a subject in need thereof.

[0069] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, comprising: administering a VMAT2 inhibitor to a subject in need thereof, thereafter determining that the subject has severe renal impairment, and continuing administration of the VMAT2 inhibitor.

[0070] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, wherein the subject has mild or moderate renal impairment: the method includes administering a VMAT2 inhibitor to a subject in need thereof, thereafter determining that the subject has severe renal impairment, and continuing administration of the VMAT2 inhibitor.

[0071] Also provided is a method for treating a disease or disorder requiring a vesicular monoamine transporter 2 (VMAT2) inhibitor in a subject in need thereof, wherein the subject has severe renal impairment; the method comprises administering a VMAT2 inhibitor to the subject in need thereof.

[0072] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, wherein the subject has severe renal impairment.

[0073] Provided herein is a method of treating a patient with tardive dyskinesia, the method comprising the steps of: Also provided is a method comprising administering to a patient 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,la]isoquinolin-2-yl ester and pharma- ceutically acceptable salts thereof, wherein the therapeutically effective amount is the same amount that would be administered to a patient with normal renal function.

[0074] 1. A method of treating a patient with tardive dyskinesia comprising: (a) orally administering to a patient 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[2,1a]isoquinolin-2-yl ester and pharma-ceutical acceptable salts thereof; (b) subsequently determining that the patient has severe renal impairment; and (c) continuing to administer the same therapeutically effective dose of the VMAT2 inhibitor; A method comprising:

[0075] 1. A method of treating a patient with tardive dyskinesia comprising: and administering to the patient 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,la]isoquinolin-2-yl ester and pharma- ceutically acceptable salts thereof, wherein the patient is administered an initial dose of about 40 mg 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,la]isoquinolin-2-yl ester and pharma- ceutically acceptable salts thereof. once daily for one week in an amount equivalent to about 80 mg 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[2,1a]isoquinolin-2-yl ester free base, and once daily one week thereafter in an amount equivalent to about 80 mg 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[2,1a]isoquinolin-2-yl ester free base; Thereafter, determining that the patient has severe renal impairment; and Continue administering a therapeutically effective amount of a VMAT2 inhibitor to the patient. Also provided is a method comprising: In some embodiments, the therapeutically effective amount is equivalent to about 40 mg 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 free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 60 mg 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 free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 80 mg 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[2,1a]isoquinolin-2-yl ester free base once daily.

[0076] 1. A method of treating a patient with tardive dyskinesia comprising: and administering to the patient 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,la]isoquinolin-2-yl ester and pharma- ceutical acceptable salts thereof, wherein the patient receives an initial dose of the VMAT2 inhibitor of about 60 mg 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,la]isoquinolin-2-yl ester once daily for one week. 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,la]isoquinolin-2-yl ester free base and one week later once daily in an amount equivalent to approximately 80 mg 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,la]isoquinolin-2-yl ester free base; Thereafter, determining that the patient has severe renal impairment; and Continue administering a therapeutically effective amount of a VMAT2 inhibitor to the patient. Also provided is a method comprising: In some embodiments, the therapeutically effective amount is an amount equivalent to about 40 mg 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[2,1a]isoquinolin-2-yl ester free base once a day. In some embodiments, the therapeutically effective amount is an amount equivalent to about 60 mg 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[2,1a]isoquinolin-2-yl ester free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 80 mg 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[2,1a]isoquinolin-2-yl ester free base once daily.

[0077] Use of a VMAT2 inhibitor or a pharmaceutical composition comprising a therapeutically effective amount of a VMAT2 inhibitor for treating a patient having a neurological or psychiatric disease or disorder and severe renal impairment is also provided.

[0078] Also provided is a pharmaceutical composition comprising a therapeutically effective amount of a VMAT2 inhibitor disclosed herein for use in treating a patient with a neurological or psychiatric disease or disorder and with severe renal impairment.

[0079] There is also provided the use of a VMAT2 inhibitor in the manufacture of a medicament for treating a patient with a neurological or psychiatric disease or disorder and with severe renal impairment.

[0080] In some embodiments, the subject is not undergoing chronic dialysis.

[0081] In some embodiments, the method further comprises determining the subject's level of renal function sufficiency before administering the VMAT2 inhibitor.

[0082] In some embodiments, the Cockcroft-Gault formula is used to determine the subject's level of renal function adequacy. In some embodiments, subjects with severe renal impairment have a renal function adequacy level between 15 and 29 mL / min / 1.73 m using the Cockcroft-Gault formula. 2 In some embodiments, subjects with mild, moderate, or severe renal impairment have a creatinine clearance rate of 15 to 90 mL / min / 1.73 m using the Cockcroft-Gault formula. 2 In some embodiments, subjects with mild or moderate renal impairment have a creatinine clearance rate of 30 to 90 mL / min / 1.73 m using the Cockcroft-Gault formula. 2 The Cockcroft-Gault formula is CrCL = {[(140-age) x WT] / S Cr} where CrCL is creatinine clearance (ml / min), age is in years, WT is actual body weight (kg), and S Cr is serum creatinine (mg / dl); for female subjects, values ​​are multiplied by a factor of 0.85.

[0083] In some embodiments, the subject's serum creatinine concentration is used to determine the subject's level of renal function sufficiency. In some embodiments, a subject with severe renal impairment: For men aged 18-20, less than 4.9 mg / dL For women aged 18-20, less than 3.5 mg / dL For men aged 21 to 30, less than 4.5 mg / dL For women aged 21 to 30, less than 3.2 mg / dL; For men aged 31 to 40, less than 4.1 mg / dL For women aged 31 to 40, less than 2.9 mg / dL For women aged 41 to 50, less than 2.7 mg / dL For men aged 51 to 60, less than 3.3 mg / dL For women aged 51 to 60, less than 2.4 mg / dL For men over 60 years of age, less than 3.0 mg / dL, or < 2.0 mg / dL for women over 60 years of age The approximate serum creatinine concentration is

[0084] In some embodiments, the VMAT2 inhibitor is administered orally. In some embodiments, the VMAT2 inhibitor is administered in the form of a tablet or capsule.

[0085] In some embodiments, the VMAT2 inhibitor is administered with or without food.

[0086] In some embodiments, the amount of VMAT2 inhibitor administered to a patient with severe renal impairment is not adjusted to the amount administered to a patient with normal renal function or a patient with mild or moderate renal impairment.In some embodiments, the amount of VMAT2 inhibitor administered to a patient with severe renal impairment is equivalent to about 40 mg of valbenazine free base once a day.In some embodiments, the amount of VMAT2 inhibitor administered to a patient with severe renal impairment is equivalent to about 60 mg of valbenazine free base once a day.In some embodiments, the amount of VMAT2 inhibitor administered to a patient with severe renal impairment is equivalent to about 80 mg of valbenazine free base once a day.

