How to treat depression using certrexant

Abstract

The present invention provides a method for treating orexin-2-mediated disorders in human subjects requiring treatment for orexin-2-mediated disorders. The method comprises administering certrexant or a pharmaceutically acceptable salt or hydrate thereof to a subject at a therapeutically effective daily dose if the subject does not have hepatic impairment. The method also comprises administering certrexant or a pharmaceutically acceptable salt or hydrate thereof to a subject at a reduced dose less than the daily dose if the subject has moderate hepatic impairment.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 524,198, filed on 29 June 2023, the disclosure of which is incorporated herein by reference.

[0002] (Field of Invention) The present invention relates to a method for treating and / or preventing depression, comprising administering a therapeutically effective amount of an orexin-2 receptor antagonist, specifically certrexant, to a subject in need thereof. [Background technology]

[0003] Orexin (also known as hypocretin) is a neuropeptide expressed by neurons in the perifornix, dorsomedial hypothalamus, and lateral hypothalamus (de Lecea et al., 1998; Proc. Natl. Acad. Sci. USA 95, 322-327, Sakaurai et al, 1998, Cell 92, 573-585). Orexin-producing neurons project to many areas of the brain, including other hypothalamic nuclei, paraventricular thalamus, brainstem nuclei, ventral tegmental region, and nucleus accumbens cutaneous tissue. (Peyron et al., 1998, J. Neurosci. 18, 9996-10016) Orexin neuropeptides, classified as either orexin-A or orexin-B, bind to the seven-transmembrane G protein-coupled receptors orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R) (de Lecea et al., 1998; J. Proc. Natl. Acad. Sci. USA 95, 322-327, Sakaurai et al, 1998, Cell 92, 573-585). Orexin-A is non-selective towards OX1R and OX2R, while orexin-B shows a higher affinity for OX2R (Sakaurai et al, 1998, Cell 92, 573-585). Orexin receptor antagonists are classified as single orexin receptor antagonists (SORAs) or dual receptor antagonists (DORAs).

[0004] Hypothalamic orexinergic neurons that express discharges during active wakefulness substantially cease expression during non-rapid eye movement sleep and show transient discharges during rapid eye movement sleep (Lee, 2005, J. Neuroscience 25(8):6716-6720, Takahashi, 2008, Neuroscience, 153:860-870). This activity pattern supports the idea that orexin is an endogenous, potent wakefulness-promoting peptide. Studies using single-unit recordings also show that OX-containing neurons are preferentially activated during reward-seeking behavior (Hassani et al., 2016. J Neuroscience 36(5):1747-1757). [Overview of the project] [Means for solving the problem]

[0005] One aspect of this application provides a method for treating orexin-2-mediated disorders in human subjects requiring treatment for orexin-2-mediated disorders. In some examples, orexin-2-mediated disorders may include, but are not limited to, depression and insomnia. Depression may include, but are not limited to, major depressive disorder with an ISI score of 15 or greater, bipolar depression, or comorbid depression and insomnia. The method comprises administering to a subject, if the subject does not have hepatic impairment, certrexant or a pharmaceutically acceptable salt or hydrate thereof (e.g., as a free base or hydrochloride) at a therapeutically effective daily dose. The method also comprises administering to a subject, if the subject has moderate hepatic impairment (e.g., a Child-Puer score of 7-9), certrexant or a pharmaceutically acceptable salt or hydrate thereof at a reduced dose less than the daily dose. In some cases, the method may further include administering certrexant or a pharmaceutically acceptable salt or hydrate thereof to a subject with mild hepatic impairment (e.g., a Child-Puer score of 5-6) at a daily dose. In additional cases, the method may also further include not administering certrexant or a pharmaceutically acceptable salt or hydrate to a subject with severe hepatic impairment (e.g., a Child-Puer score of 10 or more).

[0006] For the treatment of depression (e.g., major depressive disorder with an ISI score of 15 or higher, bipolar depression, or comorbid depression and insomnia), if the subject does not have hepatic impairment, administration of certrexant or a pharmaceutically acceptable salt or hydrate at a daily dose provides a first unbound mean plasma concentration of certrexant within an effective therapeutic range. If the subject has moderate hepatic impairment, administration at a reduced dose provides a second unbound mean plasma concentration of certrexant within an effective therapeutic range. Additionally, if the subject has mild hepatic impairment, administration of certrexant or a pharmaceutically acceptable salt or hydrate at a daily dose may provide a third unbound mean plasma concentration of certrexant within an effective therapeutic range. In some cases, if the subject has moderate hepatic impairment, administration of certrexant or a pharmaceutically acceptable salt or hydrate at a reduced dose is more therapeutically effective than the daily dose in the subject.

[0007] In some cases, subjects may have an inadequate response to antidepressants other than certrexant or its pharmaceutically acceptable salts or hydrates. In particular, subjects may have an inadequate response to selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenaline reuptake inhibitors (SNRIs). In other cases, certrexant or its pharmaceutically acceptable salts or hydrates may be administered adjunctly with a second pharmaceutically active agent. The second pharmaceutically active agent may be a selective serotonin reuptake inhibitor (SSRI) or a serotonin and noradrenaline reuptake inhibitor (SNRI).

[0008] In another aspect of this application, a method is provided for treating orexin-2 mediated disorders in human subjects with moderate hepatic impairment (e.g., Child-Puth score of 7–9). The method comprises administering certrexant or a pharmaceutically acceptable salt or hydrate thereof (e.g., as a free base or hydrochloride) at a reduced dose less than the therapeutically effective daily dose adapted for the treatment of human subjects with normal hepatic function. In some examples, orexin-2 mediated disorders may include, but are not limited to, depression and insomnia. Depression may include, but are not limited to, major depressive disorder with an ISI score of 15 or greater, bipolar depression, or comorbid depression and insomnia symptoms.

[0009] In a further aspect of this application, a method is provided for treating orexin-2 mediated disorders in human subjects with mild hepatic impairment (e.g., Child-Puth score of 5-6). The method comprises administering certrexant or a pharmaceutically acceptable salt or hydrate thereof (e.g., as a free base or hydrochloride) in a therapeutically effective daily dose adapted for the treatment of human subjects with normal hepatic function. In some examples, orexin-2 mediated disorders may include, but are not limited to, depression and insomnia. Depression may include, but are not limited to, major depressive disorder with an ISI score of 15 or greater, bipolar depression, or comorbid depression and insomnia symptoms.

[0010] This application provides an alternative method for treating orexin-2-mediated disorders in human subjects requiring treatment for orexin-2-mediated disorders. If the subject has moderate hepatic impairment (e.g., Child-Pues score 7–9), the method involves administering certrexant or a pharmaceutically acceptable salt or hydrate thereof at a reduced dose less than the therapeutically effective daily dose adapted for the treatment of human subjects with normal hepatic function. If the subject has severe hepatic impairment (e.g., Child-Pues score 10 or greater than 10), the method involves administering certrexant or a pharmaceutically acceptable salt or hydrate to the subject. If the subject does not have moderate to severe hepatic impairment, the method involves administering certrexant or a pharmaceutically acceptable salt or hydrate to the subject at a daily dose. In some cases, orexin-2-mediated disorders may include, but are not limited to, depression and insomnia. Depression may include, but is not limited to, major depressive disorder with an ISI score of 15 or higher, bipolar depression, or comorbid depression and insomnia symptoms.

[0011] Certrexant may be administered via any pharmaceutically acceptable route, in particular, certrexant may be administered orally. In some cases, the daily dose is approximately 20 mg / day to approximately 60 mg / day. Reduced doses may be approximately 5 mg / day to approximately 20 mg / day. Reduced doses are probably at least 20% less, at least 25% less, or about 50% less than the daily dose. In other cases, the daily dose is approximately 0.25 mg / kg to approximately 0.9 mg / kg per day, and reduced doses are approximately 0.07 mg / day to approximately 0.3 mg / day. In further cases, the daily dose is selected so that administration of certrexant or a pharmaceutically acceptable salt or hydrate at the daily dose to the subject provides an unbound mean plasma concentration of approximately 0.75 ng / mL to approximately 1.5 ng / mL of certrexant, provided the subject does not have hepatic impairment.

[0012] With respect to any aspect or embodiment of the method described herein for a method of treatment, for example, a method of treating orexin-2 mediated disorder, which comprises administering a compound or composition described herein, this disclosure also provides a compound or composition for use in such a method.

[0013] These and other aspects of the present invention will become apparent to those skilled in the art by reading the following detailed description of the invention, including the figures and the appended claims. [Brief explanation of the drawing]

