NMDA receptor positive allosteric modulatory compositions and methods of use thereof

Abstract

Disclosed herein are pharmaceutical compositions of Compound I having desirable pharmacokinetic properties. Also disclosed are methods of treating CNS conditions, with such pharmaceutical compositions.

Description

NMD A RECEPTOR POSITIVE ALLOSTERIC MODULATORY COMPOSITIONS AND METHODS OF USE THEREOFCross Reference To Related Applications

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 638,821, filed April 25, 2024, the disclosures of which, is incorporated by reference herein in its entirety.Background

[0002] NMDA receptors are heteromeric complexes comprised of NR1, NR2, and / or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators. NMDA receptors are expressed in the peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activating these receptors contributes to synaptic plasticity in some circumstances and exci totoxi city in others. These receptors are ligand-gated ion channels that admit Ca2+after binding of the glutamate and glycine, and are fundamental to excitatory neurotransmission and normal CNS function. Positive modulators may be useful as therapeutic agents with potential clinical uses as cognitive enhancers and in the treatment of psychiatric disorders in which glutamatergic transmission is reduced or defective (see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325).

[0003] There is a need for new pharmaceutical compositions comprising positive allosteric modulators of the NMDA receptor for the prevention and treatment of conditions associated with NMDA receptor function. The compositions, and methods described herein are directed toward this end.Summary of the Disclosure

[0004] The present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of [3p,24S]-25,25,25-trifhioro-3-methyl-26,27-dinorergost- 5-ene-3,24-diol (“Compound I”), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a pharmacokinetic profile as disclosed herein.

[0005] In one aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a Cmax of between about 2 ng / ml and about 100 ng / mL; b) an AUC2411 of between about 50 and about 1000 ng*h / mL; c) an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; d) an AUC 00 of between about 50 ng*h / mL and about 2000 ng*h / mL; or e) a tmax of between about 2 hours and about 15 hours.

[0006] In one aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a Cmax of between about 2 ng / ml and about 80 ng / mL; b) an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; c) an AUC 00 of between about 50 ng*h / mL and about 2000 ng*h / mL; or d) a tmax of between about 2 hours and about 15 hours.

[0007] In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 ng / ml and about 100 ng / mL. In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 ng / ml and about 80 ng / mL. In some embodiments, the pharmaceutical composition provides a Cmax of between about 5 ng / ml and about 50 ng / mL. In some embodiments, the pharmaceutical composition provides a Cmax of between about 5 ng / ml and about 20 ng / mL.

[0008] In some embodiments, the pharmaceutical composition provides a tmax of between about 2 hours and about 15 hours.

[0009] In some embodiments, the pharmaceutical composition provides a tmax of between about 4 hours and about 8 hours.

[0010] In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL.

[0011] In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 100 ng*h / mL and about 500 ng*h / mL.

[0012] In some embodiments, the pharmaceutical composition provides an AUCiast ot between about 50 ng*h / mL and about 1000 ng*h / mL.

[0013] In some embodiments, the pharmaceutical composition provides an AUCiast of between about 100 ng*h / mL and about 500 ng*h / mL.

[0014] In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 ng*h / mL and about 2000 ng*h / mL.

[0015] In some embodiments, the pharmaceutical composition provides an AUCoo of between about 100 ng*h / mL and about 1500 ng*h / mL.

[0016] In some embodiments, the pharmaceutical composition provides an AUCoo of between about 100 ng*h / mL and about 1100 ng*h / mL.

[0017] In some embodiments, the present disclosure provides a pharmaceutical composition, wherein the pharmaceutical composition provides the pharmacokinetic parameter: a) a Cmax of between about 2 ng / mL and about 100 ng / mL; b) an AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL; c) an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; d) an AUC 00 of between about 50 ng*h / mL and about 2000 ng*h / mL; and e) a tmax of between about 2 hours and about 15 hours.

[0018] In some embodiments, the present disclosure provides a pharmaceutical composition, wherein the pharmaceutical composition provides the pharmacokinetic parameter: a) a Cmax of between about 2 ng / mL and about 80 ng / mL; b) an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; c) an AUC 00 of between about 50 ng*h / mL and about 2000 ng*h / mL; and d) a tmax of between about 2 hours and about 15 hours.

[0019] In some embodiments, the present disclosure provides a pharmaceutical composition which comprises Compound I.

[0020] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound I.

[0021] In some embodiments, the present disclosure provides a pharmaceutical composition which comprises between about 0.3 to about 3.0 mg of Compound I, or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the pharmaceutical composition comprises between about 0.3 to about 3.0 mg of Compound I.

[0023] In some embodiments, the pharmaceutical composition comprises between about 0.3 to about 3.0 mg of a pharmaceutically acceptable salt of Compound I.

[0024] In some embodiments, the present disclosure provides a pharmaceutical composition comprises hydroxypropyl-P-cyclodextrin.

[0025] In some embodiments, the present disclosure provides a pharmaceutical composition wherein said pharmacokinetic parameter is obtained following a single administration of the pharmaceutical composition.

[0026] In some embodiments, the said pharmacokinetic parameter is obtained following multiple administrations of the pharmaceutical composition.

[0027] In some embodiments, the said pharmacokinetic parameter is obtained following 7 administrations of the pharmaceutical composition.

[0028] In some embodiments, the said pharmacokinetic parameter is obtained following 14 administrations of the pharmaceutical composition.

[0029] In some embodiments, the said pharmacokinetic parameter is obtained following 17 administrations of the pharmaceutical composition.

[0030] In some embodiments, the present disclosure provides a pharmaceutical composition wherein each of said pharmacokinetic parameter is obtained following administration of the composition comprising Compound I under fasted conditions.

[0031] In some embodiments, the present disclosure provides a pharmaceutical composition, wherein said pharmacokinetic parameter is obtained following administration of the composition comprising Compound I under fed conditions.

[0032] In some embodiments, wherein the pharmacokinetic parameter is obtained following administration of the composition comprising Compound I followed by administration of hydroxypropyl-P-cyclodextrin.

[0033] In some embodiments, the present disclosure provides a pharmaceutical composition, wherein the pharmaceutical composition is an oral dosage form.

[0034] In another aspect, the present disclosure provides a method of treating a CNS- related condition in a subject, wherein the CNS-related condition, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0035] In another aspect, the present disclosure provides a method of treating cognitive impairment in a subject having a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease andAlzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0036] In another aspect, the present disclosure provides a method of treating Mild Cognitive Impairment (MCI) associated with a CNS-related condition in a subject, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0037] In another aspect, the present disclosure provides a method of improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0038] In another aspect, the present disclosure provides a method of improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0039] In another aspect, the present disclosure provides a method of improving learning in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0040] In another aspect, the present disclosure provides a method of improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0041] In another aspect, the present disclosure provides a method of improving cognition in a subject having a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’sdisease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0042] In another aspect, the present disclosure provides a method for slowing cognitive decline in a subject having a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0043] In another aspect, the present disclosure provides a method of inducing sedation or anesthesia in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0044] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating a CNS- related condition in a subject.

[0045] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating a CNS- related condition in a subject, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0046] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating cognitive impairment in a subject having a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0047] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating Mild Cognitive Impairment (MCI) associated with a CNS-related condition in a subject, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0048] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0049] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving workingmemory in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0050] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving learning in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0051] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0052] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving cognition in a subject having a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0053] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for slowing cognitive decline in a subject having a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0054] In another aspect, the present disclosure provides the use of a pharmaceutical composition as disclosed herein, for the manufacture of a medicament for inducing sedation or anesthesia in a subject.

[0055] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, for use in treating a CNS related condition in a subject.

[0056] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, for use in treating a CNS-related condition in a subject, wherein said CNS- related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0057] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, for use in treating cognitive impairment in a subject having a CNS-relatedcondition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0058] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, for use in treating Mild Cognitive Impairment (MCI) associated with a CNS-related condition in a subject, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0059] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, for use in improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0060] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, for use in improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0061] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, for use in improving learning in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0062] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, for use in improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with a CNS-related condition, wherein said CNS- related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0063] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, for use in improving cognition in a subject having a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0064] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, for use in slowing cognitive decline in a subject having a CNS-related condition, wherein said CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

[0065] In some embodiments, the said CNS-related condition is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank group of proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraine headaches), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington’s disease and Parkinson’s disease) and tinnitus.

[0066] In some embodiments, the sterol synthesis disorder is selected from the group consisting of Smith-Lemli-Opitz Syndrome (SLOS), desmosterolosis, sitosterolemia, cerebrotendinous xanthomatosis (CTX), Mevalonate Kinase Deficiency (MKD), and SC4MOL gene mutation (SMO Deficiency).

[0067] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein for use in inducing sedation or anesthesia in a subject.Brief Description of the Drawings

[0068] Figure 1A depicts the randomization schema for Compound I in the Single Ascending Dose (SAD) study.

[0069] Figure IB depicts the randomization schema for Compound I in the Multiple Ascending Dose (MAD) study.

[0070] Figure 2A depicts the study design for the SAD study.

[0071] Figure 2B depicts the study design for the MAD study.

[0072] Figure 3A depicts mean plasma concentration of Compound I by single-ascending dose (SAD) over time (Cohorts 1 to 4; healthy participants).

[0073] Figure 3B depicts mean plasma concentration of Compound I by multipleascending dose (MAD) over time (Cohorts 1 and 2); Day 1 dosing.

[0074] Figure 3C depicts mean plasma concentration of Compound I by multipleascending dose (MAD) over time (Cohorts 1 and 2; healthy participants); day 14 dosing.

[0075] Figure 4 depicts the dose proportionality and linearity in the Compound 1 SAD study.

[0076] Figure 5 depicts the mean plasma trough concentrations of Compound I over time in the MAD study. Mean (SD) plasma trough concentrations over time following multiple dose administrations of Compound I oral solution in healthy adults (Cohorts 1 and 2) and in participants with HD (Cohort 3).

[0077] Figure 6A depicts the performance on Groton Maze Learning Test, in participants with HD and pooled healthy participants in the Compound I MAD study. Z-transformed change from baseline to day 14 (mean ± SE).

[0078] Figure 6B depicts the performance on the Two-Back Learning Task, in participants with HD and pooled healthy participants in the Compound I MAD study. Z-transformed change from baseline to day 14 (mean ± SE)

[0079] Figure 6C depicts the performance on the Detection Test, in participants with HD and pooled healthy participants in the Compound I MAD study. Z-transformed change from baseline to day 14 (mean ± SE).Detailed Description

[0080] The present disclosure provides compounds that are NMDA receptor positive allosteric modulators. The compounds of the disclosure are useful as therapeutic agents for treating, for example, CNS-related conditions including, but not limited to, adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, pain, encephalopathy secondary to a medical condition, seizure disorders, stroke, traumatic brain injury, movement disorders and tinnitus.

[0081] General Definitions

[0082] The term “herein” means the entire application.

[0083] Unless otherwise defined herein, scientific, and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. Generally, nomenclature used in connection with the compounds, composition and methods described herein, are those well-known and commonly used in the art.

[0084] It should be understood that any of the embodiments described herein, including those described under different aspects of the disclosure and different parts of the specification (including embodiments described only in the Examples) can be combined withone or more other embodiments of the disclosure, unless explicitly disclaimed or improper. Combination of embodiments are not limited to those specific combinations claimed via the multiple dependent claims. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.

[0085] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” will be understood to imply the inclusion of a stated integer (or component, element, or method) or group of integers (or components, elements, or methods), but not the exclusion of any other integer (or component, element or method) or group of integers (or components, elements, or methods).

[0086] Throughout the specification, where compositions are described as having, including, or comprising (or variations thereof), specific components, it is contemplated that compositions also may consist essentially of, or consist of, the recited components.Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also may consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0087] The term “including,” as used herein, means “including but not limited to.” “Including” and “including but not limited to” are used interchangeably. Thus, these terms will be understood to imply the inclusion of a stated integer (or component, element or method) or group of integers (or components, elements or methods), but not the exclusion of any other integer (or component, element or method) or group of integers (or components, elements or methods).

[0088] As used herein, “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0089] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construedto cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0090] The term “or” as used herein should be understood to mean “and / or,” unless the context clearly indicates otherwise.

[0091] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range and including the endpoints, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0092] All of the publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0093] The terms “active ingredient,” “active agent” and “active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, “active ingredient,” “active agent” and “active substance” may be an optically active isomer of a compound described herein.

[0094] The terms “drug,” and “therapeutic agent,” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.

[0095] “Pharmaceutically acceptable salt” refers to a salt of a compound disclosed herein that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid additionsalts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sultunc acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0096] “Bioavailability” (%F) refers to the percentage of Compound I dosed that is delivered into the general circulation of the animal or human being studied. The AUC (from zero to infinity) represents the total drug exposure across time. The total exposure (AUCinf or AUCoo) of a drug when administered intravenously is usually defined as 100% bioavailable (F%).

[0097] “Oral bioavailability” refers to the extent to which Compound I is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.

[0098] The terms “geometric mean” or “mean’ are used interchangeably herein and refer to the average value or mean which signifies the central tendency of the set of numbers by finding the product of their values. The formula to calculate the geometric mean is GM = (Xi • X2• . . . • Xn)1 / n

[0099] “Plasma concentration” refers to the concentration of Compound 1 in the plasma component of blood of a subject. It is understood that the plasma concentration of Compound I may vary significantly between subjects, due to variability with respect to metabolism and / or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the plasma concentration of Compound I may vary from subject to subject. Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (tmax), or total area under the plasma concentration time curve (AUG / ) may vary from subject to subject.

[0100] The terms “AUCo-t” and “AUCt” are used interchangeable herein and refer to the area under the plasma concentration-time curve from time 0 to time t.

[0101] The term “tmax” refers to the time of maximum concentration.

[0102] The term “ti / 2” refers to the time that it takes for the concentration to reach one-half of its steady-state value.

[0103] The term “Cmax” refers to the maximum drug concentration in the plasma.

[0104] A “subject” to which administration is contemplated includes, but is not limited to, human subject (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0105] Disease, disorder, and condition are used interchangeably herein.

[0106] As used herein, the term “treat,” “treating” or “treatment” includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in manner to improve or stabilize a subject's condition. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation, amelioration, reduction of the severity, or slowing the progression, of one or more symptoms or conditions associated with a condition, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Exemplary beneficial clinical results are described herein.

[0107] As used herein, and unless otherwise specified, the term “prophylactic, “prevention” and variations thereof, contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder, or condition.

[0108] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0109] The terms “pharmaceutically effective amount,” “therapeutically effective amount,” or “therapeutically effective dose” refer to an amount sufficient to treat a disease in a patient, e.g., effecting a beneficial and / or desirable alteration in the health of a patient suffering from a disease, treatment, healing, inhibition or amelioration of a physiological response or condition, delaying or minimizing one or more symptoms associated with the disease, disorder or condition etc. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, the nature and extent of disease, the therapeutics or combination of therapeutics selected for administration, and the mode of administration. The skilled worker can readily determine the effective amount for a given situation by routine experimentation. The terms “pharmaceutically effective amount,” “therapeutically effective amount,” or “therapeutically effective dose” also refer to the amount required to improve the clinical symptoms of a patient. A therapeutically effective amount of a compound also refers to an amount of the therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0110] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease, disorder or condition, t he term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0111] As used herein, and unless otherwise specified, “pharmacokinetics” can be defined as the study of bodily absorption, distribution, metabolism, and excretion of drugs.“Pharmacokinetics” can also be defined as the characteristic interactions of a drug and a body in terms of its absorption, distribution, metabolism, and excretion; or a branch of pharmacology concerned with the way drugs are taken into, move around, and are eliminated from, a body.

[0112] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, e.g., as a soft gel, hardshell, or oral liquid. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. In some embodiments, the administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug, or to have the drug administered by another and / or who provides a patient with a prescription for a drug is administering the drug to the patient. When a method is part of a therapeutic regimen involving more than one agent or treatment modality, the disclosure contemplates that the agents may be administered at the same or differing times and via the same or differing routes of administration. Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administering, whether the subject is cognitively impaired at the time of administering, the extent of the impairment, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity).

[0113] “Population of subjects” refers to multiple subjects or a group of subjects. Pharmaceutical Compositions

[0114] In one aspect, described herein is a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof and methods of use thereof for treating a disease or disorder associated with NMDA receptor modulation.

[0115] In some embodiments, the pharmaceutical composition is an oral composition. In some embodiments, the pharmaceutical composition is an oral solution.

[0116] In some embodiments, the pharmaceutical composition comprises hydroxypropyl-|5- cyclodextrin. In some embodiments, the pharmaceutical composition is an oral composition comprising hydroxypropyl-P-cyclodextrin. In some embodiments, the pharmaceutical composition is an oral solution comprising hydroxypropyl-P-cyclodextrin.

[0117] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a Cmax of between about 2 and about 100 ng / mL; b) an AUC2411 of between about 50 and about 1000 ng*h / mL; c) an AUCiast of between about 50 and about 1000 ng*h / mL; d) an AUC 00 of between about 50 and about 2000 ng*h / mL; or e) a tmax of between about 2 and about 15 hours.

[0118] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a Cmax of between about 2 and about 80 ng / mL; b) an AUCiast of between about 50 and about 1000 ng*h / mL; c) an AUC 00 of between about 50 and about 2000 ng*h / mL; or d) a tmax of between about 2 and about 15 hours.

[0119] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 100 ng / mL. In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL.

[0120] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between about 50 and about 1000 ng*h / mL.

[0121] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCiast of between about 50 and about 1000 ng*h / mL.