[0087] In some embodiments, a patient with severe renal impairment has a substantially similar exposure in the patient 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[2,1-a]isoquinolin-2-yl ester and its active metabolite, (+)-α-HTBZ, as compared to the exposure in a patient with normal renal function administered the same amount of a VMAT2 inhibitor. max In some embodiments, exposure is measured by AUC 0~∞ In some embodiments, the exposure is measured by C max or AUC 0~∞ In some embodiments, the exposure is measured by C max and AUC 0~∞ It is measured by:

[0088] In some embodiments, the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 120 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 60 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 80 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 120 mg of valbenazine free base.

[0089] In some embodiments, the VMAT2 inhibitor is administered once a day in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered once a day in an amount equivalent to between about 20 mg and about 120 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered once a day in an amount equivalent to about 20 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered once a day in an amount equivalent to about 40 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered once a day in an amount equivalent to about 60 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered once a day in an amount equivalent to about 80 mg of valbenazine free base. In some embodiments, the VMAT2 inhibitor is administered once a day in an amount equivalent to about 120 mg of valbenazine free base.

[0090] In some embodiments, 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. In some embodiments, the first period of time is one week. In some embodiments, the first period of time is longer than one week, for example, two weeks, three weeks, or four weeks. In some embodiments, the first period of time is one month, two months, three months, or longer. In some embodiments, the first amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the second amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the second amount is equivalent to about 80 mg of valbenazine free base once a day. In some embodiments, the first amount is equal to about 40mg of valbenazine free base once a day, and the second amount is equal to about 60mg of valbenazine free base once a day.In some embodiments, the first amount is equal to about 40mg of valbenazine free base once a day, and the second amount is equal to about 80mg of valbenazine free base once a day.In some embodiments, the first amount is equal to about 60mg of valbenazine free base once a day, and the second amount is equal to about 80mg of valbenazine free base once a day.

[0091] In some embodiments, the amount of VMAT2 inhibitor administered to the subject is reduced relative to subjects with normal renal impairment.

[0092] In some embodiments, the amount of the VMAT2 inhibitor is reduced by at least about 10%. In some embodiments, the amount of the VMAT2 inhibitor is reduced by at least about 20%. In some embodiments, the amount of the VMAT2 inhibitor is reduced by at least about 30%. In some embodiments, the amount of the VMAT2 inhibitor is reduced by at least about 40%. In some embodiments, the amount of the VMAT2 inhibitor is reduced by at least about 50%. In some embodiments, the amount of the VMAT2 inhibitor is reduced by at least about 60%. In some embodiments, the amount of the VMAT2 inhibitor is reduced by at least about 70%. In some embodiments, the amount of the VMAT2 inhibitor is reduced by at least about 80%. In some embodiments, the amount of the VMAT2 inhibitor is reduced by at least about 90%.

[0093] In certain embodiments, the therapeutically effective amount of the VMAT2 inhibitor is 10-90% less than the amount that may be administered to a subject without severe renal impairment. In certain embodiments, the therapeutically effective amount of the VMAT2 inhibitor is 20-80% less than the amount that may be administered to a subject without severe renal impairment. In certain embodiments, the therapeutically effective amount of the VMAT2 inhibitor is 30-70% less than the amount that may be administered to a subject without severe renal impairment. In certain embodiments, the therapeutically effective amount of the VMAT2 inhibitor is 40-60% less than the amount that may be administered to a subject without severe renal impairment. In certain embodiments, the therapeutically effective amount of the VMAT2 inhibitor is about 50% less than the amount that may be administered to a subject without severe renal impairment.

[0094] For example, the amount that may be administered to a subject with severe renal impairment may be 20 mg or 40 mg less per day than a subject without severe renal impairment.

[0095] For example, if the amount that can be administered to a subject without severe renal impairment is 40 mg per day, then an individual with severe renal impairment may receive a reduced dosage of 36, 32, 28, 24, 20, 16, 12, 8, or 4 mg per day. Similarly, if the amount that can be administered to a subject without severe renal impairment is 80 mg per day, then an individual with severe renal impairment may receive a reduced dosage of 72, 64, 56, 48, 40, 32, 24, 16, or 8 per day.

[0096] For example, if the dosage administered to a subject without severe renal impairment is 40 mg per day, then an individual with severe renal impairment may receive a reduced dosage of 4-36 mg per day, such as 8-32 mg per day, such as 12-28 mg per day, such as 16-24 mg per day, or in a particular embodiment, about 20 mg per day. If the dosage administered to a subject without severe renal impairment is 80 mg per day, then an individual with severe renal impairment may receive a reduced dosage of 8-72 mg per day, such as 16-64 mg per day, such as 24-56 mg per day, such as 32-48 mg per day, or in a particular embodiment, about 24 mg per day.

[0097] For example, if the dosage administered to a subject without severe renal impairment is 40 mg per day, an individual with severe renal impairment may receive a reduced dosage of 5-35 mg per day, such as 10-30 mg per day, such as 15-30 mg per day, such as 15-25 mg per day, or in certain embodiments, about 20 mg per day or about 30 mg per day. If the dosage administered to a subject without severe renal impairment is 80 mg per day, an individual with severe renal impairment may receive a reduced dosage of 5-75 mg per day, such as 10-70 mg per day, such as 15-65 mg per day, such as 20-60 mg per day, such as 25-55 mg per day, such as 30-60 mg per day, or in certain embodiments, about 40 mg per day or about 60 mg per day.

[0098] In some embodiments, the VMAT2 inhibitor is administered in an amount sufficient to achieve a maximum plasma concentration (Cmax) of between about 15 ng and about 60 ng of (+)-α-DHTBZ per mL of plasma over a 12 hour period, and a minimum plasma concentration (Cmin) of at least about 33%-50% of Cmax. In some embodiments, the VMAT2 inhibitor is administered in an amount sufficient to achieve (i) a therapeutic concentration range of about 15 ng and about 60 ng of (+)-α-DHTBZ per mL of plasma over a period of about 8 hours to about 24 hours, and (ii) a threshold concentration of at least 15 ng of (+)-α-DHTBZ per mL of plasma.

[0099] In certain embodiments, the therapeutically effective amount is not reduced.

[0100] In some embodiments, the VMAT2 inhibitor is administered to a patient to treat a neurological or psychiatric disease or disorder, in some embodiments, the neurological or psychiatric disease or disorder is hyperkinetic disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or choreoacanthocytosis.

[0101] In some embodiments, the neurological or psychiatric disease or disorder is a hyperkinetic disorder. In some embodiments, the hyperkinetic disorder is tardive dyskinesia. In some embodiments, the hyperkinetic disorder is a tic disorder. In some embodiments, the tic disorder is Tourette's syndrome. In some embodiments, the hyperkinetic disorder is Huntington's disease. In some embodiments, the hyperkinetic disorder is chorea-like movements, generalized dystonia, focal dystonia, and myoclonic movements. In some embodiments, the hyperkinetic disorder is chorea associated with Huntington's disease. In some embodiments, the hyperkinetic disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome, or tremor. In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease. In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease, and the VMAT2 inhibitor is deutetrabenazine or tetrabenazine.