[0014] [Figure 1a] The linear mean plasma concentration-time profile and the semi-log mean plasma concentration-time profile of certrexant after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 1b] The linear mean plasma concentration-time profile and the semi-log mean plasma concentration-time profile of certrexant after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 2a] The linear mean plasma concentration-time profiles and semi-logarithmic mean plasma concentration-time profiles of unbound certrexant are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 2b] The linear mean plasma concentration-time profiles and semi-logarithmic mean plasma concentration-time profiles of unbound certrexant are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 3a]The scatter plots of certrexant AUClast, AUC∞, CL / F relative to total protein, and Cmax relative to α-1-AGP levels are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 3b] The scatter plots of certrexant AUClast, AUC∞, CL / F relative to total protein, and Cmax relative to α-1-AGP levels are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 3c] The scatter plots of certrexant AUClast, AUC∞, CL / F relative to total protein, and Cmax relative to α-1-AGP levels are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 3d] The scatter plots of certrexant AUClast, AUC∞, CL / F relative to total protein, and Cmax relative to α-1-AGP levels are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 3e] The scatter plots of certrexant AUClast, AUC∞, CL / F relative to total protein, and Cmax relative to α-1-AGP levels are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 4a]The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 4b] The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 4c] The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 4d] The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 4e]The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 4f] The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 4g] The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 4h] The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 4i]The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 4j] The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 4k] The scatter plots of unbound certrexant Cmax,unbound, AUClast,unbound, and AUC∞,unbound for albumin, prothrombin time, ALP, and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, are shown. [Figure 5a] The linear mean plasma concentration-time profiles and semi-logarithmic mean plasma concentration-time profiles of M12 are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 5b] The linear mean plasma concentration-time profiles and semi-logarithmic mean plasma concentration-time profiles of M12 are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 6a]The linear mean plasma concentration-time profiles and semi-logarithmic mean plasma concentration-time profiles of unbound M12 are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 6b] The linear mean plasma concentration-time profiles and semi-logarithmic mean plasma concentration-time profiles of unbound M12 are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 7a] The scatter plots of M12 AUClast, AUC∞, and Cmax for total protein and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1, are shown. [Figure 7b] The scatter plots of M12 AUClast, AUC∞, and Cmax for total protein and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1, are shown. [Figure 7c] The scatter plots of M12 AUClast, AUC∞, and Cmax for total protein and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1, are shown. [Figure 7d] The scatter plots of M12 AUClast, AUC∞, and Cmax for total protein and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1, are shown. [Figure 8a] The following scatter plots show the unbound M12 AUClast, unbound, AUC∞, unbound, and Cmax, unbound for ALP and α-1-AGP levels, as well as for prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 8b] The following scatter plots show the unbound M12 AUClast, unbound, AUC∞, unbound, and Cmax, unbound for ALP and α-1-AGP levels, as well as for prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 8c] The following scatter plots show the unbound M12 AUClast, unbound, AUC∞, unbound, and Cmax, unbound for ALP and α-1-AGP levels, as well as for prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 8d] The following scatter plots show the unbound M12 AUClast, unbound, AUC∞, unbound, and Cmax, unbound for ALP and α-1-AGP levels, as well as for prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 8e]The following scatter plots show the unbound M12 AUClast, unbound, AUC∞, unbound, and Cmax, unbound for ALP and α-1-AGP levels, as well as for prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 8f] The following scatter plots show the unbound M12 AUClast, unbound, AUC∞, unbound, and Cmax, unbound for ALP and α-1-AGP levels, as well as for prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, according to Example 1. [Figure 9a] The linear mean plasma concentration-time profiles and semi-logarithmic mean plasma concentration-time profiles of M16 are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 9b] The linear mean plasma concentration-time profiles and semi-logarithmic mean plasma concentration-time profiles of M16 are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 10a] The linear mean plasma concentration-time profiles and semi-logarithmic mean plasma concentration-time profiles of unbound M16 are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 10b] The linear mean plasma concentration-time profiles and semi-logarithmic mean plasma concentration-time profiles of unbound M16 are shown after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 11a] The scatter plots of M16 Cmax, AUClast, and AUC∞ against α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1 are shown. [Figure 11b] The scatter plots of M16 Cmax, AUClast, and AUC∞ against α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1 are shown. [Figure 11c] The scatter plots of M16 Cmax, AUClast, and AUC∞ against α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1 are shown. [Figure 12a] The following scatter plots show the unbound M16 AUClast, unbound and AUC∞, unbound relative to albumin, prothrombin time, and α-1-AGP levels, as well as the Cmax, unbound relative to prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 12b] The following scatter plots show the unbound M16 AUClast, unbound and AUC∞, unbound relative to albumin, prothrombin time, and α-1-AGP levels, as well as the Cmax, unbound relative to prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 12c]The following scatter plots show the unbound M16 AUClast, unbound and AUC∞, unbound relative to albumin, prothrombin time, and α-1-AGP levels, as well as the Cmax, unbound relative to prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 12d] The following scatter plots show the unbound M16 AUClast, unbound and AUC∞, unbound relative to albumin, prothrombin time, and α-1-AGP levels, as well as the Cmax, unbound relative to prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 12e] The following scatter plots show the unbound M16 AUClast, unbound and AUC∞, unbound relative to albumin, prothrombin time, and α-1-AGP levels, as well as the Cmax, unbound relative to prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 12f] The following scatter plots show the unbound M16 AUClast, unbound and AUC∞, unbound relative to albumin, prothrombin time, and α-1-AGP levels, as well as the Cmax, unbound relative to prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 12g]The following scatter plots show the unbound M16 AUClast, unbound and AUC∞, unbound relative to albumin, prothrombin time, and α-1-AGP levels, as well as the Cmax, unbound relative to prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Figure 12h] The following scatter plots show the unbound M16 AUClast, unbound and AUC∞, unbound relative to albumin, prothrombin time, and α-1-AGP levels, as well as the Cmax, unbound relative to prothrombin time and α-1-AGP levels, after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3, according to Example 1. [Modes for carrying out the invention]

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in which the invention pertains. Otherwise, certain terms used herein have the meanings set forth herein. All patents, published patent applications, and publications referenced herein are incorporated by reference as if they were fully described herein. Note that where used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural nouns unless otherwise clearly indicated in the context.

[0016] Unless otherwise stated, the term “at least” preceding a set of elements should be understood to refer to all elements of the set. Those skilled in the art will be able to recognize or confirm many equivalents to the specific embodiments of the invention described herein by simply using ordinary experimental procedures. Such equivalents are intended to be encompassed by the invention.

[0017] Throughout this specification and the following claims, unless specifically required by context, the word “comprise” and variations such as “comprises” and “comprising” will be understood to mean that they include the integers or steps or groups of integers or steps described, but not any other integers or steps or groups of integers or steps. As used herein, the term “comprising” may be replaced with the terms “contains” or “including,” or as used herein, the term “has.”

[0018] As used herein, “consisting of” excludes any element, step, or component not specified in the elements of the claim. As used herein, “essentially consisting of” does not exclude materials or steps that do not substantially affect the basic and novel features of the claim. Whenever used herein in the context of aspects or embodiments of this application, any of the above terms “comprising,” “containing,” “including,” and “having” may be replaced with the terms “consisting of” or “essentially consisting of” to change the scope of the disclosure.

[0019] As used herein, the connecting term "and / or" between multiple enumerated elements is understood to encompass both individual and combined choices. For example, when two elements are connected by "and / or," the first choice refers to the applicability of the first element without the second element. The second choice refers to the applicability of the second element without the first element. The third choice refers to the applicability of the first and second elements together. It is understood that any one of these choices is included in the meaning and therefore satisfies the requirements of the term "and / or" as used herein. The simultaneous applicability of two or more of the choices is also included in the meaning and therefore satisfies the requirements of the term "and / or."

[0020] Unless otherwise stated, all numerical values, such as concentrations or concentration ranges, described herein should be understood in all cases as being modified by the term “approximately.” Therefore, numerical values ​​typically include ±10% of the stated value. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Similarly, a concentration range of 1 mg / mL to 10 mg / mL includes 0.9 mg / mL to 11 mg / mL. More specifically, numerical values ​​may include ±1%, ±3%, or ±5% of the stated value. Where used herein, the use of numerical ranges explicitly includes all possible subranges, including integers and fractions of values ​​within that range, and all individual numerical values ​​within that range, unless otherwise clearly indicated in the context.

[0021] As used herein, the terms “subject” or “patient” refer to an animal, preferably a mammal. According to certain embodiments, the subject is a mammal, including non-primates (e.g., camels, donkeys, zebras, cattle, pigs, horses, goats, sheep, cats, dogs, rats, rabbits, guinea pigs, marmosets, or mice) or primates (e.g., monkeys, chimpanzees, or humans). In certain embodiments, the subject is a human.

[0022] The term “pharmaceutically acceptable salt” refers to any salt of any of the compounds herein that is known to be nontoxic and is commonly used in the pharmaceutical literature. In some embodiments, pharmaceutically acceptable salts of compounds retain the biological efficacy of the compounds described herein and are not biologically or otherwise undesirable. Suitable pharmaceutically acceptable salts of compounds include, for example, acid addition salts that can be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, such as an inorganic acid, such as a hydrohalogen acid, for example, hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or an organic acid, such as an organic acid, such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc.

[0023] Desirable pharmaceutically acceptable salts are obtained by any suitable method available in the art, for example, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc.), or organic acids (e.g., acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidylic acid (e.g., glucuronic acid or galacturonic acid)), α-hydroxy acids (e.g. These can be prepared by treating a free base with any compatible mixture of acids, such as mandelic acid, citric acid, or tartaric acid, amino acids (e.g., aspartic acid, glutaric acid, or glutamic acid), aromatic acids (e.g., benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid), sulfonic acids (e.g., lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), as well as any other acids and mixtures thereof that are considered equivalent or acceptable substitutes in light of the usual level of skill in this art.

[0024] As used herein, the terms “treat,” “treating,” and “treatment” are all intended to mean the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or conduction, such as an orexin-2 mediated disorder, disease, or condition, including, for example, depression (e.g., major depressive disorder, bipolar depression) or insomnia. The terms “treat,” “treating,” and “treatment” may also mean regressing a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, “treat,” “treating,” and “treatment” mean the alleviation, prevention of progression or onset, or reduction of the duration of one or more symptoms associated with depression (e.g., major depressive disorder, bipolar depression) or insomnia. One or more symptoms of depression include depressed mood (e.g., sad, empty, hopeless), irritability, loss of interest or pleasure in all or almost all activities, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, difficulty thinking or concentrating, and indecisiveness. In some cases, depressive symptoms may co-occur with insomnia symptoms, such as an Insomnia Severity Index (ISI) score of 15 or higher.

[0025] The Insomnia Inventory (ISI) is a seven-item questionnaire used to assess the nature, severity, and impact of insomnia. The ISI assesses the severity of problems with falling asleep, maintaining sleep, and early morning awakening; sleep dissatisfaction; interference of sleep problems with daytime functioning; awareness of sleep problems; and distress caused by sleep disturbances. Each item is assessed using a 5-point Likert scale (0-4). The scores for all seven items are summed to obtain a total score ranging from 0 to 28. A negative change in score indicates improvement. The ISI total score is the sum of all item scores. The total score was interpreted as insomnia being none (0-7), below threshold (8-14), moderate (15-21), or severe (22-28).

[0026] In certain embodiments, “to treat,” “to treat,” and “treatment” refer to the prevention of recurrence of a disease, disability, or condition. In certain embodiments, “to treat,” “to treat,” and “treatment” refer to the improvement of the survival rate of a subject having a disease, disability, or condition. In certain embodiments, “to treat,” “to treat,” and “treatment” refer to the disappearance of a disease, disability, or condition in a subject.

[0027] When describing preventive measures, a person skilled in the art will recognize that the subjects requiring such measures (i.e., subjects in need of prevention) include any subjects who have experienced or exhibited at least one symptom of the preventable disorder, disease, or condition. Furthermore, subjects in need may also include subjects (preferably mammals, more preferably humans) who do not exhibit any symptoms of the preventable disorder, disease, or condition, but who are judged by a physician, clinician, or other healthcare professional to be at risk of progression of the disorder, disease, or condition. For example, subjects may be considered to be at risk of having a new episode of depression (and therefore in need of secondary prevention or preventive treatment) as a result of their medical history, including but not limited to family history, predisposition, comorbid disorders or conditions, and genetic testing.

[0028] The term "therapeutic dose," as used herein, means the amount of an active compound or pharmaceutical agent that elicits a biological or pharmacokinetic response in a tissue system, animal or human, which is sought by researchers, veterinarians, physicians, or other clinicians, including the relief of one or more symptoms of the disease or disorder being treated, and / or a reduction in the severity of one or more symptoms of the disease or disorder being treated.

[0029] As used herein, the term "antagonist" refers to a compound that binds to a receptor, thereby blocking or attenuating the receptor's response to an agonist.