[0122] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCoo of between about 50 and about 2000 ng*h / mL.

[0123] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a tmax of between about 2 and about 15 hours.

[0124] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL and an AUC2411 of between about 50 and about 1000 ng*h / mL.

[0125] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL and AUCiast of between about 50 and about 1000 ng*h / mL.

[0126] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL and an AUCoo of between about 50 and about 2000 ng*h / mL.

[0127] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL and a tmax of between about 2 and about 15 hours.

[0128] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between 50 and about 1000 ng*h / mL and an AUCiast of between about 50 and about 1000 ng*h / mL.

[0129] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between 50 and about 1000 ng*h / mL and an AUCoo of between about 50 and about 1000 ng*h / mL.

[0130] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between about 50 and about 1000 ng*h / mL and a tmax of between about 2 and about 15 hours.

[0131] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCiast of between about 50 and about 1000 ng*h / mL and an AUCoo of between about 50 and about 2000 ng*h / mL.

[0132] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCiast of between about 50 and about 1000 ng*h / mL and a tmax of between about 2 and about 15 hours.

[0133] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCoo of between about 50 and about 2000 ng*h / mL and a tmax of between about 2 and about 15 hours.

[0134] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL an AUC2411 of between about 50 and about 1000 ng*h / mL, and an AUCiast of between about 50 and about 1000 ng*h / mL.

[0135] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL, an AUC2411 of between about 50 and about 1000 ng*h / mL, and an AUCoo of between about 50 and about 2000 ng*h / mL.

[0136] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL, an AUC2411 of between about 50 and about 1000 ng*h / mL, and a tmax of between about 2 and about 15 hours.

[0137] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL an AUCiast of between about 50 and about 1000 ng*h / mL, and an AUCoo of between about 50 and about 2000 ng*h / mL.

[0138] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL an AUCiast of between about 50 and about 1000 ng*h / mL, and a tmax of between about 2 and about 15 hours.

[0139] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL, an AUCoo of between about 50 and about 2000 ng*h / mL and a tmax of between about 2 and about 15 hours.

[0140] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between about 50 and about 1000 ng*h / mL, an AUCiast of between about 50 and about 1000 ng*h / mL, and an AUC 00 of between about 50 and about 2000 ng*h / mL.

[0141] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between about 50 and about 1000 ng*h / mL, an AUCiast of between about 50 and about 1000 ng*h / mL, and a tmax of between about 2 and about 15 hours.

[0142] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between about 50 and about 1000 ng*h / mL, an AUCoo of between about 50 and about 2000 ng*h / mL and a tmax of between about 2 and about 15 hours.

[0143] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCiast of between about 50 and about 1000 ng*h / mL, an AUCoo of between about 50 and about 2000 ng*h / mL and a tmax of between about 2 and about 15 hours.

[0144] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL, an AUC2411 of between about 50 and about 1000 ng*h / mL, an AUCiast of between about 50 and about 1000 ng*h / mL and an AUCoo of between about 50 and about 2000 ng*h / mL.

[0145] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL, an AUC2411 of between about 50 and about 1000 ng*h / mL, an AUCiast of between about 50 and about 1000 ng*h / mL, and a tmax of between about 2 and about 15 hours.

[0146] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL, an AUC2411 of between about 50 and about 1000 ng*h / mL, AUCoo of between about 50 and about 2000 ng*h / mL and a tmax of between about 2 and about 15 hours.

[0147] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL, an AUCiast of between about 50 and about 1000 ng*h / mL, an AUCoo of between about 50 and about 2000 ng*h / mL, and a tmax of between about 2 and about 15 hours.

[0148] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between about 50 and about 1000 ng*h / mL, an AUCiast of between about 50 and about 1000 ng*h / mL, AUCoo of between about 50 and about 2000 ng*h / mL, and a tmax of between about 2 and about 15 hours.

[0149] In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL, an AUC2411 of between about 50 and about 1000 ng*h / mL, an AUCiast of between about 50 and about 1000 ng*h / mL, an AUCoo of between about 50 and about 2000 ng*h / mL, and a tmax of between about 2 and about 15 hours.

[0150] In some embodiments, the pharmaceutical composition provides a Cmax of between about 5 and about 50 ng / mL, an AUC2411 of between about 100 and about 500 ng*h / mL, an AUCiast of between about 100 and about 700 ng*h / mL, an AUCoo of between about 100 and about 1500 ng*h / mL, and a tmax of between about 4 and about 10 hours.

[0151] In some embodiments, the pharmaceutical composition provides a Cmax of between about 5 and about 20 ng / mL, an AUC2411 of between about 200 and about 500 ng*h / mL, an AUCiast of between about 200 and about 500 ng*h / mL, an AUCoo of between about 500 and about 1000 ng*h / mL, and a tmax of between about 4 and about 8 hours.

[0152] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a Cmax of between 2 and 100 ng / mL; b) an AUC2411 of between 50 and 1000 ng*h / mL; c) an AUCiast of between 50 and 1000 ng*h / mL; d) an AUCoo of between 50 and 2000 ng*h / mL; or e) a tmax of between 2 and 15 hours.

[0153] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a C max of between 2 and 80 ng / mL; b) an AUCiast of between 50 and 1000 ng*h / mL;c) an AUCoo of between 50 and 2000 ng*h / mL; or d) a tmax of between 2 and 15 hours.

[0154] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 100 ng / mL. In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL.

[0155] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between 50 and 1000 ng*h / mL.

[0156] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCiast of between 50 and 1000 ng*h / mL.

[0157] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCoo of between 50 and 2000 ng*h / mL.

[0158] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a tmax of between 2 and 15 hours.

[0159] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL and an AUC2411 of between 50 and 1000 ng*h / mL.

[0160] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL and AUCiast of between 50 and 1000 ng*h / mL.

[0161] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and about 80 ng / mL and an AUCoo of between 50 and about 2000 ng*h / mL.

[0162] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL and a tmax of between about 2 and about 15 hours.

[0163] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between 50 and 1000 ng*h / mL and an AUCiast of between 50 and 1000 ng*h / mL.

[0164] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between 50 and 1000 ng*h / mL and an AUCoo of between 50 and 1000 ng*h / mL.

[0165] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between 50 and 1000 ng*h / mL and a tmax of between about 2 and about 15 hours.

[0166] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCiast of between 50 and 1000 ng*h / mL and an AUCoo of between 50 and 2000 ng*h / mL.

[0167] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCiast of between 50 and 1000 ng*h / mL and a tmax of between 2 and 15 hours.

[0168] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCoo of between 50 and 2000 ng*h / mL and a tmax of between 2 and 15 hours.

[0169] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL an AUC2411 of between 50 and 1000 ng*h / mL, and an AUCiast of between 50 and 1000 ng*h / mL.

[0170] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL, an AUC2411 of between 50 and 1000 ng*h / mL, and an AUCoo of between about 50 and 2000 ng*h / mL.

[0171] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL, an AUC2411 of between 50 and 1000 ng*h / mL, and a tmax of between 2 and 15 hours.

[0172] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL an AUCiast of between 50 and 1000 ng*h / mL, and an AUCoo of between 50 and 2000 ng*h / mL.

[0173] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL an AUCiast of between 50 and 1000 ng*h / mL, and a tmax of between 2 and 15 hours.

[0174] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL, an AUCoo of between 50 and 2000 ng*h / mL and a tmax of between 2 and 15 hours.

[0175] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between 50 and 1000 ng*h / mL, an AUCiast of between 50 and 1000 ng*h / mL, and an AUCoo of between 50 and 2000 ng*h / mL.

[0176] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between 50 and 1000 ng*h / mL, an AUCiast of between 50 and 1000 ng*h / mL, and a tmax of between 2 and 15 hours.

[0177] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between 50 and 1000 ng*h / mL, an AUCoo of between 50 and 2000 ng*h / mL and a tmax of between 2 and 15 hours.

[0178] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUCiast of between 50 and 1000 ng*h / mL, an AUCoo of between 50 and 2000 ng*h / mL and a tmax of between 2 and 15 hours.

[0179] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL, an AUC2411 of between 50 and 1000 ng*h / mL, an AUCiast of between 50 and 1000 ng*h / mL and an AUCoo of between 50 and 2000 ng*h / mL.

[0180] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL, an AUC2411 of between 50 and 1000 ng*h / mL, an AUCiast of between 50 and 1000 ng*h / mL, and a tmax of between 2 and 15 hours.

[0181] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL, an AUC2411 of between 50 and 1000 ng*h / mL, AUCoo of between 50 and 2000 ng*h / mL and a tmax of between 2 and 15 hours.

[0182] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL, an AUCiast of between 50 and 1000 ng*h / mL, an AUCoo of between 50 and 2000 ng*h / mL, and a tmax of between 2 and 15 hours.

[0183] In some embodiments, following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides an AUC2411 of between 50 and 1000ng*h / mL, an AUCiast of between 50 and 1000 ng*h / mL, AUCoo of between 50 and 2000 ng*h / mL, and a tmax of between 2 and 15 hours.

[0184] In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL, an AUC2411 of between 50 and 1000 ng*h / mL, an AUCiast of between 50 and 1000 ng*h / mL, an AUCoo of between 50 and 2000 ng*h / mL, and a tmax of between 2 and 15 hours.

[0185] In some embodiments, the pharmaceutical composition provides a Cmax of between 5 and 50 ng / mL, an AUC2411 of between 100 and 500 ng*h / mL, an AUCiast of between 100 and 700 ng*h / mL, an AUCoo of between 100 and 1500 ng*h / mL, and a tmax of between 4 and 10 hours.

[0186] In some embodiments, the pharmaceutical composition provides a Cmax of between 5 and 20 ng / mL, an AUC2411 of between 200 and 500 ng*h / mL, an AUCiast of between 200 and 500 ng*h / mL, an AUCoo of between 500 and 1000 ng*h / mL, and a tmax of between 4 and 8 hours.

[0187] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a mean Cmax of between about 2 and about 100 ng / mL; b) a mean AUC2411 of between about 50 and about 1000 ng*h / mL; c) a mean AUCiast of between about 50 and about 1000 ng*h / mL; d) a mean AUCoo of between about 50 and about 2000 ng*h / mL; or e) a mean tmax of between about 2 and about 15 hours.

[0188] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a mean Cmax of between about 2 and about 80 ng / mL; b) a mean AUCiast of between about 50 and about 1000 ng*h / mL; c) a mean AUCoo of between about 50 and about 2000 ng*h / mL; ord) a mean tmax of between about 2 and about 15 hours.

[0189] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 100 ng / mL. In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL.

[0190] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 1000 ng*h / mL.

[0191] In some embodiments, following administration of the pharmaceutical composition a population of subjects, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 1000 ng*h / mL.

[0192] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 2000 ng*h / mL.

[0193] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean tmax of between about 2 and about 15 hours.

[0194] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL and a mean AUC2411 of between about 50 and about 1000 ng*h / mL.

[0195] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL and a mean AUCiast of between about 50 and about 1000 ng*h / mL.

[0196] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of betweenabout 2 and about 80 ng / mL and a mean AUCoo of between about 50 and about 2000 ng*h / mL.

[0197] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL and a mean tmax of between about 2 and about 15 hours.

[0198] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between 50 and about 1000 ng*h / mL and a mean AUCiast of between about 50 and about 1000 ng*h / mL.

[0199] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between 50 and about 1000 ng*h / mL and a mean AUCoo of between about 50 and about 1000 ng*h / mL.

[0200] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 1000 ng*h / mL and a mean tmax of between about 2 and about 15 hours.

[0201] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 1000 ng*h / mL and a mean AUCoo of between about 50 and about 2000 ng*h / mL.

[0202] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 1000 ng*h / mL and a mean tmax of between about 2 and about 15 hours.

[0203] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 2000 ng*h / mL and a mean tmax of between about 2 and about 15 hours.

[0204] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUC2411 of between about 50 and about 1000 ng*h / mL, and a mean AUCiast of between about 50 and about 1000 ng*h / mL.

[0205] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUC2411 of between about 50 and about 1000 ng*h / mL, and a mean AUCoo of between about 50 and about 2000 ng*h / mL.

[0206] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUC2411 of between about 50 and about 1000 ng*h / mL, and a mean tmax of between about 2 and about 15 hours.

[0207] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUCiast of between about 50 and about 1000 ng*h / mL, and a mean AUCoo of between about 50 and about 2000 ng*h / mL.

[0208] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUCiast of between about 50 and about 1000 ng*h / mL, and a mean tmax of between about 2 and about 15 hours.

[0209] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUCoo of between about 50 and about 2000 ng*h / mL and a mean tmax of between about 2 and about 15 hours.

[0210] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 1000 ng*h / mL, a mean AUCiast of between about 50 and about 1000 ng*h / mL, and a mean AUCoo of between about 50 and about 2000 ng*h / mL.

[0211] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 1000 ng*h / mL, a mean AUCiast of between about 50 and about 1000 ng*h / mL, and a mean tmax of between about 2 and about 15 hours.

[0212] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 1000 ng*h / mL, a mean AUCoo of between about 50 and about 2000 ng*h / mL and a mean tmax of between about 2 and about 15 hours.

[0213] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUCiast ofbetween about 50 and about 1000 ng*h / mL, a mean AUCoo of between about 50 and about 2000 ng*h / mL and a mean tmax of between about 2 and about 15 hours.

[0214] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUC2411 of between about 50 and about 1000 ng*h / mL, a mean AUCiast of between about 50 and about 1000 ng*h / mL and a mean AUCoo of between about 50 and about 2000 ng*h / mL.

[0215] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUC2411 of between about 50 and about 1000 ng*h / mL, a mean AUCiast of between about 50 and about 1000 ng*h / mL, and a mean tmax of between about 2 and about 15 hours.

[0216] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUC2411 of between about 50 and about 1000 ng*h / mL, a mean AUCoo of between about 50 and about 2000 ng*h / mL and a mean tmax of between about 2 and about 15 hours.

[0217] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUCiast of between about 50 and about 1000 ng*h / mL, a mean AUCoo of between about 50 and about 2000 ng*h / mL, and a mean tmax of between about 2 and about 15 hours.

[0218] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 1000 ng*h / mL, a mean AUCiast of between about 50 and about 1000 ng*h / mL, a mean AUCoo of between about 50 and about 2000 ng*h / mL, and a mean tmax of between about 2 and about 15 hours.

[0219] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL, a mean AUC2411 of between about 50 and about 1000 ng*h / mL, a mean AUCiast of between about 50 and about 1000 ng*h / mL, a mean AUCoo of between about 50 and about 2000 ng*h / mL, and a mean tmax of between about 2 and about 15 hours.

[0220] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a mean Cmax of between 2 and 100 ng / mL; b) a mean AUC2411 of between 50 and 1000 ng*h / mL; c) a mean AUCiast of between 50 and 1000 ng*h / mL; d) a mean AUCoo of between 50 and 2000 ng*h / mL; or e) a mean tmax of between 2 and 15 hours.

[0221] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a mean Cmax of between 2 and 80 ng / mL; b) a mean AUCiast of between 50 and 1000 ng*h / mL; c) a mean AUCoo of between 50 and 2000 ng*h / mL; or d) a mean tmax of between 2 and 15 hours.

[0222] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 100 ng / mL. In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL.

[0223] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between 50 and 1000 ng*h / mL.

[0224] In some embodiments, following administration of the pharmaceutical composition a population of subjects, the pharmaceutical composition provides a mean AUCiast of between 50 and 1000 ng*h / mL.

[0225] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUCoo of between 50 and 2000 ng*h / mL.

[0226] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean tmax of between 2 and 15 hours.

[0227] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL and a mean AUC2411 of between 50 and 1000 ng*h / mL.

[0228] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL and a mean AUCiast of between 50 and 1000 ng*h / mL.

[0229] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL and a mean AUCoo of between 50 and 2000 ng*h / mL.

[0230] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL and a mean tmax of between 2 and 15 hours.

[0231] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between 50 and 1000 ng*h / mL and a mean AUCiast of between 50 and 1000 ng*h / mL.

[0232] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between 50 and 1000 ng*h / mL and a mean AUCoo of between 50 and 1000 ng*h / mL.

[0233] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between 50 and 1000 ng*h / mL and a mean tmax of between 2 and 15 hours.

[0234] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUCiast of between 50 and 1000 ng*h / mL and a mean AUCoo of between 50 and 2000 ng*h / mL.

[0235] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUCiast of between 50 and 1000 ng*h / mL and a mean tmax of between 2 and 15 hours.

[0236] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUCoo of between 50 and 2000 ng*h / mL and a mean tmax of between 2 and 15 hours.

[0237] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL, a mean AUC2411 of between 50 and 1000 ng*h / mL, and a mean AUCiast of between 50 and 1000 ng*h / mL.

[0238] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL, a mean AUC2411 of between 50 and 1000 ng*h / mL, and a mean AUCoo of between 50 and 2000 ng*h / mL.

[0239] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL, a mean AUC2411 of between 50 and 1000 ng*h / mL, and a mean tmax of between 2 and 15 hours.

[0240] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL, a mean AUCiast of between 50 and 1000 ng*h / mL, and a mean AUCoo of between 50 and 2000 ng*h / mL.

[0241] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL, a mean AUCiast of between 50 and 1000 ng*h / mL, and a mean tmax of between 2 and 15 hours.

[0242] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL, a mean AUCoo of between 50 and 2000 ng*h / mL and a mean tmax of between 2 and 15 hours.

[0243] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between 50 and 1000 ng*h / mL, a mean AUCiast of between 50 and 1000 ng*h / mL, and a mean AUCoo of between 50 and 2000 ng*h / mL.