[0102] In some embodiments, the neurological or psychiatric disease or disorder is hyperkinesia in a patient with intellectual and developmental disability (IDD). In some embodiments, the hyperkinesia disorder is tardive dyskinesia in a patient with intellectual developmental disability (IDD). In some embodiments, the hyperkinesia disorder is tic disorder in a patient with intellectual developmental disability (IDD). In some embodiments, the tic disorder is Tourette's syndrome in a patient with intellectual developmental disability (IDD). In some embodiments, the hyperkinesia disorder is Huntington's disease in a patient with intellectual developmental disability (IDD). In some embodiments, the hyperkinesia disorder is choreiform movements, generalized dystonia, focal dystonia, and myoclonic movements in a patient with intellectual developmental disability (IDD). In some embodiments, the hyperkinesia disorder is chorea associated with Huntington's disease in a patient with intellectual developmental disability (IDD). In some embodiments, the hyperkinetic disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome or tremor in patients with intellectual developmental disability (IDD).In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease in patients with intellectual developmental disability (IDD).In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease in patients with intellectual developmental disability (IDD), and the VMAT2 inhibitor is deutetrabenazine or tetrabenazine.

[0103] In some embodiments, the intellectual developmental disorder (IDD) includes intellectual disability and developmental disability. In some embodiments, the intellectual developmental disorder (IDD) is an intellectual disability. In some embodiments, the intellectual developmental disorder (IDD) is a developmental disability. In some embodiments, the intellectual developmental disorder (IDD) is characterized by the part or system of the body that is affected. In further embodiments, the part or system of the body is selected from the nervous system, the sensory system, the metabolic system, and the degenerative system.

[0104] In some embodiments, the VMAT2 inhibitor is administered to a patient to treat a disease or disorder selected from the following: Ataxia or spinal muscular atrophy, such as spinocerebellar ataxia type 17 (SCA17) / HDL4, ataxia, spinal muscular atrophy, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, congenital spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, hereditary motor neuron disease, and hereditary spastic paraplegia; Chorea including benign hereditary chorea, chorea, mitochondrial disease / chorea associated with mitochondrial causes, chorea associated with Wilson's disease, chorea of ​​pregnancy, chorea acanthocytosis, drug-induced chorea, hemiballismus, rheumatic / Sydenham chorea and thyrotoxic / hyperthyroid chorea, Congenital malformations, deformities or abnormalities such as Angelman syndrome, congenital neurological disorders, Aicardi syndrome, neurofibromatosis, congenital facial nerve dysplasia, Moebius II syndrome, Cockayne syndrome, Sjögren-Larsson syndrome, Laurence-Moon-Bardét-Biedl syndrome, Fragile X syndrome and Prader-Willi syndrome; Dementia, such as AIDS-related dementia, Alzheimer's disease, congenital neurodegeneration, dementia with Lewy bodies, micro-infarct dementia, presenile dementia, senile dementia and vascular dementia, Diseases of the mouth, salivary glands and jaw, such as glossodynia / burning mouth syndrome and temporomandibular joint disorders; Dyskinesias such as pharyngeal dyskinesia, dyskinesia, dyskinesia (neonatal), dyskinesia (esophageal), levodopa-induced dyskinesia, paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigneic dyskinesia and respiratory dyskinesia; Dystonias such as blepharospasm, buccoglossal syndrome, acute drug-induced dystonia, dystonia, early onset primary dystonia, genetic torsion dystonia, hand dystonia / writer's cramp, idiopathic non-familial dystonia, idiopathic orofacial dystonia / Meige disease, laryngeal dystonia, oromandibular dystonia and spasmodic torticollis / cervical dystonia, Endocrine, nutritional and metabolic disorders such as Wilson's disease, diabetes, obesity, Syndrome X and Lesch-Nyhan syndrome, Epilepsy such as Baltic myoclonic epilepsy, benign familial neonatal convulsions, epilepsy, congenital epilepsy, Lafora myoclonic epilepsy, severe myoclonic epilepsy of infancy and convulsions, Habit and impulse disorders such as binge eating disorder, kleptomania, impulse control disorder, trichotillomania, intermittent explosive disorder, pathological gambling and pyromania, Huntington's disease or related disorders, such as Huntington's disease, Huntington's disease-related syndromes types 1-3, Huntington's chorea, and X-linked McLeod Neurocanthocytosis syndrome; Mood or psychotic disorders such as schizophrenia, psychosis, mania, bipolar disorder, depression and mood disorders; Other diseases or disorders such as fumbling, hypokinesia, hypokinesia (neonatal), movement disorders, rabbit syndrome, spasticity, up and down phenomenon, asthma, cancer, congenital nystagmus, familial hemiplegic migraine, fetal movement disorders and rheumatoid arthritis, Neurotic, stress-related and somatoform disorders, such as social anxiety disorder, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder and psychogenic movement disorder; Other degenerative diseases of the basal ganglia, such as pantothenate kinase-associated neurodegeneration, progressive supranuclear palsy, multiple system atrophy, dyslexia, basal ganglion degeneration and neuroferritinopathy, Other extrapyramidal and movement disorders such as demiballismus, extrapyramidal disorders, essential tremor, geniospasm, hyperkalemia, akathisia, ballismus / hemiballismus, myoclonus and restless legs syndrome / Willis-Ekbom syndrome, Other nervous system or motor functions such as sleep-related bruxism, abnormal involuntary movement disorders, alien limb syndrome, Alzheimer's disease (agitation), clumsiness, clonic hemifacial spasm, olfactory nerve agenesis, congenital cranial nerve palsies, ataxia syndromes, familial periodic paralysis, congenital hemiparesis, fine motor delay, fine motor skill dysfunction, gross motor delay, multiple sclerosis, congenital flaccid paralysis, congenital Horner's syndrome, alternating hemiplegia of childhood, motor developmental delay, cerebral palsy, athetoid cerebral palsy, posturing, pseudoparesis, psychomotor hyperactivity, bradykinesia, synkinesis, akinesia, Riley-Day syndrome and athetosis, Parkinsonism / Parkinsonism, such as Parkinsonism, Drug-Induced Parkinsonism, Micrographia and Parkinson's Disease, depravity, including depravity and subjective incapacity; childhood onset behavioral and emotional disorders such as attention deficit hyperactivity disorder, attention deficit disorder, hyperactivity, hyperactivity (neonatal), oppositional defiant disorder, provisional tic disorder, persistent (chronic) motor or vocal tic disorder, stereotypy, stereotypies and Tourette's syndrome; Pervasive developmental disorders, such as autism spectrum disorder, Rett syndrome, Asperger syndrome, pervasive developmental disorder (NOS) and dyslexia, and Substance abuse or dependence, including addictive disorders, alcoholism, cocaine dependence, illegal drug abuse, methamphetamine abuse, methamphetamine addiction / dependence, methamphetamine use disorder, morphine abuse, morphine analogue abuse, nicotine dependence, polydrug abuse, and prescription drug abuse.