[0030] As used herein, the term “depression” encompasses any mood disorder as defined by the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) as a “depressive disorder.” The term “depression” includes major depressive disorder (MDD), persistent depressive disorder, seasonal affective disorder, psychotic depression, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholy, middle-age depression, late-age depression, depression due to identifiable stressors, or combinations thereof. The term “depression” may also include bipolar depression, which is depression associated with bipolar disorder, characteristic of bipolar disorder, or exhibiting symptoms of bipolar disorder. In certain embodiments, depression is MDD. In other embodiments, MDD is accompanied by distress due to melancholic features or anxiety.

[0031] This application relates to a method for treating and / or preventing orexin-2-mediated disorders, diseases, or conditions in human subjects requiring treatment by administering a therapeutically effective dose of a selective orexin-2 antagonist. In particular, the orexin-2 antagonist is a compound of formula I

[0032] [ka]

[0033] The compound administered is [5-(4,6-dimethylpyrimidine-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-yl]-(2-fluoro-6-[1,2,3]triazole-2-ylphenyl)-methanone (also known as certrexant) or a pharmaceutically acceptable salt or hydrate thereof, having the structure of formula I. In one embodiment, the compound administered is [5-(4,6-dimethylpyrimidine-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-yl]-(2-fluoro-6-[1,2,3]triazole-2-ylphenyl)-methanone, having the structure of formula I, as a free base. In another embodiment, the administered compound is [5-(4,6-dimethylpyrimidine-2-yl)-hexahydropyrrolo[3,4-c]pyrrole-2-yl]-(2-fluoro-6-[1,2,3]triazole-2-ylphenyl)-methanone hydrochloride. Selective orexin-2 antagonists suitable for the methods described herein are described in PCT Patent Publication 2011 / 050198, U.S. Patent RE 48,841, U.S. Patent 9,079,911, U.S. Patent 11,059,828, and U.S. Patent 11,667,644, all of which are incorporated herein by reference. An improved synthetic method for producing condensed heterocyclic compounds such as certrexant as orexin receptor modulators is described in PCT Patent Publication 2020 / 100011, which is also incorporated herein by reference.

[0034] Orexin-2-mediated disorders treated and / or prevented by the compounds described herein include, but are not limited to, any one of the following: depressive disorders, bipolar disorders and related disorders as defined in DSM-5, and sleep-wake disorders. In particular, orexin-2-mediated disorders may be selected from the group consisting of depression (e.g., MDD, bipolar depression) and insomnia. In one embodiment, the compounds described herein are administered to human subjects for the treatment and / or prevention of MDD. In another embodiment, the compounds described herein are administered to human subjects to reduce one or more symptoms of depression. In a further embodiment, the compounds described herein are administered to human subjects for the treatment and / or prevention of depressive episodes associated with bipolar depression, i.e., bipolar disorders and related disorders as defined in DSM-5 (e.g., bipolar type I disorder, bipolar type II disorder, or cyclothymic disorder). In another embodiment, the compounds described herein are administered to human subjects for the treatment and / or prevention of insomnia. In further embodiments, the compounds described herein are administered to human subjects with concomitant depressive and insomnia symptoms having an ISI score of 15 or higher, to treat and / or prevent depression. Additionally, the compounds of formula (I) may be in the form of solvates, polymorphs, and mixtures thereof. Compounds of formula (I) or pharmaceutically acceptable salts of compounds of formula (I) may be obtained as solvates. Solvates include those formed in solution or as solids or crystals from the interaction or complexation of the compound with one or more solvents. In some embodiments, the solvent is water, in which case the solvate is a hydrate. In addition, the crystalline form of compounds of formula (I) or pharmaceutically acceptable salts of compounds of formula (I) may be obtained as cocrystals. In certain embodiments, the compound of formula (I) is obtained in crystalline form. In other embodiments, the crystalline form of the compound of formula (I) is essentially cubic. In other embodiments, pharmaceutically acceptable salts of compounds of formula (I) are obtained in crystalline form. In other embodiments, the compound of formula (I) may be obtained as one of several polymorphic forms, as a mixture of crystalline forms, as a polymorph, or as an amorphous form.In other embodiments, the compound of formula (I) transforms between one or more crystalline and / or polymorphic forms in solution.

[0035] Patients with moderate to severe hepatic impairment may have a reduced ability to metabolize and / or remove drugs compared to patients with normal hepatic function. In many cases, the pharmacokinetic profile or parameters of a drug (e.g., maximum plasma concentration (C)) may be reduced. max ), mean plasma concentration (C avg If there are significant changes in the pharmacokinetic profile or parameters, and / or the area under the plasma concentration-time curve (AUC), patients with moderate to severe hepatic impairment may be prevented from using the drug. Changes in the pharmacokinetic profile or parameters may result in increased toxicity and / or changes in efficacy of the drug. Therefore, patients with moderate to severe hepatic impairment are often excluded from the eligible treatment population. Such exclusions prevent the drug from being available as a treatment option for patients with moderate to severe hepatic impairment. The method of this application provides a method by which patients with moderate hepatic impairment, who may have a reduced ability to metabolize and / or remove certrexant, are administered a therapeutically effective dose of certrexant or a pharmaceutically acceptable salt or hydrate thereof. In some examples, the method of this application provides a method by which patients with moderate hepatic impairment are administered certrexant or a pharmaceutically acceptable salt or hydrate thereof, while maintaining the pharmacokinetic profile or parameters of certrexant in such patients with moderate hepatic impairment within an effective therapeutic range. Patients with severe hepatic impairment may still be contraindicated from receiving certrexant or its pharmaceutically acceptable salts or hydrates.

[0036] Celltrexant is mainly produced by formula II

[0037] [ka] It is metabolized into a compound having the structure (hereinafter referred to as the "M12" metabolite).

[0038] It is also Equation III

[0039] [ka] It is metabolized into a compound having the structure (hereinafter referred to as the "M16" metabolite).

[0040] M12 is an active metabolite, but its contribution to the efficacy of certrexant or its pharmaceutically acceptable salts or hydrates is estimated to be approximately 18% to 26% of the activity. However, in some cases, it may be desirable to maintain the plasma concentration of the M12 metabolite within a desired range. The M16 metabolite is also an active metabolite, but it contributes only a small amount of activity (<4%). However, in some cases, it may be desirable to maintain the plasma concentration of the M16 metabolite within a desired range.

[0041] Patients with moderate hepatic impairment may have a reduced ability to metabolize certrexant to M12 and M16, and / or remove certrexant, compared with patients with normal hepatic function. Therefore, in patients with moderate hepatic impairment, compared with patients with normal hepatic function who are administered certrexant in the same manner, certrexant may exhibit altered pharmacokinetic profiles or altered pharmacokinetic parameters (e.g., maximal plasma concentration (C)) for certrexant, its M12 metabolite, and / or its M16 metabolite. max ), mean plasma concentration (C avg It may have ), and / or area under the plasma concentration-time curve (AUC)).

[0042] In particular, when subjects with moderate hepatic impairment are administered the usual daily dose of certrexant or its pharmaceutically acceptable salt or hydrate, the levels of total exposure and / or unbound exposure (e.g., plasma concentration) to certrexant and / or its active metabolites are higher compared to the same usual daily dose administered to subjects without hepatic impairment. The usual daily dose is the daily dose adapted for subjects without hepatic impairment (e.g., with normal liver function). Therefore, subjects with moderate hepatic impairment have a pharmacokinetic profile or parameters (e.g., maximum plasma concentration (C)) that are equivalent, similar, or substantially the same as those of subjects without hepatic impairment at the usual daily dose. max ), mean plasma concentration (C avg To achieve the following, and / or the area under the plasma concentration-time curve (AUC), a lower dose than the usual daily dose is required.

[0043] In some cases, subjects with mild hepatic impairment are administered the same normal daily dose of certrexant or its pharmaceutically acceptable salt or hydrate as subjects without hepatic impairment (e.g., with normal liver function). Subjects with mild hepatic impairment may have a reduced ability to metabolize and / or remove the drug compared to subjects with normal liver function, but such reductions do not affect the pharmacokinetic profile or parameters (e.g., maximum plasma concentration (C)) of certrexant or its active metabolites. max ), mean plasma concentration C avg It is considered that this does not cause significant changes in ), and / or area under the plasma concentration-time curve (AUC). Therefore, it is considered that certrexant or its pharmaceutically acceptable salts or hydrates can be safely administered to subjects with mild hepatic impairment at the usual daily dose suitable for subjects without hepatic impairment.

[0044] Certrexant is thought to have a dose-dependent pharmacodynamic profile in treating and / or preventing orexin-2 mediated disorders in human subjects (e.g., treatment of insomnia). However, in the treatment of depression, the clinical efficacy of certrexant initially increases with increasing dosage, then plateaus, and subsequently decreases with further increases in dosage. In particular, certrexant is thought to have a dose-dependent pharmacodynamic profile in treating and / or preventing depression (e.g., MDD, bipolar depression) in human subjects, where clinical efficacy initially increases with increasing dosage, then plateaus, and subsequently decreases with further increases in dosage. In a clinical trial (clinical trial identification number: NCT03227224), certrexant administered at 20 mg / day showed a trend towards higher efficacy than 10 mg / day (no benefit shown) and higher efficacy than 40 mg / day (showed slight evidence of benefit) in terms of the mean change in MADRS score. See Savitz et al., "Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study," International Journal of Neuropsychopharmacology, 24(12):965-976 (2021). Considering this clinical data, certorexant appears to be pharmacodynamically effective for treating and / or preventing orexin-2 mediated disorders, particularly depression (e.g., MDD, bipolar depression), provided that plasma exposure to certorexant is maintained within an effective therapeutic range.The therapeutic range (including endpoints) is from the minimum therapeutic threshold (e.g., minimum plasma concentration) below which certrexant has no pharmacodynamic effect, to the maximum therapeutic threshold (e.g., maximum plasma concentration) above which certrexant is not therapeutically effective in treating and / or preventing disorders, diseases, or conditions, such as orexin-2 mediated disorders, including depression (e.g., MDD, bipolar depression). More specifically, the therapeutic range (including endpoints) is from the minimum therapeutic threshold below which certrexant is not therapeutically effective in treating and / or preventing depression, to the maximum therapeutic threshold above which certrexant is not therapeutically effective in treating and / or preventing depression.

[0045] In some cases, when subjects with moderate hepatic impairment are administered a normal daily dose of certrexant or its pharmaceutically acceptable salt or hydrate, they may have levels of total and / or unbound exposure (e.g., plasma concentration) of certrexant and / or its active metabolites that exceed the therapeutic range. However, when subjects with moderate hepatic impairment are administered a lower dose compared to a normal daily dose of certrexant or its pharmaceutically acceptable salt or hydrate, they may have levels of total and / or unbound exposure (e.g., plasma concentration) of certrexant and / or its active metabolites that are within the therapeutic range.