[0244] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between 50 and 1000 ng*h / mL, a mean AUCiast of between 50 and 1000 ng*h / mL, and a mean tmax of between 2 and 15 hours.

[0245] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between 50 and 1000 ng*h / mL, a mean AUCoo of between 50 and 2000 ng*h / mL and a mean tmax of between 2 and 15 hours.

[0246] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUCiast of between 50 and 1000 ng*h / mL, a mean AUCoo of between 50 and 2000 ng*h / mL and a mean tmax of between 2 and 15 hours.

[0247] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL, a mean AUC2411 of between 50 and 1000 ng*h / mL, a mean AUCiast of between 50 and 1000 ng*h / mL and a mean AUCoo of between 50 and 2000 ng*h / mL.

[0248] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL, a mean AUC2411 of between 50 and 1000 ng*h / mL, a mean AUCiast of between 50 and 1000 ng*h / mL, and a mean tmax of between 2 and 15 hours.

[0249] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL, a mean AUC2411 of between 50 and 1000 ng*h / mL, a mean AUCoo of between 50 and 2000 ng*h / mL and a mean tmax of between 2 and 15 hours.

[0250] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL, a mean AUCiast of between 50 and 1000 ng*h / mL, a mean AUCoo of between 50 and 2000 ng*h / mL, and a mean tmax of between 2 and 15 hours.

[0251] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of between 50 and 1000 ng*h / mL, a mean AUCiast of between 50 and 1000 ng*h / mL, a mean AUC 00 of between 50 and 2000 ng*h / mL, and a mean tmax of between 2 and 15 hours.

[0252] In some embodiments, following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides a mean Cmax of between2 and 80 ng / mL, a mean AUC2411 of between 50 and 1000 ng h / mL, a mean AUCiast of between 50 and 1000 ng*h / mL, a mean AUCoo of between 50 and 2000 ng*h / mL, and a mean tmax of between 2 and 15 hours.

[0253] In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 90 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 70 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 60 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 50 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 40 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 30 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 20 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 2 and about 10 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 10 and about 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 20 and about 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 30 and about 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 40 and about 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 50 and about 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 60 and about 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 70 and about 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 80 and about 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 90 and about 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 10 and about 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 20 and about 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of betweenabout 30 and about 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 40 and about 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 50 and about 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 60 and about 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between about 70 and about 800 ng / mL in a subject.

[0254] In some embodiments, following administration to a subject, the pharmaceutical composition provides a Cmax of about 2 ng / mL, about 5 ng / mL, about 10 ng / mL, about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / mL, or about 100 ng / mL in the subject.

[0255] In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 90 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 70 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 60 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 50 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 40 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 30 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 20 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 2 and 10 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 10 and 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 20 and 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 30 and 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 40 and 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 50 and 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 60 and 100 ng / mL in a subject. In some embodiments, the pharmaceuticalcomposition provides a Cmax of between 70 and 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 80 and 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 90 and 100 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 10 and 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 20 and 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 30 and 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 40 and 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 50 and 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 60 and 80 ng / mL in a subject. In some embodiments, the pharmaceutical composition provides a Cmax of between 70 and 800 ng / mL in a subject.

[0256] In some embodiments, following administration to a subject, the pharmaceutical composition provides a Cmax of 2 ng / mL, 5 ng / mL, 10 ng / mL, 15 ng / mL, 20 ng / mL, 25 ng / mL, 30 ng / mL, 35 ng / mL, 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, 60 ng / mL, 65 ng / mL, 70 ng / mL, 75 ng / mL, 80 ng / mL, 85 ng / mL, 90 ng / mL, 95 ng / mL, or 100 ng / mL.

[0257] In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 2 and about 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 2 and about 90 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 2 and about 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 2 and about 70 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 2 and about 60 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 2 and about 50 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 2 and about 40 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 2 and about 30 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 2 and about 20 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 2 and about 10 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax ofbetween about 10 and about 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 20 and about 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 30 and about 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 40 and about 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 50 and about 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 60 and about 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 70 and about 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 80 and about 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 90 and about 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 10 and about 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 20 and about 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 30 and about 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 40 and about 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 50 and about 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 60 and about 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between about 70 and about 800 ng / mL in a population of subjects.

[0258] In some embodiments, following administration to a population of subjects, the pharmaceutical composition provides a mean Cmax of about 2 ng / mL, about 5 ng / mL, about 10 ng / mL, about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / mL, or about 100 ng / mL.

[0259] In some embodiments, the pharmaceutical composition provides a mean Cmax of between 2 and 100 ng / mL in a population of subjects. In some embodiments, thepharmaceutical composition provides a mean Cmax of between 2 and 90 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 2 and 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 2 and 70 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 2 and 60 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 2 and 50 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 2 and 40 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 2 and 30 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 2 and 20 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 2 and 10 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 10 and 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 20 and 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 30 and 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 40 and 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 50 and 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 60 and 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 70 and 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 80 and 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 90 and 100 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 10 and 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 20 and 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 30 and 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 40 and 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 50 and 80 ng / mL in apopulation of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 60 and 80 ng / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean Cmax of between 70 and 800 ng / mL in a population of subjects.

[0260] In some embodiments, following administration to a population of subjects, the pharmaceutical composition provides a mean Cmax of 2 ng / mL, 5 ng / mL, 10 ng / mL, 15 ng / mL, 20 ng / mL, 25 ng / mL, 30 ng / mL, 35 ng / mL, 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, 60 ng / mL, 65 ng / mL, 70 ng / mL, 75 ng / mL, 80 ng / mL, 85 ng / mL, 90 ng / mL, 95 ng / mL, or 100 ng / mL.

[0261] In some embodiments, the pharmaceutical composition provides an AUCiast of between about 50 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 50 and about 900 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 50 and about 800 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 50 and about 700 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 50 and about 600 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 50 and about 500 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 50 and about 400 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 50 and about 300 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 50 and about 200 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 50 and about 100 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 100 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 200 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 300 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 400 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 500 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 600 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides anAUCiast of between about 700 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 800 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between about 900 and about 1000 ng*h / mL in a subject.

[0262] In some embodiments, following administration to a subject, the pharmaceutical composition provides an AUCiast of about 50 ng*h / mL, about 75 ng*h / mL, about 100 ng*h / mL, about 125 ng*h / mL, about 150 ng*h / mL, about 175 ng*h / mL, about 200 ng*h / mL, about 225 ng*h / mL, about 250 ng*h / mL, about 275 ng*h / mL, about 300 ng*h / mL, about 325 ng*h / mL, about 350 ng*h / mL, about 375 ng*h / mL, about 400 ng*h / mL, about 425 ng*h / mL, about 450 ng*h / mL, about 475 ng*h / mL, about 500 ng*h / mL, about 525 ng*h / mL, about 550 ng*h / mL, about 575 ng*h / mL, about 600 ng*h / mL, about 625 ng*h / mL, about 650 ng*h / mL, about 675 ng*h / mL, about 700 ng*h / mL, about 725 ng*h / mL, about 750 ng*h / mL, about 775 ng*h / mL, about 800 ng*h / mL, about 825 ng*h / mL, about 850 ng*h / mL, about 875 ng*h / mL, about 900 ng*h / mL, about 925 ng*h / mL, about 950 ng*h / mL, about 975 ng*h / mL, and about 1000 ng*h / mL in the subject.

[0263] In some embodiments, the pharmaceutical composition provides an AUCiast of between 50 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 50 and 900 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 50 and 800 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 50 and 700 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 50 and 600 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 50 and 500 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 50 and 400 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 50 and 300 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 50 and 200 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 50 and 100 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 100 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 200 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 300 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides anAUCiast of between 400 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 500 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 600 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 700 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 800 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCiast of between 900 and 1000 ng*h / mL in a subject.

[0264] In some embodiments, following administration to a subject, the pharmaceutical composition provides an AUCiast of 50 ng*h / mL, 75 ng*h / mL, 100 ng*h / mL, 125 ng*h / mL, 150 ng*h / mL, 175 ng*h / mL, 200 ng*h / mL, 225 ng*h / mL, 250 ng*h / mL, 275 ng*h / mL, 300 ng*h / mL, 325 ng*h / mL, 350 ng*h / mL, 375 ng*h / mL, 400 ng*h / mL, 425 ng*h / mL, 450 ng*h / mL, 475 ng*h / mL, 500 ng*h / mL, 525 ng*h / mL, 550 ng*h / mL, 575 ng*h / mL, 600 ng*h / mL, 625 ng*h / mL, 650 ng*h / mL, 675 ng*h / mL, 700 ng*h / mL, 725 ng*h / mL, 750 ng*h / mL, 775 ng*h / mL, 800 ng*h / mL, 825 ng*h / mL, 850 ng*h / mL, 875 ng*h / mL, 900 ng*h / mL, 925 ng*h / mL, 950 ng*h / mL, 975 ng*h / mL, and 1000 ng*h / mL in the subject.

[0265] In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 900 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 800 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 700 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 600 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 500 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 400 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 300 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 200 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 50 and about 100 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast ofbetween about 100 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 200 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 300 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 400 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 500 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 600 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 700 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 800 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between about 900 and about 1000 ng*h / mL in a population of subjects.

[0266] In some embodiments, following administration to a population of subjects, the pharmaceutical composition provides a mean AUCiast of about 50 ng*h / mL, about 75 ng*h / mL, about 100 ng*h / mL, about 125 ng*h / mL, about 150 ng*h / mL, about 175 ng*h / mL, about 200 ng*h / mL, about 225 ng*h / mL, about 250 ng*h / mL, about 275 ng*h / mL, about 300 ng*h / mL, about 325 ng*h / mL, about 350 ng*h / mL, about 375 ng*h / mL, about 400 ng*h / mL, about 425 ng*h / mL, about 450 ng*h / mL, about 475 ng*h / mL, about 500 ng*h / mL, about 525 ng*h / mL, about 550 ng*h / mL, about 575 ng*h / mL, about 600 ng*h / mL, about 625 ng*h / mL, about 650 ng*h / mL, about 675 ng*h / mL, about 700 ng*h / mL, about 725 ng*h / mL, about 750 ng*h / mL, about 775 ng*h / mL, about 800 ng*h / mL, about 825 ng*h / mL, about 850 ng*h / mL, about 875 ng*h / mL, about 900 ng*h / mL, about 925 ng*h / mL, about 950 ng*h / mL, about 975 ng*h / mL, and about 1000 ng*h / mL in the population of subject.

[0267] In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 50 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 50 and 900 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 50 and 800 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 50 and 700 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 50 and 600 ng*h / mL in a population ofsubjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast ot between 50 and 500 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 50 and 400 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 50 and 300 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 50 and 200 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 50 and 100 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 100 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 200 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 300 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 400 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 500 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 600 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 700 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 800 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCiast of between 900 and 1000 ng*h / mL in a population of subjects.

[0268] In some embodiments, following administration to a population of subjects, the pharmaceutical composition provides a mean AUCiast of 50 ng*h / mL, 75 ng*h / mL, 100 ng*h / mL, 125 ng*h / mL, 150 ng*h / mL, 175 ng*h / mL, 200 ng*h / mL, 225 ng*h / mL, 250 ng*h / mL, 275 ng*h / mL, 300 ng*h / mL, 325 ng*h / mL, 350 ng*h / mL, 375 ng*h / mL, 400 ng*h / mL, 425 ng*h / mL, 450 ng*h / mL, 475 ng*h / mL, 500 ng*h / mL, 525 ng*h / mL, 550 ng*h / mL, 575 ng*h / mL, 600 ng*h / mL, 625 ng*h / mL, 650 ng*h / mL, 675 ng*h / mL, 700 ng*h / mL, 725 ng*h / mL, 750 ng*h / mL, 775 ng*h / mL, 800 ng*h / mL, 825 ng*h / mL, 850 ng*h / mL, 875 ng*h / mL, 900 ng*h / mL, 925 ng*h / mL, 950 ng*h / mL, 975 ng*h / mL, and 1000 ng*h / mL in the population of subjects.

[0269] In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 50 and about 1000 ng*h / mL in a subject. In some embodiments, thepharmaceutical composition provides an AUC2411 of between about 50 and about 900 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 50 and about 800 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 50 and about 700 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 50 and about 600 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 50 and about 500 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 50 and about 400 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 50 and about 300 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 50 and about 200 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 50 and about 100 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 100 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 200 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 300 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 400 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 500 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 600 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 700 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 800 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between about 900 and about 1000 ng*h / mL in a subject.

[0270] In some embodiments, following administration to a subject, the pharmaceutical composition provides an AUC2411 of about 50 ng*h / mL, about 75 ng*h / mL, about 100 ng*h / mL, about 125 ng*h / mL, about 150 ng*h / mL, about 175 ng*h / mL, about 200 ng*h / mL, about 225 ng*h / mL, about 250 ng*h / mL, about 275 ng*h / mL, about 300 ng*h / mL, about 325 ng*h / mL, about 350 ng*h / mL, about 375 ng*h / mL, about 400 ng*h / mL, about 425 ng*h / mL, about 450 ng*h / mL, about 475 ng*h / mL, about 500 ng*h / mL, about 525 ng*h / mL, about 550 ng*h / mL, about 575 ng*h / mL, about 600 ng*h / mL, about 625 ng*h / mL, about 650 ng*h / mL,about 675 ng*h / mL, about 700 ng*h / mL, about 725 ng^h / mL, about 750 ng^h / mL, about 775 ng*h / mL, about 800 ng*h / mL, about 825 ng*h / mL, about 850 ng*h / mL, about 875 ng*h / mL, about 900 ng*h / mL, about 925 ng*h / mL, about 950 ng*h / mL, about 975 ng*h / mL, and about 1000 ng*h / mL in the subject.

[0271] In some embodiments, the pharmaceutical composition provides an AUC2411 of between 50 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 50 and 900 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 50 and 800 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 50 and 700 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 50 and 600 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 50 and 500 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 50 and 400 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 50 and 300 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 50 and 200 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 50 and 100 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 100 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 200 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 300 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 400 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 500 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 600 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 700 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 800 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC2411 of between 900 and 1000 ng*h / mL in a subject.

[0272] In some embodiments, following administration to a subject, the pharmaceutical composition provides an AUC2411 of 50 ng*h / mL, 75 ng*h / mL, 100 ng*h / mL, 125 ng*h / mL, 150 ng*h / mL, 175 ng*h / mL, 200 ng*h / mL, 225 ng*h / mL, 250 ng*h / mL, 275 ng*h / mL, 300ng*h / mL, 325 ng*h / mL, 350 ng*h / mL, 375 ng*h / mL, 400 ng^h / mL, 425 ng^h / mL, 450 ng*h / mL, 475 ng*h / mL, 500 ng*h / mL, 525 ng*h / mL, 550 ng*h / mL, 575 ng*h / mL, 600 ng*h / mL, 625 ng*h / mL, 650 ng*h / mL, 675 ng*h / mL, 700 ng*h / mL, 725 ng*h / mL, 750 ng*h / mL, 775 ng*h / mL, 800 ng*h / mL, 825 ng*h / mL, 850 ng*h / mL, 875 ng*h / mL, 900 ng*h / mL, 925 ng*h / mL, 950 ng*h / mL, 975 ng*h / mL, and 1000 ng*h / mL in the subject.

[0273] In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 1000 ng*h / mL in in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 900 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 800 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 700 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 600 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 500 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 400 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 300 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 200 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 50 and about 100 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 100 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 200 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 300 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 400 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 500 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 600 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about700 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 800 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between about 900 and about 1000 ng*h / mL in a population of subjects.

[0274] In some embodiments, following administration to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of about 50 ng*h / mL, about 75 ng*h / mL, about 100 ng*h / mL, about 125 ng*h / mL, about 150 ng*h / mL, about 175 ng*h / mL, about 200 ng*h / mL, about 225 ng*h / mL, about 250 ng*h / mL, about 275 ng*h / mL, about 300 ng*h / mL, about 325 ng*h / mL, about 350 ng*h / mL, about 375 ng*h / mL, about 400 ng*h / mL, about 425 ng*h / mL, about 450 ng*h / mL, about 475 ng*h / mL, about 500 ng*h / mL, about 525 ng*h / mL, about 550 ng*h / mL, about 575 ng*h / mL, about 600 ng*h / mL, about 625 ng*h / mL, about 650 ng*h / mL, about 675 ng*h / mL, about 700 ng*h / mL, about 725 ng*h / mL, about 750 ng*h / mL, about 775 ng*h / mL, about 800 ng*h / mL, about 825 ng*h / mL, about 850 ng*h / mL, about 875 ng*h / mL, about 900 ng*h / mL, about 925 ng*h / mL, about 950 ng*h / mL, about 975 ng*h / mL, and about 1000 ng*h / mL in the population of subjects.

[0275] In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 50 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 50 and 900 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 50 and 800 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 50 and 700 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 50 and 600 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 50 and 500 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 50 and 400 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 50 and 300 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 50 and 200 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 50 and 100 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 100 and 1000 ng*h / mL in a population of subjects. In some embodiments, thepharmaceutical composition provides a mean AUC2411 of between 200 and 1000 ng^h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 300 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 400 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 500 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 600 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 700 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 800 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUC2411 of between 900 and 1000 ng*h / mL in a population of subjects.