[0105] In some embodiments, the patient is determined to have 22q11.2 deletion syndrome. In some embodiments, the patient is predisposed to develop psychiatric disorders because of having 22q11.2 deletion syndrome. In some embodiments, the patient is determined to have COMT haploinsufficiency. In some embodiments, the patient is predisposed to develop psychiatric disorders because of having COMT haploinsufficiency.

[0106] In some embodiments, the patient is determined to have velopharyngeal syndrome (VCFS). In some embodiments, the patient with velopharyngeal syndrome has a 3Mb deletion. In some embodiments, the 3Mb deletion comprises a deletion of COMT and TBX1. In some embodiments, the patient with velopharyngeal syndrome has a 1.5Mb deletion. In some embodiments, the 1.5Mb deletion comprises a deletion of TBX1 and COMT.

[0107] In some embodiments, the method further comprises monitoring the subject for adverse reactions associated with the one or more exposures. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions with or without skin reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions with skin reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions without skin reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from allergic dermatitis, angioedema, pruritus, and urticaria.

[0108] In some embodiments, the hypersensitivity is Type I hypersensitivity. In some embodiments, the hypersensitivity is Type IV hypersensitivity.

[0109] In some embodiments, the adverse reaction associated with one or more exposures is selected from urticaria, pruritus, allergic dermatitis, and angioedema. In some embodiments, the adverse reaction associated with one or more exposures is selected from urticaria, allergic dermatitis, and angioedema. In some embodiments, the adverse reaction associated with one or more exposures is a hypersensitivity reaction and a rash. In some embodiments, the adverse reaction associated with one or more exposures is a rash. In some embodiments, the adverse reaction associated with one or more exposures is selected from a reaction consistent with a rash, urticaria, and angioedema.

[0110] In some embodiments, the adverse reaction associated with the one or more exposures is selected from reactions consistent with angioedema. In some embodiments, the adverse reaction associated with the one or more exposures is selected from swelling of the face, lips, and mouth, and difficulty breathing.

[0111] In some embodiments, the subject in need of the increased risk of adverse reactions associated with one or more exposures has a history of allergy.In some embodiments, the subject has a history of allergy to one or more drugs, such as penicillin or paroxetine; to one or more foods, such as egg, milk, peanut, tree nut, fish, shellfish, wheat or soybean; and / or to cat.In some embodiments, the subject has a history of urticaria.

[0112] In some embodiments, the method further comprises administering to the subject experiencing the adverse reaction associated with one or more exposures one or more drug treatments selected from steroids and antihistamines.In some embodiments, the steroid is a systemic glucocorticoid such as prednisone.In some embodiments, the steroid is a hydrocortisone cream.In some embodiments, the antihistamine is diphenhydramine.

[0113] In some embodiments, the subject is also being administered digoxin, and the method further comprises administering to the subject a therapeutically effective amount of a VMAT2 inhibitor.

[0114] In some embodiments, the subject is also being administered digoxin, and the method further comprises administering a therapeutically effective amount of a VMAT2 inhibitor to the subject, followed by determining that the subject should initiate treatment with digoxin, and continuing to administer the therapeutically effective amount of the VMAT2 inhibitor to the subject.

[0115] In some embodiments, the subject is also administered digoxin, and the method further comprises administering to the subject a therapeutically effective amount of a VMAT2 inhibitor, wherein the administration reduces the mean C of digoxin in subjects administered digoxin alone. max The mean C of digoxin is about 1.5 to 2.5 times higher than that of max , and / or the mean AUC of digoxin in subjects receiving digoxin alone 0-∞ The mean AUC of digoxin is approximately 1 to 2 times higher than that of 0-∞ This results in

[0116] In some embodiments, the subject is a poor metabolizer of cytochrome P450 2D6 (CYP2D6). In certain embodiments, the subject has a CYP2D6 poor metabolizer genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is selected from CYP2D6G1846A genotype or CYP2D6C100T genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is one of CYP2D6G1846A(AA) genotype or CYP2D6G1846A(AG) genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is CYP2D6G1846A(AA) genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is one of CYP2D6C100T(TT) genotype or CYP2D6C100T(CT) genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is the CYP2D6C100T(TT) genotype.

[0117] In some embodiments, administration to a subject who is a poor metabolizer of CYP2D6 results in increased exposure to (+)-alpha-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol. In some embodiments, administration to a subject who is a poor metabolizer of CYP2D6 results in an increased risk of one or more clinically significant Parkinsonian signs or symptoms. In some embodiments, administration to a subject who is a poor metabolizer of CYP2D6 results in the subject's QT interval prolongation. In certain embodiments, the therapeutically effective amount is less than the amount administered to a subject who is not a poor metabolizer of CYP2D6. In certain embodiments, the therapeutically effective amount is the same amount administered to a subject who is not a poor metabolizer of CYP2D6.

[0118] In some embodiments, the method further comprises monitoring the patient for one or more clinically significant Parkinson-like signs or symptoms; and administering a reduced amount of the VMAT2 inhibitor to the patient when the patient experiences one or more clinically significant Parkinson-like signs or symptoms.In some embodiments, when the VMAT2 inhibitor is tetrabenazine or deutetrabenazine, the VMAT2 inhibitor is administered to treat a disease or disorder other than Huntington's disease.

[0119] In some embodiments, the VMAT2 inhibitor is not administered to a patient with pre-existing parkinsonism.In some embodiments, the method further comprises determining whether the patient has pre-existing parkinsonism before starting treatment with the VMAT2 inhibitor.

[0120] In some embodiments, the methods further include administering to a patient experiencing one or more clinically significant Parkinson's-like signs or symptoms one or more medications used to treat Parkinson's disease.

[0121] In some embodiments, before administration, the patient is at increased risk of experiencing one or more clinically significant Parkinson-like signs or symptoms.In some embodiments, the patient at increased risk of experiencing clinically significant Parkinson-like signs or symptoms is a patient who is co-administered one or more antipsychotics, antidepressants, antiepileptics, or other drugs that are known to possibly cause Parkinsonism.In some embodiments, the patient at increased risk of experiencing clinically significant Parkinson-like signs or symptoms is a patient with existing Parkinsonism.