[0046] In one example, certrexant or its pharmaceutically acceptable salts or hydrates are administered to subjects with mild hepatic impairment at the usual daily dose if the impairment does not result in significant changes to the pharmacokinetic profile or parameters of certrexant and / or its active metabolites. Therefore, in some cases, subjects with mild hepatic impairment may receive the usual daily dose and have levels of total and / or unbound exposure (e.g., plasma concentration) of certrexant and / or its active metabolites that are within the therapeutic range.

[0047] In another example, if mild hepatic impairment results in a significant change in the pharmacokinetic profile or parameters of certrexant and / or its active metabolites, certrexant or its pharmaceutically acceptable salts or hydrates may be administered to subjects with mild hepatic impairment at a lower dose than the usual daily dose (e.g., the same lower dose administered to subjects with moderate hepatic impairment, or a different dose that is lower than the usual dose but higher than the dose administered to subjects with moderate hepatic impairment). Thus, in other examples, subjects with mild hepatic impairment may be administered at a lower dose than the usual daily dose (e.g., the same lower dose administered to subjects with moderate hepatic impairment, or a different dose that is lower than the usual dose but higher than the dose administered to subjects with moderate hepatic impairment), and may have levels of total and / or unbound exposure (e.g., plasma concentration) of certrexant and / or its active metabolites that are within the therapeutic range.

[0048] In a Phase 2 clinical trial, as further described in Example 1, involving subjects with mild hepatic impairment, the total area under the plasma concentration-time curve (AUC) for certrexant in subjects with mild hepatic impairment was 1.40 times higher than the total AUC in subjects with normal liver function. In addition, the unbound AUC of certrexant in subjects with mild hepatic impairment was 1.68 times higher than the unbound AUC in subjects with normal liver function.

[0049] The method of this application first includes determining whether a human subject has liver impairment and then determining how much certrexant or a pharmaceutically acceptable salt or hydrate thereof should be administered to the subject. The determination may be made by any preferred means for evaluating whether the subject has liver impairment. For example, the determination may be made based on a physical examination by a healthcare provider, data from clinical tests performed on the subject, and / or information in the subject's medical records. In another example, the determination may be made by analyzing data from clinical tests performed on the subject, and / or information in the subject's medical records to determine whether the subject has liver impairment and / or a degree of liver impairment.

[0050] The severity of liver impairment in the subjects can be quantified using any suitable clinical scale for quantitatively evaluating the prognosis of liver disease or cirrhosis, such as the Child-Pugh score, MELD score, or MELD-Na score. In specific cases, liver impairment is quantified using the Child-Pugh score based on the parameters shown in Table 2 below.

[0051] [Table 1]

[0052] The sum of the scores from the five categories identified above is used to classify the subject into one of the following categories: ● Less than 5 points: No evidence of liver damage, normal liver function ● 5-6 points: Mild liver damage (Child's Pew A) ●7-9 points: Moderate liver impairment (Child-Pugh B), ● 10-15 points: Severe liver damage (Child-Pew C).

[0053] It should be noted that the Child-Pugh classification is applicable only to participants with liver impairment to characterize the degree of any proven chronic condition, impairment, or cirrhosis (to avoid misunderstanding, healthy controls have a score of 5, as do those with mild liver impairment).

[0054] In one particular embodiment, the prognosis of the subject's liver disorder is quantified using the Child-Pugh score. If the subject has a Child-Pugh score of 7 - 9 points, the subject is administered a lower dosage of sertraline or a pharmaceutically acceptable salt or hydrate thereof that is less than the normal daily dosage adapted for subjects having normal liver function. In particular, the normal daily dosage of sertraline or a pharmaceutically acceptable salt or hydrate thereof is adapted for the treatment of subjects having normal liver function (e.g., having a Child-Pugh score of less than 5). The lower dosage administered to subjects with moderate liver impairment is at least 20% less, at least 25% less, at least 30% less, at least 35% less, at least 40% less, about 50% less, at least 50% less, at least 60% less, at least 75% less, at least 80% less, or at least 90% less than the normal daily dosage adapted for the treatment of subjects having normal liver function. If the subject has mild liver impairment (e.g., a Child-Pugh score of 5 - 6 points), the subject may be administered the normal daily dosage adapted for subjects having normal liver function.

[0055] The normal daily dosage in a subject not having a diminished ability to metabolize or remove sertraline (e.g., not having liver impairment) can provide the maximum plasma concentration or average plasma concentration within the therapeutic range necessary for a pharmacodynamic effect. In some embodiments, the normal daily dosage is selected such that the maximum plasma concentration (C max,normal ) or average plasma concentration (C avg,normal ) of sertraline is within each therapeutic range necessary for a pharmacodynamic effect in a subject not having a diminished ability to metabolize or remove sertraline (e.g., not having liver impairment). The normal daily dosage, when administered to a subject with liver impairment, can provide a maximum plasma concentration (C max,normal ) or average plasma concentration (C avg,normal ) that is less pharmacodynamically effective than C max,impaired or C avg,impaired . For example, C max,impaired or C avg,impaired can exceed each therapeutic range.

[0056] Certrexant or a pharmaceutically acceptable salt or hydrate thereof is preferably administered to the subject before sleep. For example, the compound is administered within about 2 hours, about 1 hour, or about 30 minutes before sleep. In other embodiments, the compound is administered at least about 4 hours before the subject wakes up or intends to wake up, including about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, or about 12 hours before the subject wakes up or intends to wake up. In certain embodiments, the compound is administered at least 6 to about 12 hours before the subject wakes up or intends to wake up. In preferred embodiments, the compound is administered at night.

[0057] After administration of the compound, the compound undergoes at least one half-life before the subject wakes from sleep. In other embodiments, the compound undergoes at least two half-lives, preferably at least three half-lives, before the subject wakes from sleep. For example, a pharmaceutical composition containing certrexant or a pharmaceutically acceptable salt or hydrate thereof has a removal half-life of about 4 hours, typically less than about 4 hours. The removal half-life may be about 2 to about 3 hours, for example, about 2 hours, about 2.1 hours, about 2.2 hours, about 2.3 hours, about 2.4 hours, about 2.5 hours, about 2.6 hours, about 2.7 hours, about 2.8 hours, or about 2.9 hours to about 3 hours. In light of the short half-life, the amount of the compound remaining in the subject upon waking is typically below the threshold required for pharmacodynamic effect.

[0058] Pharmacokinetic profiles or parameters described herein (e.g., maximum plasma concentration (C)) max , mean plasma concentration (C avg The values ​​(AUC), (A), and / or (AUC) are determined based on the subject's intake, more specifically, based on oral administration at bedtime, approximately 3 hours after the start of a standard dinner.

[0059] In some cases, the usual daily dose of certrexant or its pharmaceutically acceptable salt or hydrate, when administered to subjects with normal hepatic function and / or normal ability to metabolize or remove certrexant, can reach the maximum plasma concentration (C) of certrexant. max The time to reach ) is selected to be, in particular, less than about 3 hours, less than about 2 hours, preferably less than about 1 hour, i.e., less than about 45 minutes, less than about 30 minutes, less than about 15 minutes. Similarly, lower doses of certrexant or its pharmaceutically acceptable salts or hydrates are used when lower doses are administered to subjects with hepatic impairment. max The time to reach this point is selected to be, in particular, less than about 3 hours, less than about 2 hours, preferably less than about 1 hour, i.e., less than about 45 minutes, less than about 30 minutes, or less than 15 minutes.

[0060] In other cases, a standard daily dose of certrexant or its pharmaceutically acceptable salt or hydrate is selected so that the total and / or unbound exposure (e.g., plasma concentration) of certrexant in subjects with normal liver function and / or normal ability to metabolize or remove certrexant falls below the therapeutic range approximately 6 to 8 hours after oral administration. Similarly, a lower dose of certrexant or its pharmaceutically acceptable salt or hydrate is selected so that the total and / or unbound exposure (e.g., plasma concentration) of certrexant in subjects with liver impairment falls below the therapeutic range approximately 6 to 8 hours after oral administration. Therefore, in these cases, approximately 8 hours after administration of certrexant or its pharmaceutically acceptable salt or hydrate, the plasma concentration of certrexant decreases below the therapeutic range and remains at those levels for the remainder of the 24-hour treatment period until the next daily dose is administered.

[0061] The usual daily dose of certrexant for the treatment of subjects with normal liver function and / or normal ability to metabolize or eliminate certrexant is approximately 10 mg / day to approximately 60 mg / day. In some embodiments, the usual daily dose is within the range defined by approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, or any two of these values. In certain examples, the usual daily dose of certrexant for the treatment of subjects without liver impairment and / or reduced ability to metabolize or eliminate certrexant is a daily certrexant dose of 20 mg / day or more, with a maximum of 60 mg / day. The reduced dose may be approximately 5–20 mg / day, approximately 5–15 mg / day, approximately 5–10 mg / day, approximately 15 mg / day, approximately 10 mg / day, or approximately 5 mg / day of certrexant, depending on the indication being treated (e.g., depression or insomnia).

[0062] In other examples, the daily dose is approximately 0.25 mg / kg to 0.9 mg / kg per day, approximately 0.25 mg / kg to 0.8 mg / kg per day, approximately 0.25 mg / kg to 0.7 mg / kg per day, or approximately 0.25 mg / kg to 0.6 mg / kg per day. Reduced doses are approximately 0.07 mg / day to 0.3 mg / day, approximately 0.07 mg / day to 0.25 mg / day, or approximately 0.07 mg / day to 0.2 mg / day.

[0063] All dosages referred to herein, unless otherwise specified, refer to the free form of certrexant (i.e., free base or free base equivalent, unsalted form or unhydrated form). The dosage is given as the free form equivalent, i.e., the quantity as if the free form were administered. If a salt or solvate is administered, the dosage must be calculated as a function of the molecular weight ratio between the salt or solvate and the free form. The dosages described herein are calculated for an average body weight of approximately 70 kg unless otherwise specified, and should be adjusted for pediatric use or for use in adult patients with substantially uneven body weight. In some cases, the dosages described herein may be adjusted for an average body weight of approximately 60 kg.

[0064] In some cases, certrexant or its pharmaceutically acceptable salts or hydrates are administered orally to the subject. If the subject has moderate hepatic impairment, the subject with moderate hepatic impairment is administered certrexant or its pharmaceutically acceptable salts or hydrates orally at a lower dose than the usual daily dose. If the subject has severe hepatic impairment, the subject is not administered certrexant or its pharmaceutically acceptable salts or hydrates (i.e., the subject is excluded from certrexant treatment). In some cases, oral administration of certrexant or its pharmaceutically acceptable salts or hydrates at a lower dose to a subject with moderate hepatic impairment may be more therapeutically effective than the usual daily dose for a subject with moderate hepatic impairment. For example, oral administration of lower doses of certrexant or its pharmaceutically acceptable salts or hydrates to subjects with moderate hepatic impairment may be more therapeutically effective in treating depression than the usual daily dose for subjects with moderate hepatic impairment.