[0276] In some embodiments, following administration to a population of subjects, the pharmaceutical composition provides a mean AUC2411 of 50 ng*h / mL, 75 ng*h / mL, 100 ng*h / mL, 125 ng*h / mL, 150 ng*h / mL, 175 ng*h / mL, 200 ng*h / mL, 225 ng*h / mL, 250 ng*h / mL, 275 ng*h / mL, 300 ng*h / mL, 325 ng*h / mL, 350 ng*h / mL, 375 ng*h / mL, 400 ng*h / mL, 425 ng*h / mL, 450 ng*h / mL, 475 ng*h / mL, 500 ng*h / mL, 525 ng*h / mL, 550 ng*h / mL, 575 ng*h / mL, 600 ng*h / mL, 625 ng*h / mL, 650 ng*h / mL, 675 ng*h / mL, 700 ng*h / mL, 725 ng*h / mL, 750 ng*h / mL, 775 ng*h / mL, 800 ng*h / mL, 825 ng*h / mL, 850 ng*h / mL, 875 ng*h / mL, 900 ng*h / mL, 925 ng*h / mL, 950 ng*h / mL, 975 ng*h / mL, and 1000 ng*h / mL in the population of subjects.

[0277] In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 1900 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC 00 of between about 50 and about 1800 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 1700 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC 00 of between about 50 and about 1600 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 1500 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC 00 of between about 50 and about 1400 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 1300ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 50 and about 1200 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 1100 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 50 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 900 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 800 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 700 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 600 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 50 and about 500 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 400 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 300 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 200 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 50 and about 100 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 100 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 200 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 300 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 400 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 500 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 600 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 700 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 800 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 900 and about 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides anAUC oo of between about 100 and about 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 100 and about 1100 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 100 and about 1200 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 100 and about 1300 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 100 and about 1400 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 100 and aboutl500 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 100 and about 1600 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 100 and about 1700 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between about 100 and about 1800 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between about 100 and about 1900 ng*h / mL in a subject.

[0278] In some embodiments, following administration to a subject, the pharmaceutical composition provides an AUCoo of about 50 ng*h / mL, about 75 ng*h / mL, about 100 ng*h / mL, about 125 ng*h / mL, about 150 ng*h / mL, about 175 ng*h / mL, about 200 ng*h / mL, about 225 ng*h / mL, about 250 ng*h / mL, about 275 ng*h / mL, about 300 ng*h / mL, about 325 ng*h / mL, about 350 ng*h / mL, about 375 ng*h / mL, about 400 ng*h / mL, about 425 ng*h / mL, about 450 ng*h / mL, about 475 ng*h / mL, about 500 ng*h / mL, about 525 ng*h / mL, about 550 ng*h / mL, about 575 ng*h / mL, about 600 ng*h / mL, about 625 ng*h / mL, about 650 ng*h / mL, about 675 ng*h / mL, about 700 ng*h / mL, about 725 ng*h / mL, about 750 ng*h / mL, about 775 ng*h / mL, about 800 ng*h / mL, about 825 ng*h / mL, about 850 ng*h / mL, about 875 ng*h / mL, about 900 ng*h / mL, about 925 ng*h / mL, about 950 ng*h / mL, about 975 ng*h / mL, about 1000 ng*h / mL, about 1025 ng*h / mL, about 1050 ng*h / mL, about 1075 ng*h / mL, about 1100 ng*h / mL, about 1125 ng*h / mL, about 1150 ng*h / mL, about 1175 ng*h / mL, about 1200 ng*h / mL, about 1225 ng*h / mL, about 1250 ng*h / mL, about 1275 ng*h / mL, about 1300 ng*h / mL, about 1325 ng*h / mL, about 1350 ng*h / mL, about 1375 ng*h / mL, about 1400 ng*h / mL, about 1425 ng*h / mL, about 1450 ng*h / mL, about 1475 ng*h / mL, about 1500 ng*h / mL, about 1525 ng*h / mL, about 1550 ng*h / mL, about 1575 ng*h / mL, about 1600 ng*h / mL, about 1625 ng*h / mL, about 1650 ng*h / mL, about 1675 ng*h / mL, about 1700 ng*h / mL, about 1725 ng*h / mL, about 1750 ng*h / mL, about 1775 ng*h / mL, about 1800 ng*h / mL, about 1825 ng*h / mL, about 1850 ng*h / mL, about 1875 ng*h / mL, about 1900ng*h / mL, about 1925 ng*h / mL, about 1950 ng*h / mL, about 1975 ng^h / mL, and about 2000 ng*h / mL in the subject.

[0279] In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 1900 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 1800 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between 50 and 1700 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 1600 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 1500 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 1400 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 1300 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between 50 and 1200 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 1100 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 900 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 800 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between 50 and 700 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 600 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between 50 and 500 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 400 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 300 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between 50 and 200 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 50 and 100 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 100 and 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 200 and 2000 ng*h / mL in a subject. In some embodiments,the pharmaceutical composition provides an AUCoo of between 300 and 2000 ng^h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 400 and 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 500 and 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 600 and 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between 700 and 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 800 and 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 900 and 2000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 100 and 1000 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 100 and 1100 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between 100 and 1200 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 100 and 1300 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 100 and 1400 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 100 and aboutl500 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 100 and 1600 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUC oo of between 100 and 1700 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 100 and 1800 ng*h / mL in a subject. In some embodiments, the pharmaceutical composition provides an AUCoo of between 100 and 1900 ng*h / mL in a subject.

[0280] In some embodiments, following administration to a subject, the pharmaceutical composition provides an AUCoo of 50 ng*h / mL, 75 ng*h / mL, 100 ng*h / mL, 125 ng*h / mL, 150 ng*h / mL, 175 ng*h / mL, 200 ng*h / mL, 225 ng*h / mL, 250 ng*h / mL, 275 ng*h / mL, 300 ng*h / mL, 325 ng*h / mL, 350 ng*h / mL, 375 ng*h / mL, 400 ng*h / mL, 425 ng*h / mL, 450 ng*h / mL, 475 ng*h / mL, 500 ng*h / mL, 525 ng*h / mL, 550 ng*h / mL, 575 ng*h / mL, 600 ng*h / mL, 625 ng*h / mL, 650 ng*h / mL, 675 ng*h / mL, 700 ng*h / mL, 725 ng*h / mL, 750 ng*h / mL, 775 ng*h / mL, 800 ng*h / mL, 825 ng*h / mL, 850 ng*h / mL, 875 ng*h / mL, 900 ng*h / mL, 925 ng*h / mL, 950 ng*h / mL, 975 ng*h / mL, 1000 ng*h / mL, 1025 ng*h / mL, 1050 ng*h / mL, 1075 ng*h / mL, 1100 ng*h / mL, 1125 ng*h / mL, 1150 ng*h / mL, 1175 ng*h / mL, 1200 ng*h / mL, 1225 ng*h / mL, 1250 ng*h / mL, 1275 ng*h / mL, 1300 ng*h / mL, 1325ng*h / mL, 1350 ng*h / mL, 1375 ng*h / mL, 1400 ng*h / mL, 1425 ng^h / mL, 1450 ng^h / mL, 1475 ng*h / mL, 1500 ng*h / mL, 1525 ng*h / mL, 1550 ng*h / mL, 1575 ng*h / mL, 1600 ng*h / mL, 1625 ng*h / mL, 1650 ng*h / mL, 1675 ng*h / mL, 1700 ng*h / mL, 1725 ng*h / mL, 1750 ng*h / mL, 1775 ng*h / mL, 1800 ng*h / mL, 1825 ng*h / mL, 1850 ng*h / mL, 1875 ng*h / mL, 1900 ng*h / mL, 1925 ng*h / mL, 1950 ng*h / mL, 1975 ng*h / mL, and 2000 ng*h / mL in the subject.

[0281] In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 1900 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 1800 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 1700 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 1600 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 1500 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 1400 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 1300 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 1200 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 1100 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 900 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 800 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 700 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 600 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 2000 ng*h / mL in a population of subjects. In someembodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 500 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 400 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 300 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 200 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 50 and about 100 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100 and about 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 200 and about 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 300 and about 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 400 and about 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 500 and about 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 600 and about 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 700 and about 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 800 and about 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 900 and about 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100 and about 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100 and about 1100 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100 and about 1200 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100 and about 1300 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100 and about 1400 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100and aboutl500 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100 and about 1600 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100 and about 1700 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100 and about 1800 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between about 100 and about 1900 ng*h / mL in a population of subjects.

[0282] In some embodiments, following administration to a population of subjects, the pharmaceutical composition provides a mean AUCoo of about 50 ng*h / mL, about 75 ng*h / mL, about 100 ng*h / mL, about 125 ng*h / mL, about 150 ng*h / mL, about 175 ng*h / mL, about 200 ng*h / mL, about 225 ng*h / mL, about 250 ng*h / mL, about 275 ng*h / mL, about 300 ng*h / mL, about 325 ng*h / mL, about 350 ng*h / mL, about 375 ng*h / mL, about 400 ng*h / mL, about 425 ng*h / mL, about 450 ng*h / mL, about 475 ng*h / mL, about 500 ng*h / mL, about 525 ng*h / mL, about 550 ng*h / mL, about 575 ng*h / mL, about 600 ng*h / mL, about 625 ng*h / mL, about 650 ng*h / mL, about 675 ng*h / mL, about 700 ng*h / mL, about 725 ng*h / mL, about 750 ng*h / mL, about 775 ng*h / mL, about 800 ng*h / mL, about 825 ng*h / mL, about 850 ng*h / mL, about 875 ng*h / mL, about 900 ng*h / mL, about 925 ng*h / mL, about 950 ng*h / mL, about 975 ng*h / mL, about 1000 ng*h / mL, about 1025 ng*h / mL, about 1050 ng*h / mL, about 1075 ng*h / mL, about 1100 ng*h / mL, about 1125 ng*h / mL, about 1150 ng*h / mL, about 1175 ng*h / mL, about 1200 ng*h / mL, about 1225 ng*h / mL, about 1250 ng*h / mL, about 1275 ng*h / mL, about 1300 ng*h / mL, about 1325 ng*h / mL, about 1350 ng*h / mL, about 1375 ng*h / mL, about 1400 ng*h / mL, about 1425 ng*h / mL, about 1450 ng*h / mL, about 1475 ng*h / mL, about 1500 ng*h / mL, about 1525 ng*h / mL, about 1550 ng*h / mL, about 1575 ng*h / mL, about 1600 ng*h / mL, about 1625 ng*h / mL, about 1650 ng*h / mL, about 1675 ng*h / mL, about 1700 ng*h / mL, about 1725 ng*h / mL, about 1750 ng*h / mL, about 1775 ng*h / mL, about 1800 ng*h / mL, about 1825 ng*h / mL, about 1850 ng*h / mL, about 1875 ng*h / mL, about 1900 ng*h / mL, about 1925 ng*h / mL, about 1950 ng*h / mL, about 1975 ng*h / mL, and about 2000 ng*h / mL in the population of subjects.

[0283] In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 1900 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 1800 ng*h / mL in a population of subjects. In someembodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 1700 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 1600 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 1500 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 1400 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 1300 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 1200 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 1100 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 900 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 800 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 700 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 600 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 500 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 400 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 300 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 200 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 50 and 100 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 200 and 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 300 and 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceuticalcomposition provides a mean AUCoo of between 400 and 2000 ng h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 500 and 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 600 and 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 700 and 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 800 and 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 900 and 2000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and 1000 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and 1100 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and 1200 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and 1300 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and 1400 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and aboutl500 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and 1600 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and 1700 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and 1800 ng*h / mL in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean AUCoo of between 100 and 1900 ng*h / mL in a population of subjects.

[0284] In some embodiments, following administration to a population of subjects, the pharmaceutical composition provides a mean AUCoo of 50 ng*h / mL, 75 ng*h / mL, 100 ng*h / mL, 125 ng*h / mL, 150 ng*h / mL, 175 ng*h / mL, 200 ng*h / mL, 225 ng*h / mL, 250 ng*h / mL, 275 ng*h / mL, 300 ng*h / mL, 325 ng*h / mL, 350 ng*h / mL, 375 ng*h / mL, 400 ng*h / mL, 425 ng*h / mL, 450 ng*h / mL, 475 ng*h / mL, 500 ng*h / mL, 525 ng*h / mL, 550 ng*h / mL, 575 ng*h / mL, 600 ng*h / mL, 625 ng*h / mL, 650 ng*h / mL, 675 ng*h / mL, 700 ng*h / mL, 725 ng*h / mL, 750 ng*h / mL, 775 ng*h / mL, 800 ng*h / mL, 825 ng*h / mL, 850 ng*h / mL, 875 ng*h / mL, 900 ng*h / mL, 925 ng*h / mL, 950 ng*h / mL, 975 ng*h / mL, 1000ng*h / mL, 1025 ng*h / mL, 1050 ng*h / mL, 1075 ng*h / mL, 1100 ng^h / mL, 1125 ng^h / mL, 1150 ng*h / mL, 1175 ng*h / mL, 1200 ng*h / mL, 1225 ng*h / mL, 1250 ng*h / mL, 1275 ng*h / mL, 1300 ng*h / mL, 1325 ng*h / mL, 1350 ng*h / mL, 1375 ng*h / mL, 1400 ng*h / mL, 1425 ng*h / mL, 1450 ng*h / mL, 1475 ng*h / mL, 1500 ng*h / mL, 1525 ng*h / mL, 1550 ng*h / mL, 1575 ng*h / mL, 1600 ng*h / mL, 1625 ng*h / mL, 1650 ng*h / mL, 1675 ng*h / mL, 1700 ng*h / mL, 1725 ng*h / mL, 1750 ng*h / mL, 1775 ng*h / mL, 1800 ng*h / mL, 1825 ng*h / mL, 1850 ng*h / mL, 1875 ng*h / mL, 1900 ng*h / mL, 1925 ng*h / mL, 1950 ng*h / mL, 1975 ng*h / mL, and 2000 ng*h / mL in the population of subjects.

[0285] In some embodiments, the pharmaceutical composition provides a tmax of between about 2 and about 15 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 2 and about 14 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 2 and about 12 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 2 and about 10 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 2 and about 8 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 2 and about 6 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 2 and about 4 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 4 and about 15 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 6 and about 15 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 8 and about 15 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 10 and about 15 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between about 12 and about 15 hours in a subject.

[0286] In some embodiments, following administration to a subject the pharmaceutical composition provides a tmax of about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5 hours, about 5.25 hours, about5.5 hours, about 5.75 hours, about 6 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8 hours, about 8.25 hours, about 8.5 hours, about 8.75 hours, about 9 hours, about 9.25 hours, about9.5 hours, about 9.75 hours, about 10 hours, about 10.25 hours, about 10.5 hours, about 10.75 hours, about 11 hours, about 11.25 hours, about 11.5 hours, about 11.75 hours, about 12hours, about 12.25 hours, about 12.5 hours, about 12.75 hours, about 13 hours, about 13.25 hours, about 13.5 hours, about 13.75 hours, about 14 hours, about 14.25 hours, about 14.5 hours, about 14.75 hours, about 15 hours in the subject.

[0287] In some embodiments, the pharmaceutical composition provides a tmax of between 2 and 15 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 2 and 14 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 2 and 12 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 2 and 10 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 2 and 8 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 2 and 6 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 2 and 4 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 4 and 15 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 6 and 15 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 8 and 15 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 10 and 15 hours in a subject. In some embodiments, the pharmaceutical composition provides a tmax of between 12 and 15 hours in a subject.

[0288] In some embodiments, following administration to a subject, the pharmaceutical composition provides a tmax of 2 hours, 2.25 hours, 2.5 hours, 2.75 hours, 3 hours, 3.25 hours, 3.5 hours, 3.75 hours, 4 hours, 4.25 hours, 4.5 hours, 4.75 hours, 5 hours, 5.25 hours, 5.5 hours, 5.75 hours, 6 hours, 6.25 hours, 6.5 hours, 6.75 hours, 7 hours, 7.25 hours, 7.5 hours,7.75 hours, 8 hours, 8.25 hours, 8.5 hours, 8.75 hours, 9 hours, 9.25 hours, 9.5 hours, 9.75 hours, 10 hours, 10.25 hours, 10.5 hours, 10.75 hours, 11 hours, 11.25 hours, 11.5 hours,11.75 hours, 12 hours, 12.25 hours, 12.5 hours, 12.75 hours, 13 hours, 13.25 hours, 13.5 hours, 13.75 hours, 14 hours, 14.25 hours, 14.5 hours, 14.75 hours, 15 hours in the subject.

[0289] In some embodiments, the pharmaceutical composition provides a mean tmax of between about 2 and about 15 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between about 2 and about 14 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between about 2 and about 12 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between about 2 and about 10 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between about 2 and about 8 hours in a population ofsubjects. In some embodiments, the pharmaceutical composition provides a mean tmax ot between about 2 and about 6 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between about 2 and about 4 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between about 4 and about 15 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between about 6 and about 15 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between about 8 and about 15 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between about 10 and about 15 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between about 12 and about 15 hours in a population of subjects.

[0290] In some embodiments, following administration to a population of subjects the pharmaceutical composition provides a mean tmax of about 2 hours, about 2.25 hours, about2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5 hours, about 5.25 hours, about 5.5 hours, about 5.75 hours, about 6 hours, about 6.25 hours, about6.5 hours, about 6.75 hours, about 7 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8 hours, about 8.25 hours, about 8.5 hours, about 8.75 hours, about 9 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours, about 10 hours, about 10.25 hours, about10.5 hours, about 10.75 hours, about 11 hours, about 11.25 hours, about 11.5 hours, about 11.75 hours, about 12 hours, about 12.25 hours, about 12.5 hours, about 12.75 hours, about 13 hours, about 13.25 hours, about 13.5 hours, about 13.75 hours, about 14 hours, about 14.25 hours, about 14.5 hours, about 14.75 hours, about 15 hours in the population of subjects.