[0122] In some embodiments, the one or more clinically significant Parkinsonian signs or symptoms are selected from difficulty moving or loss of ability to move muscles voluntarily, tremor, gait disturbance, or salivation. In some embodiments, the one or more clinically significant Parkinsonian signs or symptoms are selected from immobility, severe tremor, gait disturbance (shuffling, accelerated gait), and salivation. In some embodiments, the one or more clinically significant Parkinsonian signs or symptoms are selected from falls, gait disturbance, tremor, salivation, and hypokinesia. In some embodiments, the one or more clinically significant Parkinsonian signs or symptoms are selected from tremor, stiffness, problems moving or walking, or maintaining balance.

[0123] In some embodiments, one or more clinically significant Parkinson's-like signs or symptoms occur within the first two weeks of administering the VMAT2 inhibitor.In some embodiments, one or more clinically significant Parkinson's-like signs or symptoms occur within the first two weeks of increasing the amount of the VMAT2 inhibitor administered to the patient.

[0124] Also provided herein are pharmaceutical compositions comprising a VMAT2 inhibitor as an active pharmaceutical ingredient in combination with one or more pharma- ceutically acceptable carriers or excipients.

[0125] 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.

[0126] The pharmaceutical compositions provided herein may be provided in unit dosage form or multiple dosage form. Unit dosage form, as used herein, refers to a physically separate unit suitable for administration to human and animal subjects and packaged individually 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 form include ampoules, syringes, and individually packaged tablets and capsules. A unit dosage form may be administered in part 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 form. Examples of multiple dosage form include vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0127] The pharmaceutical compositions provided herein may be administered alone or in combination with one or more other compounds provided herein, one or more other active ingredients. The pharmaceutical compositions provided herein may be formulated in various dosage forms for oral, parenteral and topical administration. The pharmaceutical compositions may also be formulated as modified release dosage forms, including delayed-release, extended-release, prolonged-release, sustained-release, pulsed-release, controlled-release, accelerated-release and fast-release, targeted-release, programmed-release and gastric retention dosage forms. These dosage forms may be prepared according to conventional methods and techniques known to those skilled in the art. The pharmaceutical compositions provided herein may be administered once or multiple times at intervals of time. It is understood that the exact dosage and duration of treatment may vary with the age, weight and condition of the subject being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro testing or diagnostic data. It will be further understood that for any particular individual, specific dosage regimens will be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

[0128] In some embodiments, the pharmaceutical composition has a high drug load, for example as described in PCT Publication WO2019 / 060322, the entirety of which is incorporated herein by reference. In some embodiments, the pharmaceutical composition comprises a VMAT2 inhibitor, silicified microcrystalline cellulose, isomalt, hydroxypropyl methylcellulose, partially pregelatinized corn starch, and magnesium stearate. In some embodiments, the pharmaceutical composition comprises valbenazine ditosylate having about 40% w / w%, silicified microcrystalline cellulose having about 25% w / w%, isomalt having about 20% w / w%, hydroxypropyl methylcellulose having about 5% w / w%, partially pregelatinized corn starch having about 7.5% w / w%, and magnesium stearate having about 2.5% w / w%.

[0129] Oral route The pharmaceutical compositions provided herein may be provided in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gums, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharma- ceutically acceptable carriers or excipients, including, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners and flavoring agents.

[0130] Binders or granulators impart cohesive properties to the tablet to ensure that it remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, extract of hornwort, breadwah gum, ghatti gum, mucilage of isabgol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, microcrystalline cellulose, such as AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, 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 about 50 to about 99% by weight.

[0131] 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.Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient quantities, can impart properties to some compressed tablets that allow them to disintegrate in the mouth by chewing.Such compressed tablets can be used as chewable tablets.

[0132] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Vee gum HV; citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn (com) starch, potato starch, tapioca starch, and pregelatinized starch; clays; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of skill in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% by weight or about 1 to about 5% by weight of disintegrant.

[0133] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols such as 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, watercress, silica or silica gel such as 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., Boston, MA) and asbestos-free talc. Coloring agents include any of the approved, certified water-soluble FD&C dyes and water-insoluble FD&C dyes and lakes suspended on alumina hydrate, and mixtures thereof. Lakes are combinations of water-soluble dyes adsorbed onto hydrated oxides of heavy metals resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners such as 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® 80), and triethanolamine oleate.Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic add, 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. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[0134] It should be understood that many carriers and excipients may perform multiple functions even within the same formulation. The pharmaceutical compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, fast dissolving tablets, multiple compressed tablets, or enteric coated tablets, sugar coated or film coated tablets. Enteric coated tablets are compressed tablets coated with a material that resists the action of stomach acid but dissolves or disintegrates in the intestine, thereby 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 that may be beneficial in masking unpleasant tastes or odors and protecting the tablet from oxidation. Film coated tablets are compressed tablets covered with a thin layer or film of 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 characteristics 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.

[0135] Tablet dosage forms may 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. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0136] The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two sections, one nested over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SEC) are soft, globular shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules may also be coated, as known to those skilled in the art, to modify or prolong the dissolution of the active ingredient.

[0137] The pharmaceutical compositions provided herein may 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 another liquid in the form of small globules, and may be oil-in-water or water-in-oil. Emulsions may contain a pharma-ceutically acceptable non-aqueous liquid or solvent, an emulsifier and a preservative. Suspensions may contain a pharma-ceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions may contain pharma-ceutically acceptable acetals, such as di(lower alkyl)acetals of lower alkyl aldehydes (the term "lower" means alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal, and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, e.g., sucrose, and may also contain preservatives. For a liquid dosage form, the solution, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharma- ceutically acceptable liquid carrier, e.g., water, to be conveniently measured for administration.

[0138] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing 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, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfites, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0139] The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres or nanosystems.

[0140] The pharmaceutical compositions provided herein may be provided as non-effervescent or effervescent granules and powders that are reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide. Colorants and flavoring agents may be used in all of the above dosage forms. The pharmaceutical compositions provided herein may be formulated as immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms.

[0141] The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impart the desired therapeutic action, or with substances that supplement the desired action, such as antacids, proton pump inhibitors, and H2 receptor antagonists.

[0142] Dosage In the treatment, prevention or amelioration of one or more symptoms of a disorder or other condition, disorder or disease associated with VMAT2 inhibition, suitable dosage levels are generally about 0.001 to 100 mg per kg of subject body weight per day (mg / kg per day), about 0.01 to about 80 mg / kg per day, about 0.1 to about 50 mg / kg per day, about 0.5 to about 25 mg / kg per day, or about 1 to about 20 mg / kg per day, which may be administered in single or multiple doses. Within this range, dosages may be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0, 1 to 15, 1 to 20, or 1 to 50 mg / kg per day. In certain embodiments, dosage levels are about 0.001 to 100 mg / kg per day.