[0065] Lower doses in subjects with moderate hepatic impairment may provide the maximum or mean plasma concentration within the respective therapeutic range required for pharmacodynamic effect. Lower doses, when administered to subjects with moderate hepatic impairment, may provide the maximum plasma concentration (C) provided by the lower dose in subjects with moderate hepatic impairment.max,lower ) or mean plasma concentration (C avg,lower ) but C max or C avg, It is within the treatment range, and therefore C max,impaired or C avg,impaired It may be selected to be more pharmacodynamically effective. More specifically, C max,lower or C avg,lower These may be within their respective therapeutic ranges. Therefore, lower doses of certrexant or its pharmaceutically acceptable salts or hydrates may be more effective in treating and / or preventing depression in subjects with moderate hepatic impairment than the usual daily dose of certrexant adapted for subjects without hepatic impairment and / or with reduced ability to metabolize or remove certrexant. If a subject has mild hepatic impairment (e.g., a Child-Puth score of 5-6), subjects with mild hepatic impairment are administered certrexant or its pharmaceutically acceptable salts or hydrates at the usual daily dose.

[0066] In certain cases, a normal daily dose of certrexant or its pharmaceutically acceptable salt or hydrate may result in an unbound mean plasma concentration (C) of certrexant. avg The glycemic index (G / mL) was selected to be approximately 0.5 ng / mL to approximately 2 ng / mL, and in Phase 2 clinical trials, it was observed that the usual daily dose was approximately 0.75 ng / mL to approximately 1.5 ng / mL when administered to subjects who did not have a reduced ability to metabolize or remove certrexant (e.g., those without liver impairment).

[0067] The compounds described herein may be administered to human subjects for the treatment and / or prevention of orexin-2 mediated disorders, such as depression (e.g., MDD or bipolar depression) or insomnia, wherein the subjects have an inadequate response to antidepressants other than certrexant or its pharmaceutically acceptable salts or hydrates (e.g., selective serotonin reuptake inhibitors (SSRIs) and / or serotonin-norepinephrine reuptake inhibitors (SNRIs)). The compounds described herein may be administered to human subjects for the treatment and / or prevention of orexin-2 mediated disorders, such as depression (e.g., MDD or bipolar depression) or insomnia, wherein the subjects have an inadequate response to SSRIs or SNRIs. More specifically, the compounds described herein may be administered to human subjects together with a second pharmaceutically active agent for the treatment and / or prevention of orexin-2 mediated disorders, such as depression (e.g., MDD or bipolar depression) or insomnia, wherein the subject has an inadequate response to SSRIs and / or SNRIs. In some examples, the second pharmaceutically active agent is an SSRI or SNRI.

[0068] A patient has an inadequate response to treatment if treatment partially reduces the severity of symptoms, but the patient continues to have symptoms. More specifically, an inadequate response can be defined as a reduction of less than 50% in symptom severity, but with some improvement (i.e., improvement greater than 0%). For example, a patient has an inadequate response to depression if treatment partially reduces the severity of depressive symptoms, but the patient continues to have depressive symptoms. More specifically, an inadequate response can be defined as a reduction of less than 50%, but with some improvement (i.e., improvement greater than 0%) in the severity of depressive symptoms with residual symptoms other than insomnia, and overall good tolerability. The level of response to treatment can be assessed using the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), a self-assessment scale used to determine treatment resistance in MDD.

[0069] In certain cases, this application provides a method for treating and / or preventing depression (e.g., MDD or bipolar depression) in subjects who require treatment and / or prevention of depression, by administering a therapeutically effective dose of certrexant or a pharmaceutically acceptable salt or hydrate thereof to a subject if the subject has no or mild hepatic impairment, and by administering a reduced dose of certrexant or a pharmaceutically acceptable salt or hydrate thereof to a subject if the subject has moderate hepatic impairment. The subjects are humans with MDD or bipolar depression who need to prevent and / or reduce depressive symptoms. In one example, the subjects are humans with MDD. Specifically, the subjects are humans with MDD who have had an inadequate response to conventional antidepressants. In another example, the subjects are humans with bipolar depression. In one example, the subjects are humans with depression, more specifically MDD or bipolar depression, who have had an inadequate response to SSRIs and / or SNRIs, and who need to prevent and / or reduce depressive symptoms.

[0070] Conventional antidepressants include, for example, N-methyl-D-aspartate receptor antagonists (NMDAs), norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), corticotropin-releasing factor (CRF) antagonists, alpha-adrenergic receptor antagonists, and atypical antidepressants. In some embodiments, the N-methyl-D-aspartate (NMDA) receptor antagonist is ketamine, esketamine, alketamine, or a combination thereof, including its racemic mixture. In further embodiments, norepinephrine reuptake inhibitors include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, reboxetine, or pharmaceutically acceptable salts thereof. In other embodiments, selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, fluvoxamine, paroxetine, sertraline, or pharmaceutically acceptable salts thereof. In further embodiments, examples of monoamine oxidase inhibitors (MAOIs) include isocarboxazede, phenelzine, tranylcypromine, selegiline, and pharmaceutically acceptable salts thereof.In further embodiments, examples of reversible inhibitors of monoamine oxidase (RIMAs) include moclobemide or pharmaceutically acceptable salts thereof. In even further embodiments, examples of serotonin and norepinephrine reuptake inhibitors (SNRIs) include citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomirunacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, bilazodone, vortioxetine, or pharmaceutically acceptable salts thereof. In other embodiments, examples of atypical antidepressants include bupropion, lithium, nefazodone, trazodone, biloxazine, sibutramine, or pharmaceutically acceptable salts thereof.

[0071] In further embodiments, conventional antidepressants include azinazolam, alaproclate, amineptin, amitriptyline / chlordiazepoxide combination, atipamezole, azamianserin, vazinapurine, beflalin, bifemelan, vinodalin, bipenamol, brophalomin, bupropion, caloxazone, cericlamin, cyanopramine, simoxatone, citalopram, kremeprole, cloboxamine, dazepinyl, deanol, demexiptyline, dibenzepine, dotiepine, droxidopa, enefexin, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracene, idazoxane, indalpine, inderoxazine, iprendol, levoprotiline, ritoxetine, lofepramine, medifosamine, metapramine, Examples include metralindol, mianserin, milnacipran, minaprin, mirtazapine, monirelin, nebracetam, nehopam, nyalamide, nomifensin, norfluoxetine, orotirelin, oxafrozan, pinazepam, pirlindone, pizotirine, ritanserine, rolipram, celchloremin, setiptilin, sibutramine, sulbutiamine, sulpiride, teniloxazine, tozarinone, thymoliberin, thianeptine, tiflucarbine, tofenacin, tofisopam, troxatone, tomoxetine, beralipride, biqualin, dimmeridine, zometapine, or pharmaceutically acceptable salts thereof; or St. John's wort herb, Hypericum perforatum, or extracts thereof.

[0072] This application includes a method comprising administering certrexant or a pharmaceutically acceptable salt or hydrate thereof to a subject to prevent and / or reduce the severity of depression or at least one symptom of depression in a subject who has no or mild hepatic impairment, and administering a reduced amount of certrexant or a pharmaceutically acceptable salt or hydrate thereof to a subject who has moderate hepatic impairment. For example, the method comprises administering certrexant or a pharmaceutically acceptable salt or hydrate thereof to prevent and / or reduce a measure that quantifies the overall severity of a set of multiple depressive symptoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15 depressive symptoms) in a subject having depression, particularly MDD or bipolar depression. Symptoms of depression that may be reduced by administration of certrexant or its pharmaceutically acceptable salts or hydrates include, for example, apparent sadness, reported sadness, entrenched tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, paresthesia, and / or pessimistic thinking.

[0073] The prevention and / or reduction of the severity of depression may be observed qualitatively (e.g., by general patient assessments by a clinician during clinic visits) or as a quantitative reduction in scores over a period of time (e.g., 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, etc.) using any suitable clinical scale (e.g., diagnostic questionnaire) for measuring the severity of depressive symptoms, which would be understood by those skilled in the art. Clinical scales include, for example, the Clinical Global Impression-Severity (CGI-S) scale, EuroQol; 5 dimension; 5 level (EQ-5D-5L), Patient Health Questionnaire-9 Item (PHQ-9), Sheehan Disability Scale (SDS), and Inventory of Depressive Symptomatology-Clinician Assessment Scale (30-item scale). Rated, 30-item scale, IDS-C 30 ), Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Rating Scale for Depression (HAM-D or HDRS), Beck Scale for Depression, Quick Inventory of Depressive Symptomology (QIDS), 17-item Hamilton Depression Rating Scale (HDRS) 17 These include the Patient Health Questionnaire (PHQ-9), the Insomnia Severity Index (ISI), and / or the PROMIS-Sleep Disturbance (PROMIS-SD) scale.

[0074] In specific cases, the method involves administering certrexant or a pharmaceutically acceptable salt or hydrate thereof to subjects with depression, particularly MDD or bipolar depression, to prevent and / or reduce a measure quantifying the overall severity of 10 depressive symptoms (e.g., the Montgomery-Asberg Depression Rating Scale (MADRS) score) if the subject has no or mild hepatic impairment, and administering a reduced dose of certrexant or a pharmaceutically acceptable salt or hydrate thereof if the subject has moderate hepatic impairment. The MADRS is a clinician rating scale designed to measure the severity of depression and detect changes due to antidepressant treatment. The scale consists of 10 items, each scored from 0 (absent or normal) to 6 (severe or persistent symptom), with a maximum total score of 60. A higher score indicates a more severe condition. The MADRS assesses apparent sadness, reported sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, numbness, pessimistic thoughts, and suicidal ideation.

[0075] Certrexant or its pharmaceutically acceptable salts or hydrates may be administered as monotherapy or in combination with or adjunct to other treatments, such as a second pharmaceutically active agent. Adjunct administration means using certrexant or its pharmaceutically acceptable salts or hydrates in conjunction with another treatment to adjunct that treatment, for example, certrexant or its pharmaceutically acceptable salts or hydrates being administered while the patient is receiving other treatments. In combination with or adjunct to another pharmaceutically active agent, certrexant or its pharmaceutically acceptable salts or hydrates may function to increase efficacy, reduce one or more side effects (for example, by enhancing the potency or effectiveness of the other pharmaceutically active agent), or reduce the required dose of certrexant or its salts or the other pharmaceutically active agent.