[0291] In some embodiments, the pharmaceutical composition provides a mean tmax of between 2 and 15 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between 2 and 14 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between 2 and 12 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between 2 and 10 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between 2 and 8 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between 2 and 6 hours in a population of subjects. Insome embodiments, the pharmaceutical composition provides a mean tmax ot between 2 and 4 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between 4 and 15 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between 6 and 15 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between 8 and 15 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between 10 and 15 hours in a population of subjects. In some embodiments, the pharmaceutical composition provides a mean tmax of between 12 and 15 hours in a population of subjects.

[0292] In some embodiments, following administration to a population of subjects, the pharmaceutical composition provides a mean tmax of 2 hours, 2.25 hours, 2.5 hours, 2.75 hours, 3 hours, 3.25 hours, 3.5 hours, 3.75 hours, 4 hours, 4.25 hours, 4.5 hours, 4.75 hours, 5 hours, 5.25 hours, 5.5 hours, 5.75 hours, 6 hours, 6.25 hours, 6.5 hours, 6.75 hours, 7 hours,7.25 hours, 7.5 hours, 7.75 hours, 8 hours, 8.25 hours, 8.5 hours, 8.75 hours, 9 hours, 9.25 hours, 9.5 hours, 9.75 hours, 10 hours, 10.25 hours, 10.5 hours, 10.75 hours, 11 hours, 11.25 hours, 11.5 hours, 11.75 hours, 12 hours, 12.25 hours, 12.5 hours, 12.75 hours, 13 hours,13.25 hours, 13.5 hours, 13.75 hours, 14 hours, 14.25 hours, 14.5 hours, 14.75 hours, 15 hours in the population of subjects.

[0293] In some embodiments, the pharmaceutical composition comprises about 0.3 to about 3 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.35 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.6 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.75 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1.5 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 3 mg of Compound I, or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the pharmaceutical composition comprises 0.3 to 3 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical composition comprises 0.35 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 0.5 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 0.75 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 1 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 1.5 mg of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 3 mg of Compound I, or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, the pharmaceutical composition comprises about 0.3 to 3 mg of Compound I. In some embodiments, the pharmaceutical composition comprises about 0.35 mg of Compound I. In some embodiments, the pharmaceutical composition comprises about 0.5 mg of Compound I. In some embodiments, the pharmaceutical composition comprises about 0.75 mg of Compound I. In some embodiments, the pharmaceutical composition comprises about 1 mg of Compound I. In some embodiments, the pharmaceutical composition comprises about 1.5 mg of Compound I. In some embodiments, the pharmaceutical composition comprises about 3 mg of Compound I.

[0296] In some embodiments, the pharmaceutical composition comprises 0.3 to 3 mg of Compound I. In some embodiments, the pharmaceutical composition comprises 0.35 mg ofCompound I. In some embodiments, the pharmaceutical composition comprises 0.5 mg ofCompound I. In some embodiments, the pharmaceutical composition comprises 0.75 mg ofCompound I. In some embodiments, the pharmaceutical composition comprises 1 mg ofCompound I. In some embodiments, the pharmaceutical composition comprises 1.5 mg ofCompound I. In some embodiments, the pharmaceutical composition comprises 3 mg ofCompound I.

[0297] In some embodiments, the pharmaceutical composition comprises about 0.3 to 3 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises about 0.35 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises about 0.75 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises about 1 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises about 1.5 mg of a pharmaceutically acceptable salt ofCompound I. In some embodiments, the pharmaceutical composition comprises about 3.0 mg of a pharmaceutically acceptable salt of Compound I.

[0298] In some embodiments, the pharmaceutical composition comprises 0.3 to 3 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises 0.35 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises 0.5 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises 0.75 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises 1 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises 1.5 mg of a pharmaceutically acceptable salt of Compound I. In some embodiments, the pharmaceutical composition comprises 3.0 mg of a pharmaceutically acceptable salt of Compound I.

[0299] In some embodiments, the pharmaceutical composition provides the pharmacokinetic parameter described herein following a single administration of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following multiple administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following one administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 2 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 3 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 4 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 5 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 6 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 7 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 8 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 9 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 10 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 11 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter isobtained following 12 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 13 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 14 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 15 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 16 administrations of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameter is obtained following 17 administrations of the pharmaceutical composition.

[0300] In some embodiments, the pharmaceutical composition provides each of said pharmacokinetic parameters following administration of Compound I under fasted conditions. In some embodiments, the pharmaceutical composition provides each of said pharmacokinetic parameters following administration of Compound I under fed conditions.

[0301] In some embodiments, the pharmaceutical composition is administered with a hydroxypropyl-P-cyclodextrin chaser.Methods of Use

[0302] Compound I as described herein, is useful for the treatment and prevention of, e.g., certain CNS-related conditions in a subject.

[0303] In one aspect, the disclosure provides a method for treating a disease, disorder or condition requiring positive allosteric NMD A receptor modulation in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition as disclosed herein.

[0304] In some embodiments, the disclosure provides a method for treating a CNS-related condition in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition as disclosed herein.

[0305] In some embodiments, the disclosure provides a method for preventing a disease, disorder or condition requiring positive allosteric NMD A receptor modulation in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition as disclosed herein.

[0306] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in treating a disease, disorder or condition requiring positive NMDA receptor modulation in a subject.

[0307] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in preventing a disease, disorder or condition requiring positive NMD A receptor modulation in a subject.

[0308] In some embodiments, the disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating a disease, disorder or condition requiring positive allosteric NMD A receptor modulation in a subject.

[0309] In some embodiments, the disclosure provides the use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for preventing a disease, disorder or condition requiring positive allosteric NMDA receptor modulation in a subject.

[0310] In some embodiments, the said CNS-related condition is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank group of proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraine headaches), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington’s disease and Parkinson’s disease) and tinnitus.

[0311] In some embodiments, the sterol synthesis disorder is selected from the group consisting of Smith-Lemli-Opitz Syndrome (SLOS), desmosterolosis, sitosterolemia, cerebrotendinous xanthomatosis (CTX), Mevalonate Kinase Deficiency (MKD), and SC4MOL gene mutation (SMO Deficiency).

[0312] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein for use in inducing sedation or anesthesia in a subject.

[0313] In some embodiments, the CNS-related condition is selected from the group consisting of Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.Movement Disorders

[0314] Also described herein are methods for treating a movement disorder. As used herein, “movement disorders” refers to a variety of diseases and disorders that are associated with hyperkinetic movement disorders and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson’s disease and Parkinsonism (defined particularly by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

[0315] Tremor is an involuntary, at times rhythmic, muscle contraction and relaxation that can involve oscillations or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk, legs). Tremor includes hereditary, degenerative, and idiopathic disorders such as Wilson’s disease, Parkinson’s disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiologic tremor, enhanced physiologic tremor, essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes’ tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor. Other forms of tremor include cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, or rubral tremor.

[0316] Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities that occurs after a purposeful movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from, e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inherited degenerative disorder).

[0317] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and / or painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body. Dystonic tremors occurs irregularly and often can be relieved by complete rest.

[0318] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor may be mild and nonprogressive in some, and may be slowly progressive, starting on one side of the body but affect both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremor frequency may decrease as the person ages, but severity may increase. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and / or increase their severity. Symptoms generally evolve over time and can be both visible and persistent following onset.

[0319] Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz) rhythmic muscle contractions that occurs in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. Orthostatic tremor may occur in patients with essential tremor.

[0320] Parkinsonian tremor is caused by damage to structures within the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson’s disease and is typically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after age 60. Movement starts in one limb or on one side of the body and can progress to include the other side.

[0321] Physiological tremor can occur in normal individuals and have no clinical significance. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. The tremor classically has a frequency of about 10 Hz.

[0322] Psychogenic tremor or hysterical tremor can occur at rest or during postural or kinetic movement. Patient with psychogenic tremor may have a conversion disorder or another psychiatric disease.

[0323] Rubral tremor is characterized by coarse slow tremor which can be present at rest, at posture, and with intention. The tremor is associated with conditions that affect the red nucleus in the midbrain, classical unusual strokes.

[0324] Parkinson ’s disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms found in Parkinson ’s disease, but is a symptom complex rather than a progressive neurodeg enerative disease.

[0325] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures. Dystonic movementscan be patterned, twisting, and may be tremulous. Dystonia is otten initiated or worsened by voluntary action and associated with overflow muscle activation.

[0326] Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hips, and face.

[0327] Huntington’s Disease is an inherited disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington’s disease can hinder walk, talk, and swallowing.

[0328] Ataxia refers to the loss of full control of bodily movements, and may affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0329] Myoclonus and Startle is a response to a sudden and unexpected stimulus, which can be acoustic, tactile, visual, or vestibular.

[0330] Tics are an involuntary movement usually onset suddenly, brief, repetitive, but non- rhythmical, typically imitating normal behavior and often occurring out of a background of normal activity. Tics can be classified as motor or vocal, motor tics associated with movements while vocal tics associated with sound. Tics can be characterized as simple or complex. For example, simple motor tics involve only a few muscles restricted to a specific body part.

[0331] Tourette Syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic.

[0332] Restless Legs Syndrome is a neurologic sensorimotor disorder characterized by an overwhelming urge to move the legs when at rest.

[0333] Stiff Person Syndrome is a progressive movement disorder characterized by involuntary painful spasms and rigidity of muscles, usually involving the lower back and legs. Stiff-legged gait with exaggerated lumbar hyperlordosis typically results.Characteristic abnormality on EMG recordings with continuous motor unit activity of the paraspinal axial muscles is typically observed. Variants include “stiff-limb syndrome” producing focal stiffness typically affecting distal legs and feet.

[0334] Gait disorders refer to an abnormality in the manner or style of walking, which results from neuromuscular, arthritic, or other body changes. Gait is classified according to the system responsible for abnormal locomotion, and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.Mood disorders

[0335] Also provided herein are methods for treating a mood disorder, for example clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cationic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior.

[0336] Clinical depression is also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical depression affects how an individual feels, thinks, and behaves and may lead to a variety of emotional and physical problems.Individuals with clinical depression may have trouble doing day-to-day activities and make an individual feel as if life is not worth living.

[0337] Postnatal depression (PND) is also referred to as postpartum depression (PPD), and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleeping and eating habits, reduced sexual desire, crying episodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., a refractory depression as described herein).

[0338] In some embodiments, a subject having PND also experienced depression, or a symptom of depression during pregnancy. This depression is referred to herein as) perinatal depression. In an embodiment, a subject experiencing perinatal depression is at increased risk of experiencing PND.

[0339] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain or increased appetite. Patients suffering from AD also may have excessive sleep or somnolence (hypersomnia), a sensation of limb heaviness, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.

[0340] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, failures to react to pleasurable stimuli, depressed mood more pronounced than that of grief or loss, excessive weight loss, or excessive guilt.

[0341] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, in particular of melancholic nature, where the individual experiences psychotic symptoms such as delusions and hallucinations.

[0342] Catatonic depression refers to major depression involving disturbances of motor behavior and other symptoms. An individual may become mute and stuporose, and either is immobile or exhibits purposeless or bizarre movements.

[0343] Seasonal affective disorder (SAD) refers to a type of seasonal depression wherein an individual has seasonal patterns of depressive episodes coming on in the fall or winter.

[0344] Dysthymia refers to a condition related to unipolar depression, where the same physical and cognitive problems are evident. They are not as severe and tend to last longer (e.g., at least 2 years).

[0345] Double depression refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression.

[0346] Depressive Personality Disorder (DPD) refers to a personality disorder with depressive features.

[0347] Recurrent Brief Depression (RBD) refers to a condition in which individuals have depressive episodes about once per month, each episode lasting 2 weeks or less and typically less than 2-3 days.

[0348] Minor depressive disorder or minor depression refers to a depression in which at least 2 symptoms are present for 2 weeks.

[0349] Bipolar disorder or manic depressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During periods of mania the individual may feel or act abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced. During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life. The risk of suicide among those with the disorder is high at greater than 6% over 20 years, while self-harm occurs in 30-40%. Other mental health issues such as anxiety disorder and substance use disorder are commonly associated with bipolar disorder.

[0350] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress.

[0351] Treatment-resistant depression refers to a condition where the individuals have been treated for depression, but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not ease depression symptoms forindividuals with treatment-resistant depression. In some cases, individuals with treatmentresistant depression improve symptoms, but come back.

[0352] Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytic drugs, as well as non- pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation and / or transcranial magnetic stimulation).

[0353] Suicidality, suicidal ideation, suicidal behavior refers to the tendency of an individual to commit suicide. Suicidal ideation concerns thoughts about or an unusual preoccupation with suicide. The range of suicidal ideation varies greatly, from e.g., fleeting thoughts to extensive thoughts, detailed planning, role playing, incomplete attempts.Symptoms include talking about suicide, getting the means to commit suicide, withdrawing from social contact, being preoccupied with death, feeling trapped or hopeless about a situation, increasing use of alcohol or drugs, doing risky or self-destructive things, saying goodbye to people as if they won’t be seen again.

[0354] Symptoms of depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, sleeplessness, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, appetite loss, insomnia, self-harm, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary on a case to case basis. Symptoms of depression, and relief of the same, may be ascertained by a physician or psychologist (e.g., by a mental state examination).Anxiety Disorders

[0355] Provided herein are methods for treating anxiety disorders. Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0356] Generalized anxiety disorder is a common chronic disorder characterized by long- lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

[0357] In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficultybreathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).

[0358] Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.

[0359] The single largest category of anxiety disorders is that of phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.

[0360] Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.Epilepsy

[0361] Epilepsy is a brain disorder characterized by repeated seizures over time, types ot epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.Epileptogenesis

[0362] Epileptogenesis is a gradual process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from neuronal damage precipitated by the initial insult (e.g., status epilepticus).Status epilepticus (SE)

[0363] Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.

[0364] Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non- convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non- convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.Seizure

[0365] A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person’s body shakes rapidly and uncontrollably. During convulsions, the person’s muscles contract and relax repeatedly.

[0366] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.

[0367] Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

[0368] There are six types of generalized seizures. The most common and dramatic, and therefore the most well-known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the "tonic" phase of the seizure) for 30 to 60 seconds, then by violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the "postictal" or after-seizure phase). During grand-mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.

[0369] Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of "losing time."

[0370] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.

[0371] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

[0372] Tonic seizures are characterized by stiffening of the muscles.

[0373] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

[0374] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non- convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizure is a generalized seizure associated with Dravet Syndrome, Lennox-Gastaut Syndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 Female Pediatric Epilepsy.Huntington ’s Disease

[0375] Huntington’s Disease is an inherited disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington’s disease can hinder walk, talk, and swallowing.

[0376] In one aspect, the disclosure provides a method of treating or preventing Huntington’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0377] In some embodiments, the disclosure provides a method of treating Huntington’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein. In some embodiments, the disclosure provides a method of preventing Huntington’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0378] In some embodiments, the disclosure provides a method of treating cognitive impairment in a subject having Huntington’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0379] In some embodiments, the disclosure provides a method of treating Mild Cognitive Impairment (MCI) associated with Huntington’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0380] In some embodiments, the disclosure provides a method of improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0381] In some embodiments, the disclosure provides a method of improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0382] In some embodiments, the disclosure provides a method of improving learning in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0383] In some embodiments, the disclosure provides a method of improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0384] In some embodiments, the disclosure provides a method of improving cognition in a subject having Huntington’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0385] In one aspect, the disclosure provides a pharmaceutical composition as described herein, for use in treating or preventing Huntington’s disease in a subject. In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in treating Huntington’s disease in a subject. In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in preventing Huntington’s disease in a subject.

[0386] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in treating cognitive impairment in a subject having Huntington’s disease.

[0387] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in treating Mild Cognitive Impairment (MCI) associated with Huntington’s disease in a subject.

[0388] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease.

[0389] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease.

[0390] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving learning in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease.

[0391] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease.

[0392] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving cognition in a subject having Huntington’s disease.

[0393] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in slowing cognitive decline in a subject having Huntington’s disease.

[0394] In some embodiments, the disclosure provides a method for slowing cognitive decline in a subject having Huntington’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0395] In one aspect, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating or preventing Huntington’s disease in a subject. In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating Huntington’s disease in a subject. In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for preventing Huntington’s disease in a subject.

[0396] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating cognitive impairment in a subject having Huntington’s disease.

[0397] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating Mild Cognitive Impairment (MCI) associated with Huntington’s disease in a subject.

[0398] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease.

[0399] In some embodiments, the disclosure provides a se of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease.

[0400] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving learning in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease.

[0401] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with Huntington’s disease.

[0402] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving cognition in a subject having Huntington’s disease.

[0403] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for slowing cognitive decline in a subject having Huntington’s disease.

[0404] In some embodiments, the methods disclosed herein comprise administering the pharmaceutical composition described herein in combination with other therapeutic agents used for treating Huntington’s disease. Examples of such other therapeutic agents include but are not limited to chorea medications (e.g., tetrabenazine (TBZ), deutetetrabenazine (DBZ)), antipsychotics (e.g., olanzapine, risperidone), antidepressants (citalopram, fluoxetine, sertraline) and mood stabilizers (e.g., lamotrigine, carbamazepine).Parkinson ’s Disease

[0405] Parkinson’s disease affects nerve cells in the brain that produce dopamine.Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms found in Parkinson’s disease but is a symptom complex rather than a progressive neurodegenerative disease.