[0143] In certain embodiments, the dosage level is about 25 to 100 mg / kg per day. In certain embodiments, the dosage level is about 0.01 to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.1 to about 80 mg / kg per day. In certain embodiments, the dosage level is about 0.1 to about 50 mg / kg per day. In certain embodiments, the dosage level is about 0.1 to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.5 to about 80 mg / kg per day. In certain embodiments, the dosage level is about 0.5 to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.5 to about 25 mg / kg per day. In certain embodiments, the dosage level is about 1 to about 80 mg / kg per day. In certain embodiments, dosage levels are from about 1 to about 75 mg / kg per day. In certain embodiments, dosage levels are from about 1 to about 50 mg / kg per day. In certain embodiments, dosage levels are from about 1 to about 40 mg / kg per day. In certain embodiments, dosage levels are from about 1 to about 25 mg / kg per day.

[0144] In certain embodiments, the dosage level is about 5.0-150 mg per day, and in certain embodiments, 10-100 mg per day. In certain embodiments, the dosage level is about 80 mg per day. In certain embodiments, the dosage level is about 40 mg per day.

[0145] 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, in particular about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 75, about 80, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900 and about 1,000 mg of active ingredient, for symptomatic adjustment of the dosage to the subject to be 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.

[0146] It will be understood, however, that the specific dose level and frequency of dosing for any particular subject may vary and will depend upon a variety of factors including the activity of the particular compound employed, 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.

[0147] 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, as well as other conditions commonly treated with antipsychotic medication.

[0148] In certain embodiments, the compounds provided herein may also be combined with or used in combination with typical antipsychotics.In certain embodiments, typical antipsychotics are fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine or trifluoperazine.In certain embodiments, antipsychotics are atypical antipsychotics.In certain embodiments, atypical antipsychotics are aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone or ziprasidone.In certain embodiments, atypical antipsychotics are clozapine.

[0149] Such other agents or drugs may 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 may be utilized, but are not required.Therefore, the pharmaceutical compositions provided herein include those containing one or more other active ingredients or therapeutic agents in addition to the compounds provided herein.

[0150] The weight ratio of the compound provided herein to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, each effective dose is used. Thus, for example, when the compound provided herein is used in combination with a second drug, or a pharmaceutical composition containing such other drug, the weight ratio of the particulate material 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.

[0151] Combinations of particulate materials provided herein with other active ingredients will generally also be within the aforementioned ranges, but in each case, an effective dose of each active ingredient should be used.

[0152] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented for illustrative purposes only and to assist those skilled in the art in using the present disclosure. The examples are not intended to otherwise limit the scope of the present disclosure in any way. EXAMPLES

[0153] Example 1 This was a Phase I, open-label, single-dose PK study of valbenazine to evaluate the safety and PK of valbenazine and its metabolites in subjects with normal renal function or severe renal impairment.A total of 16 subjects (8 with severe renal impairment and 8 with normal renal function) received a single dose of 40 mg valbenazine (free base equivalent as the ditosylate salt) under fasting conditions.

[0154] Administration of 40 mg of valbenazine to subjects with severe renal impairment did not result in a significant increase in the C of valbenazine, NBI-98782, or NBI-136110 compared with subjects with normal renal function. max AUC 0~∞ had no clinically meaningful effect on the protein binding of valbenazine or NBI-98782, the active metabolite of valbenazine (Figure 1). Furthermore, renal status had little effect on protein binding of valbenazine or NBI-98782, valbenazine's active metabolite. Although there was a reduction in the urinary clearance of valbenazine and metabolites in subjects with severe renal impairment compared with subjects with normal renal function, this was not associated with clinically relevant changes in systemic exposure due to an overall small fraction of the administered dose being excreted in the urine.

[0155] Valbenazine 40 mg administered as a single dose was well tolerated in 16 subjects, including 8 subjects with normal renal function and 8 subjects with severe renal impairment. All 16 subjects completed the study, and no deaths, serious or severe TEAEs, or discontinuations due to TEAEs were reported. Overall, 4 (25.0%) subjects experienced TEAEs, including 2 (25.0%) subjects from each of the renal function groups. Treatment-related TEAEs were reported in 3 subjects, including blurred vision (1 subject in the severe renal impairment group), headache (1 subject in the normal renal function group), and somnolence (1 subject from the normal renal function group and 1 subject in the severe renal impairment group).

[0156] There were no clinically significant changes in clinical research tests, vital sign measurements, body weight, or ECG parameters during the study, and no clinically important differences were noted between groups. No subjects had a QTcF interval >480 msec or an increase from baseline >60 msec.

[0157] Overall conclusion: Administration of 40 mg of valbenazine to subjects with severe renal impairment did not result in a significant increase in the C of valbenazine or metabolites compared with subjects with normal renal function. max or AUC 0~∞ had no clinically meaningful effect on

[0158] Valbenazine was well tolerated in subjects with severe renal impairment and in subjects with normal renal function.

[0159] 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 herein and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified as necessary to use concepts from various patents, applications, and publications to provide further embodiments.