[0076] Other treatments may include the administration of another pharmaceutically active drug or psychotherapy (e.g., interpersonal and social rhythm therapy (IPSRT) or cognitive behavioral therapy (CBT)). The other pharmaceutically active drug may be any one or more of the conventional antidepressants identified above. In one example, certrexant or its pharmaceutically acceptable salt hydrate and another pharmaceutically active drug may be administered over the same period. More specifically, a patient may receive therapy in which both certrexant or its pharmaceutically acceptable salt or hydrate and the other pharmaceutically active drug are administered on the same day (e.g., within a 24-hour period). Certrexant or its pharmaceutically acceptable salt or hydrate and the other pharmaceutically active drug may be administered simultaneously, at different times, or intermittently. They may be administered intermittently. The length of time between the administration of the two therapeutic agents may be adjusted to achieve the desired therapeutic effect. For example, one therapeutic agent may be administered just a few minutes after the administration of the other therapeutic agent (e.g., about 1, 2, 5, 10, 30, or 60 minutes). Alternatively, one therapeutic agent may be administered several hours after the administration of the other therapeutic agent (e.g., about 2, 4, 6, 10, 12, 24, or 36 hours). In certain embodiments of the present invention, it may be advantageous to administer more than one dose of one therapeutic agent between the administrations of the other therapeutic agents. In certain embodiments of the present invention, the therapeutic effects of the two therapeutic agents may overlap over at least a portion of the duration of each therapeutic agent.

[0077] In some embodiments, certrexant or its pharmaceutically acceptable salts or hydrates are administered adjunct to conventional antidepressants. For example, certrexant or its pharmaceutically acceptable salts or hydrates are administered adjunct to SSRIs or SNRIs. In other embodiments, certrexant or its pharmaceutically acceptable salts or hydrates are administered concurrently with esketamine. In further embodiments, certrexant or its pharmaceutically acceptable salts or hydrates are administered separately from esketamine, for example, sequentially. Certrexant or its pharmaceutically acceptable salts or hydrates may be administered before or after esketamine.

[0078] Certrexant or its pharmaceutically acceptable salts or hydrates may be administered by any preferred route of administration, such as orally, parenterally (including subcutaneously, intramuscularly, and intravenously), rectally, percutaneously, orally, or nasally. The compound may also be administered directly to the nervous system, including, but not limited to, intracranial, ventricular, lateral ventricle, subarachnoid, sacral, intraspinal, and / or perispinal routes, by delivery via a catheter equipped with or without an intracranial or intravertebral needle and / or pump device. Suitable compositions for oral administration include powders, granules, aggregates, tablets, compressed or coated pills, hard or gelatin capsules, syrups, emulsions, and suspensions. Suitable compositions for parenteral administration include aqueous or non-aqueous solutions or emulsions. In preferred embodiments, the compound is administered orally, for example, by tablets, gelatin capsules, or orally ingested liquids.

[0079] The compounds described herein may be formulated as pharmaceutical compositions for administration to human subjects. Thus, a pharmaceutical composition may comprise (a) an effective amount of the compounds described herein, and (b) a pharmaceutically acceptable excipient. A “pharmaceutically acceptable excipient” means a non-toxic, bioacceptable, and otherwise biosuitable substance for administration to a subject, such as an inert substance, which is added to a pharmaceutical composition or used as a vehicle, carrier, or diluent to facilitate the administration of the drug, and which is compatible with the drug. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0080] The delivery forms of pharmaceutical compositions containing one or more dosing units of the compounds described herein may be prepared using suitable pharmaceutical excipients and formulation techniques known to or available to those skilled in the art. The preparations may be in the form of tablets, capsules, sachets, sugar-coated tablets, powders, granules, lozenges, reconstituted powders, or liquid preparations. In some embodiments, the compositions are formulated for intravenous injection, topical administration, or oral administration. In certain embodiments, the compositions are formulated for immediate release.

[0081] For oral administration, the compound may be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. In certain embodiments, the compound may be taken with food.

[0082] Oral tablets may contain the compounds described herein mixed with pharmaceutically acceptable excipients such as inert fillers, diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, flow enhancers, and preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, lactose monohydrate, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and hypromellose. Exemplary oral liquid excipients include ethanol, glycerol, and water. Suitable disintegrants include starch, polyvinylpyrrolidone, sodium starch glycolate, microcrystalline cellulose, crospovidone (cross-linked polyvinyl N-pyrrolidone or polyvinyl N-pyrrolidone, PVP), and alginic acid. Binders may include hypromellose (hydroxypropyl methylcellulose or hydroxypropyl methylcellulose, HPMC), starch, and gelatin. The lubricant, if present, may be magnesium stearate, stearic acid, or talc. The flow enhancer, if present, may be silica (Sift), such as colloidal silica. If desired, the tablets may be coated with a substance such as glyceryl monostearate or glyceryl distearate, or with an enteric coating, to delay absorption in the gastrointestinal tract.

[0083] In exemplary embodiments, the tablets containing certrexant include the components listed in Table 1 below.

[0084] [Table 2]

[0085] Examples of orally administered capsules include rigid gelatin capsules and soft gelatin capsules. To prepare rigid gelatin capsules, the compound may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules can be prepared by mixing the mixture with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0086] Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups, or may be freeze-dried for reconstitution with water or other suitable vehicles before use, or may be presented as dried products. Such liquid compositions may optionally contain pharmaceutically acceptable excipients, e.g., suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles, e.g., oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate, or sorbic acid); humectants such as lecithin; and, if necessary, flavorings or colorants.

[0087] The compounds described herein may also be formulated for administration via parenteral routes. For example, the compounds may be formulated for rectal administration. For parenteral applications, including intravenous, intramuscular, or intraperitoneal routes, the compounds may be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or in an oil that is parenterally acceptable. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit dose forms such as ampoules or disposable injection devices, multi-dose forms such as vials from which appropriate doses can be drawn, or in solid or pre-concentrated forms that can be used to prepare injectable formulations. Illustrative infusion doses may range from about 1 to 1000 μg / kg / min of the compound mixed with a pharmaceutical carrier over a period ranging from a few minutes to several days.

[0088] For topical administration, the compound can be mixed with a pharmaceutical carrier at a drug concentration of approximately 0.1% to 10% relative to the vehicle. Another mode of administration of the compound may involve the use of a patch formulation for transdermal delivery.

[0089] Alternatively, the compound may be formulated for administration by inhalation, via nasal or oral routes, for example, in a spray formulation that also contains a suitable carrier.

[0090] manner Embodiment 1. A method for treating orexin-2 mediated disorder in human subjects requiring treatment for orexin-2 mediated disorder, If the subject does not have liver impairment, administer certrexant or a pharmaceutically acceptable salt or hydrate thereof at a therapeutically effective daily dose. A method comprising administering certrexant or a pharmaceutically acceptable salt or hydrate thereof to a subject who has moderate hepatic impairment at a reduced dose less than the daily dose.

[0091] Appearance 2. The method according to embodiment 1, further comprising administering certrexant or a pharmaceutically acceptable salt or hydrate thereof to a subject who has mild hepatic impairment at a daily dose.

[0092] Appearance 3. The method according to embodiment 1, further comprising not administering certrexant or a pharmaceutically acceptable salt or hydrate to a subject who has severe liver impairment.

[0093] Appearance 4. The method according to embodiment 2, further comprising not administering certrexant or a pharmaceutically acceptable salt or hydrate to a subject who has severe liver impairment.

[0094] Embodiment 5. The method according to Embodiment 2, wherein a subject with mild liver impairment has a Child-Puth score of 5 to 6.

[0095] Embodiment 6. The method according to any one of Embodiments 1 to 4, wherein a subject with moderate liver impairment has a Child-Puth score of 7 to 9.

[0096] Embodiment 7. The method according to Embodiment 3 or 4, wherein the subject having severe liver impairment has a Child Puer score of 10 or more than 10.

[0097] Embodiment 8. The method according to any one of Embodiments 1 to 4, wherein certrexant is administered as a free base.

[0098] Embodiment 9. The method according to any one of Embodiments 1 to 4, wherein certrexant hydrochloride is administered.

[0099] Embodiment 10. The method according to any one of Embodiments 1 to 4, wherein the orexin-2 mediated disorder is selected from the group consisting of depression and insomnia.

[0100] Embodiment 11. The method according to Embodiment 10, wherein the orexin-2 mediated disorder is depression.

[0101] Embodiment 12. The method according to Embodiment 11, wherein the depression is major depressive disorder.

[0102] Embodiment 13. The method according to Embodiment 11, wherein the depression is bipolar depression.

[0103] Embodiment 14. The method according to Embodiment 11, wherein the subject has comorbid depression and insomnia symptoms with an ISI score of 15 or higher.

[0104] Embodiment 15. The method according to Embodiment 10, wherein the orexin-2 mediated disorder is insomnia.

[0105] Embodiment 16. The method according to any one of Embodiments 1 to 4, wherein certrexant is administered orally.

[0106] Embodiment 17. The method according to any one of Embodiments 1 to 4, wherein the daily dose is approximately 20 mg / day to approximately 60 mg / day.

[0107] Embodiment 18. The method according to Embodiment 17, wherein the reduced dose is approximately 5 mg / day to approximately 20 mg / day.

[0108] Embodiment 19. The method according to Embodiment 18, wherein the reduced dose is approximately 20 mg / day.

[0109] Embodiment 20. The method according to Embodiment 18, wherein the reduced dose is approximately 15 mg / day.

[0110] Embodiment 21. The method according to Embodiment 18, wherein the reduced dose is approximately 10 mg / day.

[0111] Embodiment 22. The method according to Embodiment 18, wherein the reduced dose is approximately 5 mg / day.

[0112] Embodiment 23. The method according to any one of Embodiments 1 to 4, wherein the reduced dose is at least 20% less than the daily dose.

[0113] Embodiment 24. The method according to any one of Embodiments 1 to 4, wherein the reduced dose is at least 25% less than the daily dose.

[0114] Embodiment 25. The method according to any one of Embodiments 1 to 4, wherein the reduced dose is approximately 50% less than the daily dose.

[0115] Embodiment 26. The method according to any one of Embodiments 1 to 4, wherein the daily dose is approximately 0.25 mg / kg to approximately 0.9 mg / kg per day, and the reduced dose is approximately 0.07 mg / day to approximately 0.3 mg / day.

[0116] Embodiment 27. The method according to any one of Embodiments 1 to 4, wherein, when the subject does not have liver impairment, administration of certrexant or a pharmaceutically acceptable salt or hydrate thereof at a daily dose to the subject provides an unbound mean plasma concentration of certrexant of approximately 0.75 ng / mL to approximately 1.5 ng / mL.

[0117] Appearance 28. If the subject does not have liver impairment, administration of certrexant or a pharmaceutically acceptable salt or hydrate thereof at a daily dose to the subject provides a first unbound mean plasma concentration of certrexant within an effective therapeutic range. The method according to any one of embodiments 11 to 14, wherein, in cases where the subject has moderate hepatic impairment, administration of a reduced dose of certrexant or a pharmaceutically acceptable salt thereof to the subject provides a second unbound mean plasma concentration of certrexant within an effective therapeutic range.