[0406] In one aspect, the disclosure provides a method of treating or preventing Parkinson’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0407] In some embodiments, the disclosure provides a method of treating Parkinson’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein. In some embodiments, thedisclosure provides a method of preventing Parkinson’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0408] In some embodiments, the disclosure provides a method of treating cognitive impairment in a subject having Parkinson’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0409] In some embodiments, the disclosure provides a method of treating Mild Cognitive Impairment (MCI) associated with Parkinson’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0410] In some embodiments, the disclosure provides a method of improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0411] In some embodiments, the disclosure provides a method of improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0412] In some embodiments, the disclosure provides a method of improving learning in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0413] In some embodiments, the disclosure provides a method of improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0414] In some embodiments, the disclosure provides a method of improving cognition in a subject having Parkinson’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0415] In some embodiments, the disclosure provides a method for slowing cognitive decline in a subject having Parkinson’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0416] In one aspect, the disclosure provides a pharmaceutical composition as described herein, for use in treating or preventing Parkinson’s disease in a subject. In someembodiments, the disclosure provides a pharmaceutical composition as disclosed herein, tor use in treating Parkinson’s disease in a subject. In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in preventing Parkinson’s disease in a subject.

[0417] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in treating cognitive impairment in a subject having Parkinson’s disease.

[0418] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in treating Mild Cognitive Impairment (MCI) associated with Parkinson’s disease in a subject.

[0419] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease.

[0420] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease.

[0421] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving learning in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease.

[0422] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease.

[0423] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving cognition in a subject having Parkinson’s disease.

[0424] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in slowing cognitive decline in a subject having Parkinson’s disease.

[0425] In one aspect, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating or preventing Parkinson’s disease in a subject. In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating Parkinson’s disease in a subject. In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for preventing Parkinson’s disease in a subject.

[0426] In some embodiments, the disclosure provides a use ot a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating cognitive impairment in a subject having Parkinson’s disease.

[0427] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating Mild Cognitive Impairment (MCI) associated with Parkinson’s disease in a subject.

[0428] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease.

[0429] In some embodiments, the disclosure provides a se of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease.

[0430] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving learning in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease.

[0431] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with Parkinson’s disease.

[0432] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving cognition in a subject having Parkinson’s disease.

[0433] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for slowing cognitive decline in a subject having Parkinson’s disease.

[0434] In some embodiments, the methods disclosed herein comprise administering the pharmaceutical composition described herein in combination with other therapeutic agents used for treating Parkinson’s disease.Alzheimer ’s Disease

[0435] Alzheimer’s disease (AD) is an age-related neurodegenerative disease. Clinically, this disorder is characterized by global cognitive dysfunction, especially memory loss, behavior and personality changes. AD progression has been associated with a gradualdamage in function and structure in the hippocampus and neocortex, the vulnerable brain areas used for memory and cognition.

[0436] In one aspect, the disclosure provides a method of treating or preventing Alzheimer’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0437] In some embodiments, the disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein. In some embodiments, the disclosure provides a method of preventing Alzheimer’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0438] In some embodiments, the disclosure provides a method of treating cognitive impairment in a subject having Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0439] In some embodiments, the disclosure provides a method of treating Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0440] In some embodiments, the disclosure provides a method of improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0441] In some embodiments, the disclosure provides a method of improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0442] In some embodiments, the disclosure provides a method of improving learning in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0443] In some embodiments, the disclosure provides a method of improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0444] In some embodiments, the disclosure provides a method of improving cognition in a subject having Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0445] In some embodiments, the disclosure provides a method for slowing cognitive decline in a subject having Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0446] In some embodiments, the disclosure provides a method of treating mild dementia associated with Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0447] In some embodiments, the disclosure provides a method of improving executive function in a subject having mild dementia associated with Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0448] In some embodiments, the disclosure provides a method of improving working memory in a subject having mild dementia associated with Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0449] In some embodiments, the disclosure provides a method of improving learning in a subject having mild dementia associated with Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0450] In some embodiments, the disclosure provides a method of improving learning and working memory in a subject having mild dementia associated with Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.

[0451] In one aspect, the disclosure provides a pharmaceutical composition as described herein, for use in treating or preventing Alzheimer’s disease in a subject. In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in treating Alzheimer’s disease in a subject. In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in preventing Alzheimer’s disease in a subject.

[0452] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in treating cognitive impairment in a subject having Alzheimer’s disease.

[0453] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in treating Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease in a subject.

[0454] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease.

[0455] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease.

[0456] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving learning in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease.

[0457] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease.

[0458] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving cognition in a subject having Alzheimer’s disease.

[0459] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in slowing cognitive decline in a subject having Alzheimer’s disease.

[0460] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in treating mild dementia associated with Alzheimer’s Disease.

[0461] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving executive function in a subject having mild dementia associated with Alzheimer’s disease.

[0462] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving working memory in a subject having mild dementia associated with Alzheimer’s disease.

[0463] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving learning in a subject having mild dementia associated with Alzheimer’s disease.

[0464] In some embodiments, the disclosure provides a pharmaceutical composition as disclosed herein, for use in improving learning and working memory in a subject having mild dementia associated with Alzheimer’s disease.

[0465] In one aspect, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating or preventing Alzheimer’s disease in a subject. In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating Alzheimer’s disease in a subject. In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for preventing Alzheimer’s disease in a subject.

[0466] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating cognitive impairment in a subject having Alzheimer’s disease.

[0467] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease in a subject.

[0468] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving executive function in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease.

[0469] In some embodiments, the disclosure provides a se of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving working memory in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease.

[0470] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving learning in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease.

[0471] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving learning and working memory in a subject having Mild Cognitive Impairment (MCI) associated with Alzheimer’s disease.

[0472] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving cognition in a subject having Alzheimer’s disease.

[0473] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for slowing cognitive decline in a subject having Alzheimer’s disease.

[0474] In some embodiments, the disclosure provides a use ot a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating mild dementia associated with Alzheimer’s Disease.

[0475] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving executive function in a subject having mild dementia associated with Alzheimer’s disease.

[0476] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving working memory in a subject having mild dementia associated with Alzheimer’s disease.

[0477] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving learning in a subject having mild dementia associated with Alzheimer’s disease.

[0478] In some embodiments, the disclosure provides a use of a pharmaceutical composition as disclosed herein for the manufacture of a medicament for improving learning and working memory in a subject having mild dementia associated with Alzheimer’s disease.

[0479] In some embodiments, the methods disclosed herein comprise administering the pharmaceutical composition described herein in combination with other therapeutic agents used for treating Alzheimer’s disease.

[0480] In some embodiments, the method comprises administering to the subject a daily oral composition comprising about 0.35 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral composition comprising about 0.5 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral composition comprising about 0.75 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral composition comprising about 1 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral composition comprising about 1.5 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral composition comprising about 3 mg of Compound I.

[0481] In some embodiments, the method comprises administering to the subject a daily oral composition comprising 0.35 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral composition comprising 0.5 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral composition comprising 0.75 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral composition comprising 1 mg ofCompound I. In some embodiments, the method comprises administering to the subject a daily oral composition comprising 1.5 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral composition comprising 3 mg of Compound I. In some embodiments, the method comprises administering a composition comprising Compound I followed by a hydroxypropyl-P-cyclodextrin chaser composition. In some embodiments, the method comprises administering a composition comprising Compound I and hydroxypropyl-P-cyclodextrin followed by a hydroxypropyl-P-cyclodextrin chaser composition.

[0482] In some embodiments, the method comprises administering to the subject a daily oral solution comprising about 0.35 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral solution comprising about 0.5 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral solution comprising about 0.75 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral solution comprising about 1 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral solution comprising about 1.5 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral solution comprising about 3 mg of Compound I.

[0483] In some embodiments, the method comprises administering to the subject a daily oral solution comprising 0.35 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral solution comprising 0.5 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral solution comprising 0.75 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral solution comprising 1 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral solution comprising 1.5 mg of Compound I. In some embodiments, the method comprises administering to the subject a daily oral solution comprising 3 mg of Compound I. In some embodiments, the method comprises administering a composition comprising Compound I followed by a hydroxypropyl-P-cyclodextrin chaser composition. In some embodiments, the method comprises administering a composition comprising Compound I and hydroxypropyl- P-cyclodextrin followed by a hydroxypropyl-P-cyclodextrin chaser composition.Numbered Embodiments1. A pharmaceutical composition comprising a therapeutically effective amount ofCompound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptablecarrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a Cmax of between about 2 ng / mL and about 80 ng / mL; b) an AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL; c) an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; d) an AUC 00 of between about 50 ng*h / mL and about 2000 ng*h / mL; and e) a tmax of between about 2 hours and about 15 hours.2. A pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides one or more of the following pharmacokinetic parameters: a) a Cmax of between about 2 ng / mL and about 80 ng / mL; b) an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; c) an AUC 00 of between about 50 ng*h / mL and about 2000 ng*h / mL; and d) a tmax of between about 2 hours and about 15 hours.3. The pharmaceutical composition according to Embodiment 1 or 2 wherein the pharmaceutical composition provides a Cmax of between about 2 ng / ml and about 80 ng / mL.4. The pharmaceutical composition according to any one of Embodiments 1-3 wherein the pharmaceutical composition provides a Cmax of between about 5 ng / ml and about 50 ng / mL.5. The pharmaceutical composition according to any one of Embodiments 1-4 wherein the pharmaceutical composition provides a Cmax of between about 5 ng / ml and about 20 ng / mL.6. The pharmaceutical composition according to any one of Embodiments 1-5, wherein the pharmaceutical composition provides a tmax of between about 2 hours and about 15 hours.7. The pharmaceutical composition according to Embodiment 6, wherein the pharmaceutical composition provides a tmax of between about 4 hours and about 8 hours.8. The pharmaceutical composition according to any one of Embodiments 1-7, wherein the pharmaceutical composition provides an AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL.9. The pharmaceutical composition according to Embodiment 8, wherein the pharmaceutical composition provides an AUC2411 of between about 100 ng*h / mL and about 500 ng*h / mL.10. The pharmaceutical composition according to any one of Embodiments 1-9, wherein the pharmaceutical composition provides an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL.11. The pharmaceutical composition according to Embodiment 10 wherein the pharmaceutical composition provides an AUCiast of between about 100 ng*h / mL and about 500 ng*h / mL.12. The pharmaceutical composition according to any one of Embodiments 1-11, wherein the pharmaceutical composition provides an AUCoo of between about 50 ng*h / mL and about 2000 ng*h / mL.13. The pharmaceutical composition according to Embodiment 12, wherein the pharmaceutical composition provides an AUCoo of between about 100 ng*h / mL and about 1500 ng*h / mL.14. The pharmaceutical composition according to Embodiment 13, wherein the pharmaceutical composition provides an AUCoo of between about 100 ng*h / mL and about 1100 ng*h / mL.15. The pharmaceutical composition according to Embodiment 1, wherein the pharmaceutical composition provides the pharmacokinetic parameter: a) a Cmax of between about 2 ng / mL and about 80 ng / mL; b) an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; c) an AUC 00 of between about 50 ng*h / mL and about 2000 ng*h / mL; and d) a tmax of between about 2 hours and about 15 hours.16. The pharmaceutical composition according to Embodiment 1, wherein the pharmaceutical composition provides the pharmacokinetic parameter: a) a Cmax of between about 2 ng / mL and about 80 ng / mL; b) an AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL; c) an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; d) an AUC 00 of between about 50 ng*h / mL and about 2000 ng*h / mL; and e) a tmax of between about 2 hours and about 15 hours.17. The pharmaceutical composition according to any one of Embodiments 1-16, wherein the pharmaceutical composition comprises Compound I.18. The pharmaceutical composition according to any one of Embodiments 1-16, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound I.19. The pharmaceutical composition of any one of Embodiments 1-18, wherein the pharmaceutical composition comprises between about 0.3 to about 3.0 mg of Compound I, or a pharmaceutically acceptable salt thereof.20. The pharmaceutical composition of Embodiment 19, wherein the pharmaceutical composition comprises between about 0.3 to about 3.0 mg of Compound I.21. The pharmaceutical composition of any Embodiment 19, wherein the pharmaceutical composition comprises between about 0.3 to about 3.0 mg of a pharmaceutically acceptable salt of Compound I.22. The pharmaceutical composition of any one of Embodiments 1-21, wherein the pharmaceutical composition comprises hydroxypropyl-P-cyclodextrin.23. The pharmaceutical composition according to any one of Embodiments 1-22, wherein said pharmacokinetic parameter is obtained following a single administration of the pharmaceutical composition.24. The pharmaceutical composition according to any one of Embodiments 1-22, wherein said pharmacokinetic parameter is obtained following multiple administrations of the pharmaceutical composition.25. The pharmaceutical composition according to any one of Embodiments 1-22, wherein said pharmacokinetic parameter is obtained following 7 administrations of the pharmaceutical composition.26. The pharmaceutical composition according to any one of claim Embodiments 1-22, wherein said pharmacokinetic parameter is obtained following 14 administrations of the pharmaceutical composition.27. The pharmaceutical composition according to any one of Embodiments 1-22, wherein said pharmacokinetic parameter is obtained following 17 administrations of the pharmaceutical composition.28. The pharmaceutical composition according to any one of Embodiments 1-27, wherein each of said pharmacokinetic parameter is obtained following administration of the composition under fasted conditions.29. The pharmaceutical composition according to any one of Embodiments 1-27, wherein said pharmacokinetic parameter is obtained following administration of the composition under fed conditions.30. The pharmaceutical composition according to any one of Embodiments 1-29, wherein the pharmaceutical composition is an oral dosage form.31. A method of treating a CNS-related condition in a subject, wherein the CNS-related condition, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 1-30.32. The method of Embodiment 31, wherein said CNS-related condition is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive- compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank group of proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraine headaches), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington’s disease and Parkinson’s disease) and tinnitus.33. The method of Embodiment 32, wherein the sterol synthesis disorder is selected from the group consisting of Smith-Lemli-Opitz Syndrome (SLOS), desmosterolosis, sitosterolemia, cerebrotendinous xanthomatosis (CTX), Mevalonate Kinase Deficiency (MKD), and SC4MOL gene mutation (SMO Deficiency).34. A method of inducing sedation or anesthesia in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 1-30.35. Use of a pharmaceutical composition according to any one of Embodiments 1-30 for the manufacture of a medicament for treating a CNS-related condition in a subject.36. The use according to Embodiment 35, wherein said CNS-related condition is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive- compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders(including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank group of proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraine headaches), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington’s disease and Parkinson’s disease) and tinnitus.37. The use of Embodiment 34, wherein the sterol synthesis disorder is selected from the group consisting of Smith-Lemli-Opitz Syndrome (SLOS), desmosterolosis, sitosterolemia, cerebrotendinous xanthomatosis (CTX), Mevalonate Kinase Deficiency (MKD), and SC4M0L gene mutation (SMO Deficiency).38. Use of a pharmaceutical composition according to any one of Embodiments 1-30 for the manufacture of a medicament for inducing sedation or anesthesia in a subject.39. A pharmaceutical composition according to Embodiments 1-30 for use in treating a CNS related condition in a subject.40. The pharmaceutical composition for use according to Embodiment 39, wherein said CNS-related condition is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse- related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank group of proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraine headaches), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington’s disease and Parkinson’s disease) and tinnitus.41. The pharmaceutical composition for use according to Embodiment 40, wherein the sterol synthesis disorder is selected from the group consisting of Smith-Lemli-Opitz Syndrome (SLOS), desmosterolosis, sitosterolemia, cerebrotendinous xanthomatosis (CTX), Mevalonate Kinase Deficiency (MKD), and SC4MOL gene mutation (SMO Deficiency).42. A pharmaceutical composition according to any one of Embodiments 1-30 for use in inducing sedation or anesthesia in a subject.EXAMPLES

[0484] In order that the invention described herein may be more fully understood, the following examples are set forth. The Examples are offered for illustrative purposes and are not to be construed in any way as limiting the scope of the invention.Abbreviations

[0485] AUC - area under the curve; AUCo-® (or AUG / rarea under the concentration-time curve from the time of dosing extrapolated to infinity; AUC0-24 (or AUC24)- area under the plasma concentration-time curve from time 0 to 24-h postdose; AUCo-t (or AUCt)- area under the plasma concentration-time curve from time 0 to the time of the last measured concentration; AUCo-iast (or AUCiast)- area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration; LCL - lower control limit; SAD - single-ascending dose; MAD - multiple-ascending dose; UCL - upper control limit; h - hour; LLOQ - lower limit of quantification; SD - standard deviation; TEAE - treatment emergent adverse effect; Cmax - maximum concentration; Cmin - minimum concentration over the 24 hour dosing interval; CV% - percentage coefficient of variation; NC - not calculated; R2 - coefficient of determination; RA - accumulation ratio; RA AUC0-24 - RA calculated as AUCo- 24 multiple dose / AUCo-24 single dose (same as RA AUCtau); RA Cmax - RA calculated as Cmax multiple dose / Cmax single dose; T1 / 2 - terminal half-life; Tau - dosing interval; Tmax - time of maximum concentration; CRU - clinical research unit; HP - healthy participant; CAG, Cytosine- Adenine-Guanine; HD - Huntington’s disease; HTT - Huntingtin; IP - investigational product; BMI - body mass index; C-SSRS - Columbia-Suicide Severity Rating Scale; ECG - electrocardiogram; EEG - electroencephalogram; HP-P-CD - 2- hydroxypropyl-P-cyclodextrin; ALT - alanine transaminase; AST - aspartate aminotransferase; HIV - human immunodeficiency virus; QTcF - QT interval corrected according to Fridericia’s formula.Summary

[0486] A first-in-human, Phase 1, double-blind, dose-finding studies to assess safety, tolerability, and clinical pharmacology of Compound I was conducted. A single-ascendingdose study (SAD) (Compound I 0.35, 0.75, 1.5, or 3.0 mg or placebo) was conducted in healthy participants and included food effect. A multiple-ascending dose study (MAD) (14 days) was conducted in healthy participants (Compound I 0.5 or 1.0 mg or placebo) and HD participants (open-label Compound 1 1.0 mg) and included exploratory pharmacodynamics on cognitive performance.