[0160] These and other changes can be made to the embodiments in light of the above detailed description. Generally, in the following claims, the terms used should not be construed to limit the scope of the claims to the specific embodiments disclosed in the specification and the claims, but rather to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by this disclosure. In certain embodiments, for example, the following are provided: (Item 1) 1. A method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, the subject having severe renal impairment, administering said VMAT2 inhibitor to said subject in need thereof. A method comprising: (Item 2) 1. A method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, comprising: administering said VMAT2 inhibitor to said subject in need thereof; thereafter determining that the subject has severe renal impairment; and Continue administering the VMAT2 inhibitor. A method comprising: (Item 3) 1. A method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, the subject having mild or moderate renal impairment, administering said VMAT2 inhibitor to said subject in need thereof; thereafter determining that the subject has severe renal impairment; and Continue administering the VMAT2 inhibitor. A method comprising: (Item 4) 1. A method of treating a disease or disorder requiring a vesicular monoamine transporter 2 (VMAT2) inhibitor in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor ... comprising administering to said subject a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor in said subject; administering said VMAT2 inhibitor to said subject in need thereof. A method comprising: (Item 5) 1. A method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to said subject in need thereof. wherein the subject has severe renal impairment. (Item 6) 6. The method of any one of items 1 to 5, wherein the subject is not undergoing chronic dialysis. (Item 7) The method of any one of the preceding items, wherein the amount of the VMAT2 inhibitor administered to the subject is not adjusted for subjects with normal renal function. (Item 8) 7. The method of any one of items 1 to 6, wherein the amount of the VMAT2 inhibitor administered to the subject is reduced relative to a normal subject with renal impairment. (Item 9) The method of any one of the preceding items, further comprising determining the subject's renal function sufficiency level prior to administering the VMAT2 inhibitor. (Item 10) 10. The method of claim 9, wherein the Cockcroft-Gault formula is used to determine the subject's level of renal function adequacy. (Item 11) The subject has a blood glucose level of 15 to 29 mL / min / 1.73 m using the Cockcroft-Gault method. 2 The method according to item 10, having a creatinine clearance rate of (Item 12) 10. The method of claim 9, wherein the subject's serum creatinine concentration is used to determine the subject's level of renal function sufficiency. (Item 13) The subject, For men aged 18-20, less than 4.9 mg / dL For women aged 18-20, less than 3.5 mg / dL For men aged 21 to 30, less than 4.5 mg / dL For women aged 21 to 30, less than 3.2 mg / dL; For men aged 31 to 40, less than 4.1 mg / dL For women aged 31 to 40, less than 2.9 mg / dL For women aged 41 to 50, less than 2.7 mg / dL For men aged 51 to 60, less than 3.3 mg / dL For women aged 51 to 60, less than 2.4 mg / dL For men over 60 years of age, less than 3.0 mg / dL, or < 2.0 mg / dL for women over 60 years of age The method according to item 12, wherein the serum creatinine concentration is approximately (Item 14) The method of any one of items 1 to 4, wherein the VMAT2 inhibitor is administered to treat a neurological or psychiatric disease or disorder. (Item 15) 15. The method according to any one of items 5 to 14, wherein said neurological or psychiatric disease or disorder is hyperkinetic disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome or choreoacanthocytosis. (Item 16) 16. The method of claim 15, wherein the neurological or psychiatric disease or disorder is a hyperkinetic disorder. (Item 17) 17. The method of claim 16, wherein the hyperkinetic disorder is tardive dyskinesia. (Item 18) 17. The method of claim 16, wherein the hyperkinetic disorder is Tourette's syndrome. (Item 19) 17. The method of claim 16, wherein the hyperkinetic disorder is Huntington's disease. (Item 20) 17. The method of claim 16, wherein the hyperkinetic disorder is a tic. (Item 21) 17. The method of claim 16, wherein the hyperkinetic disorder is chorea associated with Huntington's disease. (Item 22) 17. The method of item 16, wherein the hyperkinetic disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome or tremor. (Item 23) The method of any one of the preceding items, wherein the VMAT2 inhibitor is administered orally. (Item 24) The method of any one of the preceding items, wherein the VMAT inhibitor is administered in the form of a tablet or capsule. (Item 25) The method of any one of the preceding items, wherein the VMAT2 inhibitor is administered with or without food. (Item 26) The method of any one of the preceding items, wherein the VMAT2 inhibitor is 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 pharma- ceutically acceptable salts and / or isotopic variants thereof. (Item 27) 27. The method of claim 26, wherein the VMAT2 inhibitor is 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 its pharma-ceutical acceptable salts. (Item 28) 28. The method of claim 27, wherein the VMAT2 inhibitor is the tosylate 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. (Item 29) 29. The method of claim 28, 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. (Item 30) 30. The method of any one of items 26 to 29, wherein the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base. (Item 31) 31. The method of claim 30, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg of valbenazine free base. (Item 32) 31. The method of claim 30, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg of valbenazine free base. (Item 33) 31. The method of claim 30, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 60 mg of valbenazine free base. (Item 34) 31. The method of item 30, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 80 mg of valbenazine free base. (Item 35) 31. The method of claim 30, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 120 mg of valbenazine free base. (Item 36) 30. The method of any one of items 1 to 29, 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 37) Item 37. The method of item 36, wherein the first period of time is one week. (Item 38) 38. The method of claim 36 or 37, wherein the first amount is equivalent to about 40 mg of valbenazine free base. (Item 39) 39. The method of any one of items 36 to 38, wherein the second amount is equivalent to about 80 mg of valbenazine free base. (Item 40) 26. The method according to any one of items 1 to 25, 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 pharma- ceutically acceptable salt and / or isotopic variant thereof. (Item 41) 41. The method of claim 40, 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 pharma- ceutically acceptable salt thereof. (Item 42) The VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-di(methoxy-d 3 41. The method according to item 40, wherein the compound is an isotopic variant of 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharma- ceutically acceptable salt thereof. (Item 43) 1. A method of treating a patient with tardive dyskinesia, the patient having severe renal impairment, 20. A method comprising administering to the patient 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 pharma-ceutically acceptable salts thereof, wherein the therapeutically effective amount is the same amount that would be administered to a patient with normal renal function. (Item 44) The patient is receiving a rate of 15 to 29 mL / min / 1.73 m using the Cockcroft-Gault system. 2 44. The method according to item 43, having a creatinine clearance rate of (Item 45) The patient, For men aged 18-20, less than 4.9 mg / dL For women aged 18-20, less than 3.5 mg / dL For men aged 21 to 30, less than 4.5 mg / dL For women aged 21 to 30, less than 3.2 mg / dL; For men aged 31 to 40, less than 4.1 mg / dL For women aged 31 to 40, less than 2.9 mg / dL For women aged 41 to 50, less than 2.7 mg / dL For men aged 51 to 60, less than 3.3 mg / dL For women aged 51 to 60, less than 2.4 mg / dL For men over 60 years of age, less than 3.0 mg / dL, or < 2.0 mg / dL for women over 60 years of age 45. The method according to item 43 or 44, wherein the patient has an approximate serum creatinine concentration of (Item 46) 46. ​​The method of any one of items 43 to 45, wherein the VMAT2 inhibitor is administered orally. (Item 47) 47. The method according to any one of items 43 to 46, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. (Item 48) 48. The method according to any one of items 43 to 47, 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. (Item 49) 49. The method according to any one of items 43 to 48, 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. (Item 50) 50. The method according to item 49, wherein the ditosylate 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 is in crystalline form I. (Item 51) 51. The method of any one of items 43 to 50, wherein the patient has a substantially similar exposure 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[2,1-a]isoquinolin-2-yl ester and its active metabolite, (+)-α-HTBZ, in the patient compared to the exposure in a patient with normal renal function administered the same amount of the VMAT2 inhibitor. (Item 52) The exposure is max or AUC 0-∞ 52. The method according to item 51, wherein the measurement is performed by (Item 53) 53. The method of any one of items 43 to 52, wherein the therapeutically effective amount is an amount equivalent to about 40 mg 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 free base once daily. (Item 54) 53. The method of any one of items 43 to 52, wherein the therapeutically effective amount is an amount equivalent to about 60 mg 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 free base once daily. (Item 55) 53. The method of any one of items 43 to 52, wherein the therapeutically effective amount is an amount equivalent to about 80 mg 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 free base once daily. (Item 56) 53. The method of any one of items 43 to 52, wherein the therapeutically effective amount is a first amount once per day for one week, followed by a second amount once per day after one week. (Item 57) 57. The method of claim 56, wherein the first 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. (Item 58) 57. The method of claim 56, wherein the first amount is an amount equivalent to about 60 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. (Item 59) 58. The method of claim 56 or 57, wherein the second amount is an amount equivalent to about 60 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. (Item 60) 59. The method of any one of items 56 to 58, wherein the second amount is 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. (Item 61) 61. The method of any one of items 43 to 60, wherein the VMAT2 inhibitor does not undergo primary renal clearance. (Item 62) 1. A method of treating a patient with tardive dyskinesia, comprising: (a) orally administering to said patient 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 pharma-ceutically acceptable salts thereof; (b) thereafter determining that the patient has severe renal impairment; and (c) continuing to administer the same therapeutically effective amount of said VMAT2 inhibitor. A method comprising: (Item 63) The patient is receiving a rate of 15 to 29 mL / min / 1.73 m using the Cockcroft-Gault system. 2 63. The method according to item 62, having a creatinine clearance rate of (Item 64) 64. The method of item 62 or 63, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. (Item 65) 65. The method according to any one of items 62 to 64, 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. (Item 66) Item 66. The method of item 65, 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. (Item 67) 67. The method of any one of items 62 to 66, wherein the patient has a substantially similar exposure 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[2,1-a]isoquinolin-2-yl ester and its active metabolite, (+)-α-HTBZ, in the patient compared to the exposure in a patient with normal renal function administered the same amount of the VMAT2 inhibitor. (Item 68) The exposure is max or AUC 0-∞ Item 68. The method according to item 67, wherein the concentration is measured by (Item 69) 69. The method of any one of items 62 to 68, wherein the therapeutically effective amount is an amount equivalent to about 40 mg 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 free base once daily. (Item 70) 69. The method of any one of items 62 to 68, wherein the therapeutically effective amount is an amount equivalent to about 60 mg 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 free base once daily. (Item 71) 69. The method of any one of items 62 to 68, wherein the therapeutically effective amount is an amount equivalent to about 80 mg 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 free base once daily. (Item 72) 69. The method of any one of items 62 to 68, wherein the therapeutically effective amount is a first amount once per day for one week, followed by a second amount once per day after one week. (Item 73) 73. The method of claim 72, wherein the first 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. (Item 74) 73. The method of claim 72, wherein the first amount is an amount equivalent to about 60 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. (Item 75) 74. The method of claim 72 or 73, wherein the second amount is an amount equivalent to about 60 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. (Item 76) 75. The method of claim 73 or 74, wherein the second amount is 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. (Item 77) 77. The method of any one of items 62 to 76, wherein the VMAT2 inhibitor does not undergo primary renal clearance. (Item 78) A pharmaceutical composition 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 pharma- ceutical acceptable salts thereof for treating patients with a neurological or psychiatric disease or disorder having severe renal impairment. (Item 79) Use 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 in the manufacture of a medicament for treating a patient with a neurological or psychiatric disease or disorder with severe renal impairment.