[0118] Embodiment 29. The method according to Embodiment 28, wherein, in cases where the subject has mild hepatic impairment, administration of certrexant or a pharmaceutically acceptable salt or hydrate thereof at a daily dose to the subject provides a third unbound mean plasma concentration of certrexant within an effective therapeutic range.

[0119] Aspect 30. The method according to any one of Aspects 11 to 14, wherein when the subject has moderate liver impairment, administration of sertorexant or a pharmaceutically acceptable salt thereof at a reduced dose is more therapeutically effective than the daily dose in the subject.

[0120] Aspect 31. The method according to any one of Aspects 11 to 14, wherein the subject has an inadequate response to an antidepressant other than sertorexant or a pharmaceutically acceptable salt or hydrate thereof.

[0121] Aspect 32. The method according to Aspect 31, wherein the subject has an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI).

[0122] Aspect 33. The method according to any one of Aspects 1 to 4, wherein sertorexant or a pharmaceutically acceptable salt or hydrate thereof is administered adjunctively with a second pharmaceutically active agent.

[0123] Aspect 34. The method according to Aspect 33, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI).

[0124] Aspect 35. A method of treating an orexin-2-mediated disorder in a human subject who requires treatment of the orexin-2-mediated disorder, wherein the subject has moderate liver impairment and the method comprises administering sertorexant or a pharmaceutically acceptable salt or hydrate thereof at a reduced dose that is less than the therapeutically effective daily dose adapted for treatment of a human subject with normal liver function.

[0125] Aspect 36. The method according to Aspect 35, wherein the subject having moderate liver impairment has a Child-Pugh score of 7 to 9.

[0126] Aspect 37. The method according to Aspect 35, wherein sertorexant is administered as the free base.

[0127] Embodiment 38. The method according to Embodiment 35, wherein certrexant hydrochloride is administered.

[0128] Embodiment 39. The method according to Embodiment 35, wherein the orexin-2 mediated disorder is selected from the group consisting of depression and insomnia.

[0129] Apparatus 40. The method according to Apparatus 39, wherein the orexin-2 mediated disorder is depression.

[0130] Apparatus 41. The method according to Apparatus 39, wherein the depression is major depressive disorder.

[0131] Apparatus 42. The method according to Apparatus 39, wherein the depression is bipolar depression.

[0132] Embodiment 43. The method according to Embodiment 39, wherein the subject has comorbid depression and insomnia symptoms with an ISI score of 15 or higher.

[0133] Apparatus 44. The method according to Apparatus 39, wherein the orexin-2 mediated disorder is insomnia.

[0134] Embodiment 45. The method according to any one of Embodiments 35 to 44, wherein certrexant is administered orally.

[0135] Embodiment 46. The method according to any one of Embodiments 35 to 44, wherein the daily dose is approximately 20 mg / day to approximately 60 mg / day.

[0136] Embodiment 47. The method according to Embodiment 46, wherein the reduced dose is approximately 5 mg / day to approximately 20 mg / day.

[0137] Embodiment 48. The method according to Embodiment 47, wherein the reduced dose is approximately 20 mg / day.

[0138] Embodiment 49. The method according to Embodiment 47, wherein the reduced dose is approximately 15 mg / day.

[0139] Aspect 50. The method according to aspect 47, wherein the reduced dose is about 10 mg / day.

[0140] Aspect 51. The method according to aspect 47, wherein the reduced dose is about 5 mg / day.

[0141] Aspect 52. The method according to any one of aspects 35 - 45, wherein the reduced dose is at least 20% less than the daily dose.

[0142] Aspect 53. The method according to any one of aspects 35 - 45, wherein the reduced dose is at least 25% less than the daily dose.

[0143] Aspect 54. The method according to any one of aspects 35 - 45, wherein the reduced dose is about 50% less than the daily dose.

[0144] Aspect 55. The method according to any one of aspects 35 - 45, wherein the daily dose is about 0.25 mg / kg per day to about 0.9 mg / kg per day, and the reduced dose is about 0.07 mg / day to about 0.3 mg / day.

[0145] Aspect 56. The method according to any one of aspects 35 - 45, wherein the daily dose is selected to provide an unbound mean plasma concentration of sertraline of about 0.75 ng / mL to about 1.5 ng / mL when administered to a human subject with normal liver function.

[0146] Aspect 57. The method according to any one of aspects 40 - 43, wherein administration of sertraline or a pharmaceutically acceptable hydrate salt thereof at a reduced dose to a subject with moderate liver impairment provides an unbound mean plasma concentration of sertraline within the effective therapeutic range.

[0147] Aspect 58. The method according to any one of aspects 40 - 43, wherein administration of sertraline or a pharmaceutically acceptable salt thereof at a reduced dose is more therapeutically effective than the daily dose in a control with moderate liver impairment.

[0148] Embodiment 59. The method according to any one of Embodiments 40 to 43, wherein the subject has an insufficient response to an antidepressant other than certrexant or a pharmaceutically acceptable salt or hydrate thereof.

[0149] Embodiment 60. The method according to Embodiment 59, wherein the subject has an insufficient response to a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI).

[0150] Embodiment 61. The method according to any one of Embodiments 35 to 45, wherein certrexant or a pharmaceutically acceptable salt or hydrate thereof is administered adjunctly with a second pharmaceutically active agent.

[0151] Embodiment 62. The method according to Embodiment 61, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI).

[0152] Apparatus 63. A method for treating orexin-2 mediated disorder in a human subject requiring treatment for orexin-2 mediated disorder, wherein the subject has mild liver impairment, and the method is A method comprising administering certrexant or a pharmaceutically acceptable salt or hydrate thereof in a therapeutically effective daily dose suitable for treatment in human subjects with normal liver function.

[0153] Embodiment 64. The method according to Embodiment 63, wherein a subject with mild liver impairment has a Child-Puth score of 5 to 6.

[0154] Embodiment 65. The method according to Embodiment 63, wherein certrexant is administered as a free base.

[0155] Embodiment 66. The method according to Embodiment 63, wherein certrexant hydrochloride is administered.

[0156] Embodiment 67. The method according to Embodiment 63, wherein the orexin-2 mediated disorder is selected from the group consisting of depression and insomnia.

[0157] Embodiment 68. The method according to Embodiment 67, wherein the orexin-2 mediated disorder is depression.

[0158] Apparatus 69. The method according to Apparatus 68, wherein the depression is major depressive disorder.

[0159] Embodiment 70. The method according to Embodiment 68, wherein the depression is bipolar depression.

[0160] Embodiment 71. The method according to Embodiment 67, wherein the subject has comorbid depression and insomnia symptoms with an ISI score of 15 or higher.

[0161] Embodiment 72. The method according to Embodiment 67, wherein the orexin-2 mediated disorder is insomnia.

[0162] Embodiment 73. The method according to any one of Embodiments 63 to 72, wherein certrexant is administered orally.

[0163] Embodiment 74. The method according to any one of Embodiments 63 to 72, wherein the daily dose is approximately 20 mg / day to approximately 60 mg / day.

[0164] Embodiment 75. The method according to any one of Embodiments 63 to 72, wherein the daily dose is approximately 0.25 mg / kg to approximately 0.9 mg / kg per day.

[0165] Embodiment 76. The method according to Embodiment 63, wherein the daily dose is selected to provide an unbound mean plasma concentration of approximately 0.75 ng / mL to approximately 1.5 ng / mL of certrexant when administered to human subjects with normal liver function.

[0166] Embodiment 77. The method according to any one of Embodiments 68 to 71, wherein administration of certrexant or a pharmaceutically acceptable salt or hydrate thereof at a daily dose to a subject with mild hepatic impairment provides an effective therapeutic range of unbound mean plasma concentration of certrexant.

[0167] Embodiment 78. The method according to any one of Embodiments 68 to 71, wherein the subject has an insufficient response to an antidepressant other than certrexant or a pharmaceutically acceptable salt or hydrate thereof.

[0168] Embodiment 79. The method according to Embodiment 78, wherein the subject has an insufficient response to a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI).

[0169] Embodiment 80. The method according to any one of Embodiments 68 to 71, wherein certrexant or a pharmaceutically acceptable salt or hydrate thereof is administered adjunctly with a second pharmaceutically active agent.

[0170] Embodiment 81. The method according to Embodiment 80, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI).

[0171] Embodiment 82. A method for treating orexin-2 mediated disorder in a human subject requiring treatment for orexin-2 mediated disorder, If the subject has moderate hepatic impairment, administer certrexant or a pharmaceutically acceptable salt or hydrate thereof at a reduced dose lower than the therapeutically effective daily dose suitable for human subjects with normal liver function. If the subject has severe liver impairment, do not administer certrexant or a pharmaceutically acceptable salt or hydrate to the subject. A method comprising administering certrexant or a pharmaceutically acceptable salt or hydrate thereof to a subject who does not have moderate to severe liver impairment, at a daily dose.

[0172] Embodiment 83. The method according to Embodiment 82, wherein a subject with mild liver impairment has a Child-Puth score of 5 to 6.

[0173] Embodiment 84. The method according to Embodiment 82, wherein a subject with moderate liver impairment has a Child-Puth score of 7 to 9.

[0174] Embodiment 85. The method according to Embodiment 82, wherein a subject with severe liver impairment has a Child Puer score of 10 or more than 10.

[0175] Embodiment 86. The method according to Embodiment 82, wherein certrexant is administered as a free base.

[0176] Embodiment 87. The method according to Embodiment 82, wherein certrexant hydrochloride is administered.

[0177] Embodiment 88. The method according to Embodiment 82, wherein the orexin-2 mediated disorder is selected from the group consisting of depression and insomnia.

[0178] Embodiment 89. The method according to Embodiment 88, wherein the orexin-2 mediated disorder is depression.

[0179] Apparatus 90. The method according to Apparatus 89, wherein the depression is major depressive disorder.

[0180] Apparatus 91. The method according to Apparatus 89, wherein the depression is bipolar depression.

[0181] Embodiment 92. The method according to Embodiment 89, wherein the subject has comorbid depression and insomnia symptoms with an ISI score of 15 or higher.

[0182] Embodiment 93. The method according to Embodiment 88, wherein the orexin-2 mediated disorder is insomnia.

[0183] Embodiment 94. The method according to any one of Embodiments 80 to 93, wherein certrexant is administered orally.

[0184] Embodiment 95. The method according to any one of Embodiments 80 to 93, wherein the daily dose is approximately 20 mg / day to approximately 60 mg / day.

[0185] Embodiment 96. The method according to Embodiment 95, wherein the reduced dose is approximately 5 mg / day to approximately 20 mg / day.

[0186] Embodiment 97. The method according to Embodiment 95, wherein the reduced dose is approximately 20 mg / day.

[0187] Embodiment 98. The method according to Embodiment 95, wherein the reduced dose is approximately 15 mg / day.