[0487] Compound I was generally well tolerated with no adverse events leading to discontinuation. Compound I exhibited pharmacokinetic parameters appropriate for once- daily dosing. Following single and multiple doses in healthy participants, median terminal half-life was 7-116 h, and median time to reach maximum plasma concentration was 4-7 h. Exposures were dose proportional after single dose (6-46 ng / mL) and more than dose proportional after multiple doses (6-41 ng / mL). With multiple dosing, steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Compound I exposure decreased slightly with food. In HD participants, results suggest Compound I may improve cognitive performance on tests of executive function.MethodsSAD study design

[0488] The objectives of SAD were to evaluate safety, tolerability, and pharmacokinetics of single-dose Compound I in healthy participants and included a placebo-controlled, randomized study (Cohorts 1 to 4a and 4b) and a food effect study (Cohort 5). Cohort 4b received the same dose and had the same assessments as Cohort 4a plus an additional exploratory biomarker assessment. The maximum dose of Compound I 3.0 mg in Cohorts 4a and 4b was selected based on a predetermined exposure limit from nonclinical studies. In Cohort 5, Compound 10.75 mg was selected as <25% of the maximum dose (Compound I 3.0 mg) administered in Cohorts 4a and 4b.

[0489] In Cohorts 1 to 4a and 4b, eight participants were enrolled per cohort; six participants received Compound I (Cohort 1, 0.35 mg; Cohort 2, 0.75 mg; Cohort 3, 1.5 mg; Cohorts 4a and 4b, 3.0 mg), and two received matched placebo. Cohort 5 (Compound I 0.75 mg) enrolled eight participants. Sentinel dosing of the first two participants in Cohorts 1 to 4a and 4b (randomized 1 : 1 to Compound I and placebo) was used to mitigate risk. The remaining six participants were randomized 5: 1 to Compound I or placebo. (See Figure 1A).

[0490] Eligible participants were admitted to the clinical research unit (CRU) on Day -1 (evening before dosing) and fasted overnight for >8 h. The morning of Day 1 (day of dosing), Cohorts 1 to 4a and 4b received Compound I or placebo under fasting conditions, and Cohort 5 received Compound I approximately 30 minutes after a high-fat meal (seeHigh-fat meal). Water was prohibited 2-h predose through 2-h postdose in all cohorts. Participants were monitored as inpatients until 72-h postdose and were subsequently followed as outpatients through Day 14 (±2 days) (Figure 2A).High Fat Meal

[0491] The high-fat meal used in the Compound I SAD study was equivalent to the high-fat meal in Appendix 1 of the US FDA CDER guidance: Assessing the Effects of Food on Drugs in INDs and ND As - Clinical Pharmacology Considerations. Composition of High-Fat Meal: Total calories: 800 - 1000; Calories from protein: 150; Calories from carbohydrates: 250 Calories from fat: 500 - 600. Percent calories from fat: >50MAD study design

[0492] The SAD and MAD studies were staggered to allow results from SAD to inform dosing in MAD. The starting dose for Cohort 1 was Compound I 0.5 mg / day, which was well tolerated in SAD. In Cohort 2, Compound 1 1.0 mg was selected based on the maximum exposure from SAD coupled with pharmacokinetic modeling of multidose accumulation. After the healthy participant cohorts were completed, participants with Huntington’s Disease (HD) were recruited in Cohort 3 to receive Compound 1 1.0 mg, the highest dose evaluated from Cohorts 1 and 2.

[0493] The objectives of MAD were to evaluate safety, tolerability, pharmacokinetics, and preliminary pharmacodynamics of Compound I in healthy and HD participants using a double-blind, placebo-controlled, randomized study (healthy participants, Cohorts 1 and 2) and an open-label study (HD participants, Cohort 3). Cohorts 1 and 2 included twelve participants each (Compound I n=9, Cohort 1 [0.5 mg] and Cohort 2 [1.0 mg]; placebo n=3). Cohort 3 included six participants (Compound I 1.0 mg). Sentinel dosing was used for Cohorts 1 and 2; the first three participants in each cohort received Compound I or placebo at a 2:1 ratio, and the subsequent nine received Compound I or placebo at a 7:2 ratio (See Figure IB).

[0494] Healthy participants were admitted to the CRU on Day -2 and remained until Day 17. A single dose of Compound I or placebo was administered once daily in the morning under fasting conditions from Days 1 through 14. Water was prohibited from 2-h predose through 2-h postdose; participants were allowed to eat approximately 4 h after dosing.

[0495] HD participants were admitted to the CRU on Day -1 and received a single dose of Compound I after a light meal in the morning from Days 1 through 14; food and water were allowed >3 h after dosing. Participants were discharged from the CRU on Day 2, had daily outpatient visits from Days 3 through 13, and were readmitted to the CRU on Day 14. Allparticipants were discharged after completing Day 17 assessments and returned for a followup visit on Day 21 (±2 days) (See Figure 2B).Study drug formulation and administration

[0496] Active and placebo treatments were identical in appearance in each study.Compound I oral solution was a 40-mL dose containing Compound I drug substance and the inactive ingredients of hydroxypropyl-P-cyclodextrin, sucralose, and water. Placebo was a 40-mL oral solution containing only inactive ingredients. Healthy participants received placebo or Compound I per a randomization schedule (see Randomization and administration details).Randomization and administration details

[0497] In the SAD study, randomization schedules were generated. The allocation to study drug (Compound I oral solution or placebo) was based on the randomization schedule for each double-blind cohort. The appropriate dose of Compound I oral solution or placebo was administered according to the randomization schedule. Subject received a placebo or the appropriate dose of Compound in a 40 mL oral solution I, followed by a HPpCD chaser.

[0498] In the MAD study, randomization schemes were generated. Subject received a placebo or the appropriate dose of Compound in a 40 mL oral solution I, followed by a HPpCD chaser.

[0499] Compound I drug substance was supplied in bulk requiring further compounding to prepare the Compound I oral solution. The stock solution was prepared as an aqueous solution of Compound I drug substance, 2-hydroxypropyl-P-cyclodextrin (HPpCD), and sucralose. Individual doses of Compound I oral solution were prepared by diluting the appropriate amount of stock solution with a 5%-by-weight solution of HPpCD to an approximately 40-mL total volume. Placebo was appearance-matched to Compound I oral solution.Participants

[0500] Healthy participants in SAD and MAD were aged 18-65 years. HD participants in MAD were eligible if aged 18-70 years, with objective cognitive impairment (Montreal Cognitive Assessment score <28), confirmed HD (positive for mutant huntingtin gene [>36 CAG repeats]), and no more than mild functional impairment (Unified Huntington’s Disease Rating Scale Total Functional Capacity score >6) within 6 months of Screening.HD Assessments

[0501] The most accurate method of testing for HD counts the number of CAG (cytosine, adenine, guanine) repeats in the HD gene using DNA from a blood sample. The presence of >36 repeats informed a diagnosis of HD.

[0502] Stages of HD progression may be defined using a component of the UnifiedHuntington Disease Rating Scale, the Total Functional Capacity (TFC) rating scale. The TFC is a brief assessment that scores an individual’s ability to perform basic living activities such as handling finances, eating, dressing, and bathing. Higher total scores on the TFC indicate better functional capacity, and 5 stages of disease progression are defined as: stage 1, TFC 11-13; stage 2, TFC 7-10; stage 3, TFC 3-6; stage 4, TFC 1-2; and stage 5, TFC 0.

[0503] As an early sign of HD may involve mild cognitive impairment, the Montreal Cognitive Assessment (MoCA) may be used to investigate HD progression. The MoCA ranges for cognitive impairment are: mild, 18-25; moderate, 10-17; and severe <10.

[0504] Select exclusion criteria for all participants included a clinically significant finding during physical examination, heart rate <50 or >100 beats per minute, systolic blood pressure(BP) <90 or >140 mmHg, or diastolic BP <60 or >90 mmHg at Screening / Admission (see Tables 1-3)Table 1. Inclusion / exclusion criteria for the Compound I SAD studyTable 2. Inclusion criteria for the Compound I MAD studyTable 3. Exclusion criteria for the Compound I MAD studySafety and tolerability assessments

[0505] Safety and tolerability of Compound I was assessed by frequency and severity of reported adverse events (AEs) and standard clinical assessments, including change from baseline (CFB) in vital signs, electrocardiograms (ECGs), EEGs, clinical laboratory parameters, and the Columbia-Suicide Severity Rating Scale. Predefined stopping criteria included serious or severe AEs considered related to study drug, seizures, QTc prolongation, or abnormalities in certain laboratory values, BP, or heart rate.Pharmacokinetic sampling, bioanalytical methods, and analyses

[0506] Trough pharmacokinetic analyses samples were collected only for MAD.

[0507] In SAD, pharmacokinetic parameters included maximum plasma concentration (Cmax), time to Cmax (Tmax), area under concentration time curve (AUC) from 0-24 h (AUCo- 24), AUC from 0 h to time of last measured concentration (AUCo-t), AUC from 0 h extrapolated to infinity (AUCo-co), and elimination T1 / 2. In MAD, parameters included Cmax, minimum observed concentration (Cmin), Tmax, AUC0-24, AUC from 0 h to end of dosing interval (AUCo-tau), AUC from 0 h to time of last quantifiable concentration (AUCo-iast), AUCo-00, accumulation ratios (RAs) of Cmax and AUCo-tau, and T1 / 2.Plasma samples for pharmacokinetic analysis

[0508] SAD study

[0509] Blood samples for pharmacokinetic analyses were collected on Days 1, 2 (>24 to 48 h), and 3 (48 to 72 h) prior to dosing (0 h) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 72 h after drug administration (±1 minute through 6-h postdose, ±3 minutes 7 through 72 h), with sampling times in h relative to dosing.

[0510] MAD study

[0511] Blood samples from both healthy participants and participants with HD were collected on Days 1, 2, and 14 predose and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, and 24-h postdose. Day 14 included sampling at 36, 48, and 72-h postdose, collected on Days 15, 16, and 17, respectively. The sample collection windows for all collections were: predose (<2 h); through Hour 1 (±5 minutes); and through Hour 24 (±15 minutes).

[0512] A blood sample (10 mL from healthy participants and 7 mL from participants with HD) for metabolite identification was collected 6- to 8-h postdose on Day 7, immediately followed by the 1-h postdose EEG.

[0513] Samples for trough pharmacokinetic data were collected once per day within 15 to 45 minutes predose on Days 3, 5, 7, 9, 11, 12, and 13 for healthy participants and on Days 3, 7, and 13 for participants with HD.Bioanalytical methods

[0514] For both studies, plasma samples for pharmacokinetic analysis were collected into tubes containing K2EDTA as the anticoagulant at predefined time points. The samples were kept frozen at approximately -60 to -80 °C until analyzed.

[0515] Bioanalysis to determine Compound I plasma concentrations was conducted using validated liquid chromatography with tandem mass spectrometry at Covance Laboratories Inc. (Salt Lake City, UT, USA) for healthy participants and at QPS (Newark, DE, USA) for participants with HD.

[0516] For healthy participants, plasma samples (200 pL) were spiked with stable isotopic- labeled internal standard (Compound I-ds;). For participants with HD, plasma samples (50 pL) were spiked with Compound I.

[0517] Each sample was extracted using protein precipitation and multiple reaction monitoring was used to quantify Compound I. The peak area ratio of Compound I to internal standard was used to determine the concentration. The concentrations of the quality control (QC) samples and pharmacokinetic samples were interpolated from the calibration standard curve, validated using linear regression with 1 / x2weighting. The method was validated with a dynamic range of 1 to 1000 ng / mL. Undiluted QC samples were considered acceptable if the overall (mean) accuracy and precision (% relative standard deviation) of the QC samples from all accepted analytical runs at each level were within ±15.0% of the nominal concentration and <15.0% respectively.Pharmacodynamic assessments

[0518] Cognitive assessments in MAD evaluated exploratory pharmacodynamic effects of Compound I on cognitive performance in healthy and HD participants. Cognitive performance was evaluated using Cogstate, a validated computerized neuropsychological assessment battery from which assessments that reflect cognitive domains most affected in early-stage HD were selected: the Stop Signal Reaction Test (response inhibition and impulse control), Detection Test (psychomotor function), Identification Test (simple attention), One- Back Learning Task (simple working memory), Two-Back Learning Task (working memory and executive function), and Groton Maze Learning Test (executive function).

[0519] Assessments were performed on Day -1 (baseline) and Days 2, 4, 6, 8, 10, 12, and 14, at the same time of day (±2 h). To minimize learning effects, 2 practice tests wereadministered in both groups (participants with HD and healthy participants) prior to performing the Day -1 baseline assessment. Learning effects are typically largest between the first and second time points and diminish after subsequent repetitions. Therefore, reliability of testing has been shown to improve with repeated testing sessions. Additionally, individuals with mild cognitive impairment are less prone to learning effects seen in studies using serial cognitive assessments. The ability to learn and retain a motor or cognitive skill is a form of implicit or subconscious memory which may be differentially affected in subcortical dementia syndromes such as HD.Statistical analyses

[0520] SAD cohorts 4a and 4b (3.0-mg cohorts) are combined in the present analysis and identified as Cohort 4.

[0521] The safety population was defined as all participants exposed to study drug. The pharmacokinetic population was a subset of the safety population that included participants with at least one Compound I plasma concentration bioanalytical result. Participants receiving placebo were pooled across study cohorts for analyses. Safety data were descriptively summarized. Plasma concentrations and pharmacokinetic parameters were shown by dose level and summarized descriptively, with concentrations presented using geometric mean and geometric coefficient of variation (%) and time described using median and range.

[0522] Pharmacokinetic parameters were determined via noncompartmental analysis methods, calculated and analyzed using Phoenix® WinNonlin® (SAD: version 6.3, MAD: version, 7.0; Certara®, Princeton, NJ, USA), Phoenix® Connect™ (SAD: version 1.3.1), and SAS® (MAD: version 9.3.4; SAS, Cary, NC, USA) software. Other analyses used SAS version 9.3 or later (SAD) and Phoenix WinNonlin version 6.3 (MAD).

[0523] Dose proportionality used an analysis of covariance model with log-transformed AUC or Cmax as dependent variables and log-transformed dose as independent variable. Food effect was evaluated using a t-test comparing log-transformed AUC and Cmax between Cohort 5 (fed) and Cohort 2 (fasted).

[0524] Least-squares (LS) mean CFB in all postbaseline cognitive performance assessment scores were analyzed using a mixed-effect model for repeated measures. Dose, visit, and interaction between dose and visit were fixed effects; baseline was a covariate; and participants (healthy vs HD) were a random effect.Results

[0525] Forty-eight healthy participants were enrolled in SAD (Compound I n=38; placebo n=10). One participant (Cohort 2, Compound I 0.75 mg) was lost to follow-up and discontinued the study. In MAD, twenty-four healthy participants were enrolled into Cohorts 1 and 2 (Compound I n=18; placebo n=6) and six into Cohort 3 (Compound I). One healthy participant receiving placebo withdrew from MAD early (see Table 4).Table 4. Baseline characteristics in the Compound I MAD studyTarticipants were fasted until approximately 4 h after dosing, when they were provided a meal.bParticipants were dosed approximately 30 minutes after consumption of a high-fat meal.cCollected for only n=3 HD participants, after a protocol amendment added these measures to the inclusion criteria. Participant 12: 41 CAG repeats; participant 13: 48 CAG repeats; participant 14: 49 CAG repeats.dAssessed for only n=4 HD participants, after a protocol amendment added these measures to the inclusion criteria.eAdministered at screening only if not available in medical history within the previous 6 months.Safety and tolerability

[0526] Eight treatment-emergent AEs (TEAEs) were reported in SAD participants receiving Compound I (Cohort 2 [0.75 mg], n=l; Cohort 4 [3.0 mg], n=3; Cohort 5 [0.75 mg], n=4), and three were reported with placebo. TEAEs of nausea, headache, and somnolence were reported as related to study drug. In MAD, three TEAEs were reported in healthy participants receiving Compound I (Cohort 1 [0.5 mg], n=l; Cohort 2 [1.0 mg], n=2), with orthostatic hypotension reported as related to study drug. No TEAEs were reported in HD participants (Cohort 3).