Claims

1. 1. A composition for treating a patient having a neurological or psychiatric disease or disorder, the composition comprising 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 pharma- ceutically acceptable salts thereof, characterized in that a therapeutically effective amount of the VMAT2 inhibitor is administered to the patient, the patient having severe renal impairment, the therapeutically effective amount being the same effective amount as would be administered to a patient having normal renal function, and the patient having severe renal impairment has a creatinine clearance of <30 mL / min.

2. 2. The composition of claim 1, wherein the therapeutically effective amount is equivalent to about 40 mg 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 free base once daily.

3. 2. The composition of claim 1, wherein the therapeutically effective amount is equivalent to about 60 mg 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 free base once daily.

4. 2. The composition of claim 1, wherein the therapeutically effective amount is equivalent to about 80 mg 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 free base once daily.

5. 5. The composition according to claim 1, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule.

6. 6. The composition of any one of claims 1 to 5, 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.

7. 7. The composition of claim 6, wherein the VMAT2 inhibitor is the ditosylate 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.

8. 8. The composition of claim 7, wherein the ditosylate 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 is polymorphic Form I.

9. 9. The composition of any one of claims 1 to 8, wherein the exposure 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 and its active metabolite [+]-α-HTBZ in said patient with severe renal impairment is substantially similar to the exposure 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 and its active metabolite [+]-α-HTBZ in said patient with normal renal function.

10. 10. The composition of claim 9, wherein the exposure is measured by Cmax.

11. The exposure is ０～∞ The composition of claim 10, wherein the concentration is measured by

12. 9. The composition of any one of claims 1 to 8, wherein the VMAT2 inhibitor does not undergo primary renal clearance.

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

14. The composition of claim 13, wherein the hyperkinetic disorder is chorea.

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

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

17. 1. A composition for treating a patient having a neurological or psychiatric disease or disorder, the composition comprising 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 pharma-ceutically acceptable salts thereof, wherein a therapeutically effective amount of the VMAT2 inhibitor is orally administered to the patient; After said administering, said patient is examined to determine whether said patient has severe renal impairment; The composition wherein administration of the same therapeutically effective amount of said VMAT2 inhibitor to said patient continues, and said patient with severe renal impairment has a creatinine clearance of <30 mL / min.

18. 18. The composition of claim 17, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule.

19. 19. The composition of claim 17 or 18, 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.

20. 20. The composition of claim 19, wherein the VMAT2 inhibitor is the ditosylate 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.

21. 21. The composition of claim 20, wherein the ditosylate 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 is polymorphic Form I.

22. 22. The composition of any one of claims 17 to 21, wherein the therapeutically effective amount is an amount equivalent to about 40 mg 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 free base once daily.

23. 22. The composition of any one of claims 17 to 21, wherein the therapeutically effective amount is an amount equivalent to about 60 mg 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 free base once daily.

24. 22. The composition of any one of claims 17 to 21, wherein the therapeutically effective amount is an amount equivalent to about 80 mg 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 free base once daily.

25. 25. The composition of any one of claims 17 to 24, wherein the exposure 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 and its active metabolite [+]-α-HTBZ in said patient with severe renal impairment is substantially similar to the exposure 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 and its active metabolite [+]-α-HTBZ in said patient with normal renal function.

26. The exposure is ｍａｘ The composition of claim 25, wherein the concentration is measured by

27. The exposure is ０～∞ The composition of claim 25, wherein the measurement is based on the following:

28. 28. The composition of any one of claims 17 to 27, wherein the VMAT2 inhibitor does not undergo primary renal clearance.

29. 29. The composition of any one of claims 17 to 28, wherein the neurological or psychiatric disease or disorder is a hyperkinetic disorder.

30. 30. The composition of claim 29, wherein the hyperkinetic disorder is chorea.

31. 31. The composition of claim 30, wherein the hyperkinetic disorder is chorea associated with Huntington's disease.

32. 30. The composition of claim 29, wherein the hyperkinetic disorder is tardive dyskinesia.

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