[0527] No clinically significant findings were observed in laboratory parameters, vital signs, ECGs, or EEGs in either study. In SAD, no clinical signs of convulsions occurred at any dose. Independent review of EEGs in Cohort 4 (i.e., the first eight participants receiving the highest dose of Compound I [3.0 mg]) did not identify epileptiform activity. No participants reported suicidal ideation or behavior at baseline or at any time point as measured by the Columbia-Suicide Severity Rating Scale.Pharmacokinetics

[0528] Data from all participants receiving Compound I with at least one bioanalysis result for the plasma concentration were included in the pharmacokinetic analyses. Mean plasma concentration-time profiles for SAD and MAD are presented in Figures 3A-C (Note: The LLOQ is 1 ng / mL in plasma. For the calculation of the descriptive statistics of concentrations at each time point, plasma concentrations less than the LLOQ are set to zero). Pharmacokinetic parameters are summarized in Table 5. Concentrations and AUC values are given as geometric mean (geometric coefficient of variation, %); time values are medians. Table 5. Pharmacokinetic parameters in the Compound I SAD and MAD studies.MAD pharmacokinetic parameters (healthy participants and participants with HD)Note: Concentration and AUC data are presented as geometric mean (geometric CV%). Time data are presented as median and range.'Participants were fasted until approximately 4 hours after dosing, when they were provided a meal.bParticipants were dosed approximately 30 minutes after consumption of a high-fat meal.cSummarized by median (range).dThe sample size for this parameter was n=7.Tour participants in this cohort were permitted a light breakfast after an overnight fast.Participants who had R2adjusted <0.80 were excluded from the summary statistics (n=5 and n=4 for the healthy participant 0.5 and 1.0 mg cohorts, respectively, and n=3 for the cohort of participantswith HD).8The sample size for this parameter was n=l.hThe sample size for this parameter was n=5.‘The sample size for this parameter was n=0.JThe sample size for this parameter was n=4.kThe sample size for this parameter was n=3.SAD

[0529] After a single Compound I dose (Cohorts 1-4), plasma concentrations increased to a maximum at a Tmax range of 4.2-7.0 h; concentrations decreased in a biphasic manner (T1 / 2 range 27.9-40.1 h). Compound I exposure increased dose proportionally, with Cmax ranging from 5.7 (11.9) to 45.5 (18.7) ng / mL and AUCo-24from 75.2 (10.5) to 664.8 (19.8) ng*h / mL. AUCo-t and AUCo- / increased with dose and ranged from 105.9 (15.0) to 1162.7 (19.2) ng*h / mL and 150.1 (12.6) to 1508.5 (18.1) ng*h / mL, respectively.

[0530] Tmax was similar in the fed (5.5 h, Cohort 5) and fasted (4.2 h, Cohort 2) states. Fasted Cmax and AUC0-24 (11.2 [17.4] ng / mL and 144.4 [9.3] ng*h / mL) were approximately 1.3-fold higher than fed (8.6 [24.9] ng / mL and 112.6 [19.3] ng*h / mL). Fasted AUCo-t and AUCo-00 (239.5 [11.3] ng / mL and 358.4 [25.7] ng*h / mL) were approximately 1.5- and 1.7- fold higher than fed (158.6 [36.3] ng / mL and 204.9 [39.4] ng*h / mL). Fasted vs fed T1 / 2 was 40.1 vs 24.6 h.

[0531] SAD Compound I dose proportionality (Cohorts 1-5) is presented in Figure 4 (Note: LCL to UCL = 95% CI for slope. AUCo-®, area under the concentration-time curve from the time of dosing extrapolated to infinity; AUC0-24, area under the plasma concentration-time curve from time 0 to 24-h postdose; AUCo-t, area under the plasma concentration-time curve from time 0 to the time of the last measured concentration; Cmax, maximum concentration; LCL, lower control limit; SAD, single-ascending dose; UCL, upper control limit); slope point estimates were near 1, and 95% confidence intervals contain 1 for C max and AUC.MAD (healthy participants)

[0532] In healthy participants (Cohorts 1 [Compound I 0.5 mg] and 2 [Compound 1 1.0 mg]), Day 1 C max was 6.1 (28.2) and 15.7 (25.1) ng / mL at Tmax of 6.0 and 5.0 h, respectively. After 14 days of repeated daily dosing, Cmax reached 15.0 (17.3) and 41.2 (18.9) ng / mL, respectively, at the same T max of 6.0 h.

[0533] AUCo-24 in Cohort 1 was 86.9 (26.1) ng*h / mL on Day 1, increasing to 267 (15.2) ng*h / mL after multiple doses on Day 14. AUCo-iast was 643 (13.7) ng*h / mL on Day 14. In Cohort 2, AUCo-24 was 211 (27.0) ng*h / mL on Day 1, increasing to 662 (19.0) ng*h / mL after multiple doses on Day 14. AUCo-iast was 1513 (19.3) ng*h / mL.

[0534] Consistent with observed increases in exposure after repeated dosing, 0.5-mg RAs for Cmax and AUCo-tau were 2.5 and 3.1, respectively, and 2.6 and 3.1 with the 1.0-mg dose. Overall, exposures (AUCo-iast and AUCo-24) were approximately 2.4-times higher with 1.0 mg than 0.5 mg. Comparing Compound I 1.0 mg with 0.5 mg for dose proportionality, geometric LS mean for systemic exposure pharmacokinetic parameters (AUCo-iast, AUCo-24, and Cmax) indicated that exposure increase was more than dose proportional (1.0 vs 0.5 mg; Day 1 : 121%, 121%, and 129% higher, respectively; Day 14: 118%, 124%, and 137% higher, respectively).

[0535] Mean trough plasma Compound I concentrations increased over time until an apparent steady state between 11 and 15 days following 0.5-mg dosing and between 11 and13 days following 1.0-mg dosing (Figure 5). With 1.0 mg, trough concentration increased after the last dose administration on Day 14.MAD (HD participants)

[0536] In HD participants (Cohort 3 [Compound I 1.0 mg]), Cmax was 12.2 (36.5) ng / mL on Day 1 and 23.9 (26.3) ng / mL on Day 14 at the same Tmax of 4.5 h. AUC0-24 was 135 (40.4) ng*h / mL on Day 1, increasing to 403 (30.6) ng*h / mL after multiple doses on Day 14. At the end of treatment (Day 14), AUCo-iast was 911 (29.7) ng*h / mL. RAs for Cmax and AUCo-tau were 2.0 and 3.0, respectively.

[0537] After single doses of Compound 1 1.0 mg, the HD (Cohort 3) to healthy participant (Cohort 2) ratio of geometric LS mean AUCo-iast value was 0.63 (90% CI: 0.47-0.85). After14 days of daily dosing, AUCo-iast and AUCo-tau in Cohort 3 remained approximately 60% of those for Cohort 2.

[0538] The mean trough plasma Compound I concentrations in HD participants increased over time until an apparent steady state after 13 days (Figure 5). Similar to healthy participants, levels were observed to increase after Day 14 dose administration. Mean trough concentrations were lower in HD participants vs healthy participants.Pharmacodynamic assessments

[0539] Statistical comparisons of exploratory cognitive baseline assessments between pooled healthy participants (Cohorts 1 and 2) and HD participants (Cohort 3) are presented in Table 6. Participants with HD performed similarly at baseline to healthy participants on tests of psychomotor performance (Detection Test) and attention (Identification Test) and on one test of executive function (Groton Maze Learning Test). Healthy participants performed significantly better at baseline on tests of simple attention (One-Back Learning Task), working memory and executive function (Two-Back Learning Task), and response inhibition and impulse control (Stop Signal Reaction Test), consistent with the expected neuropsychological profile of early-stage HD.Table 6. Comparison of cognitive assessment baseline scores between healthy participants (pooled) and participants with HD in the Compound I MAD study.aAnalysis via two-sample t tests with pooled healthy participants from healthy cohorts as the reference.bValues meeting statistical significance at p<0.05 appear in bold.cEffect size is calculated based on Cohen d. defined as the difference in the mean between compared groups divided by pooled standard deviation.dHigher scores in the Two-Back Learning Task represent better performance, so a negative value for Cohen’s d indicates that the participants with HD performed worse on the task than the pooled healthy participants. For all other measures, positive effect sizes confirm worse performance in the participants with HD than in the healthy participants.

[0540] CFB results for cognitive assessments over 14 days of Compound 1 1.0-mg dosing in healthy and HD participants are presented in Table 7. On the Groton Maze Learning Test, a trend toward improvement, although not statistically significant, occurred across all cohorts (Figure 6A). On the Two-Back Learning Task, compared with healthy participants, HD participants improved from baseline at all time points, which was statistically significant onDays 8, 10, 12, and 14 (Figure 6B). No clinically meaningful changes were observed on theDetection Test (Figure 6C).I l lTable 7. Summary of cognitive assessment tests between Compound 1 1.0 mg in healthy participants (Cohort 2) and participants with HD (Cohort 3) in the Compound I MAD study.aDecrease from baseline in test score indicates better performance.bIncrease from baseline in test score indicates better performance.

[0541] Cognitive impairment is a common, early manifestation of neurodegenerative disorders, including HD, PD, and AD, and is associated with difficulties in performing everyday activities, loss of independence, and decreased quality of life for affected individuals and their family. Effective and well-tolerated therapies to treat cognitive impairment in neurodegenerative disorders remain an area of significant unmet need.

[0542] NMD AR function plays a critical role in cognitive processes. Multiple lines of evidence suggest that NMD AR hypofunction (i.e., decreased expression and / or function) may contribute to cognitive impairment in HD, PD, and AD. NMD AR PAMs represent a potential therapeutic strategy to enhance NMD AR activity, restore brain network balance, and improve cognitive impairment in disorders associated with NMD AR hypofunction.Herein we report the findings from Phase 1 studies of Compound I, an investigational NMD AR PAM developed based on endogenous brain biology being evaluated for the potential treatment of cognitive impairment in neurodegenerative disorders.

[0543] Compound I was well tolerated at single doses of <3.0 mg and multiple doses of <1.0 mg once daily for 2 weeks. Safety and tolerability profiles were comparable between Compound I and placebo. TEAEs across studies were mild, with no discontinuations or serious AEs due to Compound I on single or multiple dosing. There were no clinically significant changes in laboratory parameters, vital signs, or ECGs, and no epileptiform activity was noted in EEGs.

[0544] In SAD, Compound I demonstrated linear pharmacokinetics and low intracohort variability in plasma concentrations. Mean Cmax and AUC exposure increased in a doseproportional manner from 0.35 to 3.0 mg. Compound I 0.75-mg fed-state exposure was approximately 1.5-fold lower than in the fasted state.

[0545] In MAD, Compound I exhibited oral bioavailability, plasma exposures in the range for expected target engagement, and a T1 / 2 suitable for once-daily, oral dosing based on the pharmacokinetic profile across the range of doses assessed. Compound 1 1.0 vs 0.5 mg resulted in a more-than-proportional elevation in plasma concentrations on Day 14, possibly representing high interindividual variability, while Tmax (6 h) and T1 / 2 (116 and 104 h, respectively) were similar with both doses. Overall RAs of approximately 3 suggested that Compound I accumulated after repeated dosing.

[0546] While the pharmacokinetic profile of Compound I in HD participants on multiple dosing was also consistent with once-daily oral dosing, pharmacokinetic exposures were approximately 40% lower in HD participants vs healthy participants. Possible explanations included fasted vs fed states, i.e., healthy participants were dosed in the fasted state whereasHD participants were dosed after a light breakfast; different bioanalytical laboratories used to process samples from the two studies; unknown disease-specific considerations; and demographic differences between the study populations. Of note, in subsequent studies using the same bioanalytical laboratory as the HD participants in MAD, plasma exposures in adults with HD appear consistent with those of healthy adults.

[0547] Exploratory assessments were conducted to evaluate the pharmacodynamic effects of Compound I on cognitive performance in a small cohort (n=6) of HD participants and in healthy participants. While we cannot rule out learning effects, improvement was seen in the HD cohort on the Two-Back Learning Task, an assessment of executive function, which is the cognitive domain predominantly affected in early-stage HD.

[0548] Compound I was generally well tolerated, exhibited a pharmacokinetic profile appropriate for once-daily oral dosing, and demonstrated preliminary signals toward improved cognitive performance in HD participants.

[0549] Compound I was generally well tolerated in healthy participants and participants with HD. The pharmacokinetic profile of Compound I supported long-term once-daily dosing. Preliminary pharmacodynamic assessments of Compound I on cognitive performance indicated signals toward improved cognition in participants with HD.

[0550] In disorders of NMD AR hypofunction, positive allosteric modulation of NMDARs may represent a potential therapeutic strategy to enhance NMD AR function and improve cognition.

[0551] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation various equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the claims.

Claims

ClaimsWhat we claim is:

1. A pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a subject, the pharmaceutical composition provides one or more of pharmacokinetic parameters in the subject selected from the group consisting of: a) a Cmax of between about 2 ng / mL and about 100 ng / mL; b) an AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL; c) an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; d) an AUC 00 of between about 50 ng*h / mL and about 2000 ng*h / mL; and e) a tmax of between about 2 hours and about 15 hours.

2. The pharmaceutical composition according to claim 1 wherein the pharmaceutical composition provides a Cmax of between about 2 ng / ml and about 100 ng / mL.

3. The pharmaceutical composition according to any one of claims 1-2, wherein the pharmaceutical composition provides a tmax of between about 2 hours and about 15 hours.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the pharmaceutical composition provides an AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the pharmaceutical composition provides an AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the pharmaceutical composition provides an AUCoo of between about 50 ng*h / mL and about 2000 ng*h / mL.

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition provides the pharmacokinetic parameter in the subject of: a) a Cmax of between about 2 ng / mL and about 100 ng / mL; b) an AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL;c) an AUCiast of between about 50 ng*h / mL and about 1000 ng h / mL; d) an AUC oo of between about 50 ng*h / mL and about 2000 ng*h / mL; and e) a tmax of between about 2 hours and about 15 hours.

8. A pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein following administration of the pharmaceutical composition to a population of subjects, the pharmaceutical composition provides one or more pharmacokinetic parameters in the population of subjects selected from the group consisting of: a) a mean Cmax of between about 2 ng / mL and about 100 ng / mL; b) a mean AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL; c) a mean AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; d) a mean AUCoo of between about 50 ng*h / mL and about 2000 ng*h / mL; and e) a mean tmax of between about 2 hours and about 15 hours.

9. The pharmaceutical composition according to claim 8 wherein the pharmaceutical composition provides a mean Cmax of between about 2 ng / ml and about 100 ng / mL.

10. The pharmaceutical composition according to any one of claims 8-9, wherein the pharmaceutical composition provides a mean tmax of between about 2 hours and about 15 hours.

11. The pharmaceutical composition according to any one of claims 8-10, wherein the pharmaceutical composition provides a mean AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL.

12. The pharmaceutical composition according to any one of claims 8-11, wherein the pharmaceutical composition provides a mean AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL.

13. The pharmaceutical composition according to any one of claims 8-12, wherein the pharmaceutical composition provides a mean AUCoo of between about 50 ng*h / mL and about 2000 ng*h / mL.

14. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition provides the pharmacokinetic parameter in the population of subjects of: a) a mean Cmax of between about 2 ng / mL and about 100 ng / mL; b) a mean AUC2411 of between about 50 ng*h / mL and about 1000 ng*h / mL; c) a mean AUCiast of between about 50 ng*h / mL and about 1000 ng*h / mL; d) a mean AUCoo of between about 50 ng*h / mL and about 2000 ng*h / mL; and e) a mean tmax of between about 2 hours and about 15 hours.

15. The pharmaceutical composition according to any one of claims 1-14, wherein the pharmaceutical composition comprises Compound I.

16. The pharmaceutical composition according to any one of claims 1-14, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound I.

17. The pharmaceutical composition of any one of claims 1-14, wherein the pharmaceutical composition comprises between about 0.3 to about 3.0 mg of Compound I, or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises between about 0.3 to about 3.0 mg of Compound I.

19. The pharmaceutical composition of any claim 17, wherein the pharmaceutical composition comprises between about 0.3 to about 3.0 mg of a pharmaceutically acceptable salt of Compound I.

20. The pharmaceutical composition of any one of claims 1-19, wherein the pharmaceutical composition comprises hydroxypropyl-P-cyclodextrin.

21. The pharmaceutical composition according to any one of claims 1-20, wherein said pharmacokinetic parameter is obtained following a single administration of the pharmaceutical composition.

22. The pharmaceutical composition according to any one of claims 1-20, wherein said pharmacokinetic parameter is obtained following multiple administrations of the pharmaceutical composition.

23. The pharmaceutical composition according to any one of claims 1-22, wherein each of said pharmacokinetic parameter is obtained following administration of the composition under fasted conditions.

24. The pharmaceutical composition according to any one of claims 1-22, wherein said pharmacokinetic parameter is obtained following administration of the composition under fed conditions.

25. The pharmaceutical composition according to any one of claims 1-24, wherein the pharmaceutical composition is an oral dosage form.

26. A method of treating a CNS-related condition in a subject, wherein the CNS-related condition, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1-25.

27. The method of claim 26, wherein said CNS-related condition is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive- compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank group of proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraine headaches), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington’s disease and Parkinson’s disease) and tinnitus.

28. A method of inducing sedation or anesthesia in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1-25.

29. Use of a pharmaceutical composition according to any one of claims 1-25 for the manufacture of a medicament for treating a CNS-related condition in a subject.

30. The use according to claim 29, wherein said CNS-related condition is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank group of proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraine headaches), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington’s disease and Parkinson’s disease) and tinnitus.

31. Use of a pharmaceutical composition according to any one of claims 1-25 for the manufacture of a medicament for inducing sedation or anesthesia in a subject.

32. A pharmaceutical composition according to claims 1-25 for use in treating a CNS related condition in a subject.

33. The pharmaceutical composition for use according to claim 32, wherein said CNS-related condition is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse- related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank groupof proteins (e.g., Shank3)), neurodevelopmental disorders (including Kett syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraine headaches), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington’s disease and Parkinson’s disease) and tinnitus.

34. A pharmaceutical composition according to any one of claims 1-25 for use in inducing sedation or anesthesia in a subject.

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