[0188] Embodiment 99. The method according to Embodiment 95, wherein the reduced dose is approximately 10 mg / day.

[0189] Embodiment 100. The method according to Embodiment 95, wherein the reduced dose is approximately 5 mg / day.

[0190] Embodiment 101. The method according to any one of Embodiments 80 to 93, wherein the reduced dose is at least 20% less than the daily dose.

[0191] Embodiment 102. The method according to any one of Embodiments 80 to 93, wherein the reduced dose is at least 25% less than the daily dose.

[0192] Embodiment 103. The method according to any one of Embodiments 80 to 93, wherein the reduced dose is approximately 50% less than the daily dose.

[0193] Embodiment 104. The method according to any one of Embodiments 80 to 93, wherein the daily dose is approximately 0.25 mg / kg to approximately 0.9 mg / kg per day, and the reduced dose is approximately 0.07 mg / day to approximately 0.3 mg / day.

[0194] Embodiment 105. The method according to any one of Embodiments 80 to 93, wherein the daily dose is selected to provide an unbound mean plasma concentration of approximately 0.75 ng / mL to approximately 1.5 ng / mL of certrexant when administered to human subjects with normal liver function.

[0195] Embodiment 106. The method according to any one of Embodiments 87 to 90, wherein, in cases where the subject has moderate hepatic impairment, administration of certrexant or a pharmaceutically acceptable salt thereof at a reduced dose is more therapeutically effective than the daily dose in the subject.

[0196] Embodiment 107. The method according to any one of Embodiments 87 to 90, wherein the subject has an insufficient response to an antidepressant other than certrexant or a pharmaceutically acceptable salt or hydrate thereof.

[0197] Embodiment 108. The method according to Embodiment 107, wherein the subject has an insufficient response to a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI).

[0198] Embodiment 109. The method according to any one of Embodiments 80 to 93, wherein certrexant or a pharmaceutically acceptable salt or hydrate thereof is administered adjunctly with a second pharmaceutically active agent.

[0199] Embodiment 110. The method according to Embodiment 109, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI). [Examples]

[0200] The following examples are provided to further illustrate the essence of the present invention. These examples are not intended to limit the present invention, and it should be understood that the scope of the present invention is defined by the appended claims.

[0201] (Example 1) Example 1 was an open-label, parallel-group, single-dose phase 1 clinical trial to characterize the pharmacokinetics (PK) and safety of certrexant and its metabolites M12 and M16 in participants aged 18 to 79 years, including participants with varying stages of hepatic impairment and healthy participants (clinical trial identification number: NCT04960124, a description of which is available at https: / / clinicaltrials.gov / ct2 / show / NCT04960124 and is incorporated herein by reference). This example was conducted to evaluate the pharmacokinetics of a single oral dose of certrexant in adult participants with hepatic impairment compared to healthy participants with normal hepatic function.

[0202] Participants were screened for eligibility to participate in the study. Diagnosis of hepatic impairment was based on medical history, Child-Pugh clinical assessment scores of 5-6 (grade A, mild hepatic impairment), 7-9 (grade B, moderate hepatic impairment), and 10-15 (grade C, severe hepatic impairment), and the presence of physical signs (liver stiffness with palpitations, splenomegaly, spider angioma, palmar erythema, parotid hypertrophy, testicular atrophy, or gynecomastia) or other modalities (computed tomography, ultrasound, magnetic resonance imaging, radionuclear liver / spleen scan or abdominal laparoscopy, or liver biopsy). Underlying diseases contributing to hepatic impairment were documented (e.g., hepatitis B, hepatitis C, alcoholic steatohepatitis, non-alcoholic fatty liver disease [hereditary / metabolic], or others). Grading of hepatic encephalopathy was performed by the principal investigator. Individual components of the Child-Pugh clinical assessment score were documented. Participants who had undergone liver transplantation were excluded.

[0203] The clinical trial in Example 1 consisted of an open-label treatment phase (days 1-5) including a screening phase (within 21 days before the intervention dose) and an end-of-study (EOS) or withdrawal evaluation (conducted on day 5 or at the time of early withdrawal). The trial period for each participant was approximately 4 weeks, from screening (-21 days to -1 day) to the EOS evaluation.

[0204] 18-38 kg / m 2Healthy men and women aged 18–79 years with a body mass index (BMI) and a weight of 50 kg or more were enrolled in the study according to their liver function. The degree of liver impairment was based on the Childe-Pugh classification. Using this classification, participants were grouped based on two clinical features (hepatic encephalopathy and ascites) and three laboratory-based parameters (albumin, bilirubin, and prothrombin time).

[0205] The trial included 24 human patients divided into three different cohorts: ● Cohort 1: Eight healthy participants with normal liver function and no evidence of liver damage. ● Cohort 2: Eight participants with mild hepatic impairment (with Child-Puth scores of 5-6), and ● Cohort 3: Eight participants with moderate hepatic impairment (Child-Puth score 7-9).

[0206] Participants in Cohorts 1 and 2 received a single 20 mg dose of certrexant. Preliminary physiologically based pharmacokinetic (PBPK) modeling and simulations predicted a 2.5-fold increase in total certrexant exposure in participants with moderate hepatic impairment; therefore, participants in Cohort 3 received a lower dose of 10 mg of certrexant.

[0207] Based on liver impairment classified during screening, eight participants with mild liver impairment (Cohort 2) and eight participants with moderate liver impairment (Cohort 3) were enrolled. After eight participants from each of Cohort 2 and Cohort 3 completed study-related procedures, including 96-hour PK samples, participants with normal liver function (Cohort 1) were enrolled. Using a group matching procedure, healthy participants with normal liver function were demographically matched with the participants enrolled in Cohort 2 and Cohort 3 in terms of sex, age, and weight. At the start of the control group, a total of eight participants with normal liver function (Cohort 1), with similar mean age (±10 years) and mean weight (±10 kg), were enrolled with a similar male-to-female participant ratio for all combined completers from the mild (Cohort 2) and moderate (Cohort 3) liver impairment groups. Participants in the control group (Cohort 1) who tested positive for hepatitis B surface antigen (HbsAg) or hepatitis C antibody were not permitted to participate in the study.

[0208] In the group with normal liver function (Cohort 1), at least three participants with individual values ​​exceeding the combined mean age / mean weight values ​​of the mild (Cohort 2) and moderate (Cohort 3) liver impairment groups, and at least three participants with individual values ​​below these values, were enrolled. Two to four women were enrolled in each cohort.

[0209] Of the eight participants enrolled in Cohort 1, four (50.0%) were male and four (50.0%) were female. The mean age was 63.6 years (±6.55 years), and the mean weight was 75.10 kg (±8.76 kg). The median BMI was 25.10 kg / m². 2 (Range: 22.5~28.5 kg / m 2 All participants were of Caucasian race and not of Hispanic or Latino ethnicity. The mean estimated glomerular filtration rate (eGFR) for this cohort was 94.03 mL / min / 1.73 m². 2 (±12.34mL / min / 1.73m 2The mean psychometric hepatic encephalopathy score (PHES) was 0 (±3.07).

[0210] Of the eight participants enrolled in Cohort 2, six (75.0%) were male and two (25.0%) were female. The mean age was 60.5 years (±12.81 years), and the mean weight was 79.86 kg (±13.32 kg). The median BMI was 24.60 kg / m². 2 (Range: 22.6~30.3 kg / m 2 All participants were of Caucasian race and not Hispanic or Latino ethnicity. The mean Child-Puth score for this cohort was 5.3 (±0.46). The mean eGFR for this cohort was 103.12 mL / min / 1.73 m². 2 (±15.22mL / min / 1.73m 2 The mean PHES was -3.3 (±2.71). In this cohort, one participant (12.5%) was diagnosed with mild ascites.

[0211] Of the eight participants enrolled in Cohort 3, four (50.0%) were male and four (50.0%) were female. The mean age was 63.0 years (±5.45 years), and the mean weight was 75.59 kg (±20.06 kg). The median BMI was 24.75 kg / m². 2 (Range: 19.2~35.8 kg / m 2 All participants were of Caucasian race and not Hispanic or Latino ethnicity. The mean Child-Puth score for this cohort was 7.1 (±0.35). The mean eGFR for this cohort was 90.63 mL / min / 1.73 m². 2 (±12.89 mL / min / 1.73 m 2 The mean PHES was -4.0 (±2.88). In this cohort, all 8 participants (100%) were diagnosed with slight ascites.

[0212] All participants enrolled in the mild to moderate hepatic impairment group had active medical conditions of cirrhosis (primarily alcoholic / ethyltoxic cirrhosis). The most common impairments / infections in the mild to moderate hepatic impairment group included hypertension in seven participants, as well as ascites, hepatitis B infection, hepatitis C infection, and chronic obstructive pulmonary disease, each reported in three participants.

[0213] Participants entered the study facility on the morning of day 1 and remained there until after the collection of 96-hour PK samples on day 5. On day 1, participants with normal liver function and those with mild liver impairment received a single 20 mg oral dose of certrexant (given as a 20 mg tablet), while participants with moderate liver impairment received a single 10 mg oral dose of certrexant (given as a 10 mg tablet). Subsequently, continuous blood and urine samples were collected to measure the plasma and urine concentrations of certrexant and its metabolites, M12 and M16. In addition, blood samples were collected to determine plasma protein binding (PPB).

[0214] Certrexant was administered orally with 240 mL of room temperature non-carbonated water at bedtime, approximately 3 hours after the start of a standard dinner. The certrexant was swallowed whole without chewing, splitting, dissolving, or crushing. Participants remained in a supine position from the pre-administration assessment until 4 hours post-administration, but were permitted to stand briefly for urgent needs (e.g., using the toilet) and during meal intake. Fluid intake (e.g., water) was restricted 1 hour before and 1 hour after administration, with the exception of water administered with the study intervention. Participants were provided with a standard dinner 3 hours before administration of the study intervention. The standard dinner was consumed completely within 30 minutes.

[0215] Participants with liver impairment were instructed not to take any approved concomitant medications before or for at least two hours after certrexant administration.

[0216] Descriptive statistics were calculated for plasma concentrations of certrexant and its metabolites, M12 and M16, and derived plasma and urinary PK parameters at each application time point per cohort, as follows: C max : Observed maximum plasma analyte concentration t max : Time to reach peak plasma concentration AUC last Area under the plasma analyte concentration versus time curve from time zero to the time of the last measurable concentration. AUC∞: Area under the time curve of plasma analyte concentration from time zero to infinite time. λ z Removal rate constant determined by linear regression of the endpoint of the log-linear plasma concentration-time curve. t 1 / 2 :0.693λ z Terminal phase half-life is defined as CL / F: Total drug clearance after extravasation, calculated as Dose / AUC∞, without correction for absolute bioavailability. V d / F: Apparent volume of distribution after extravasation, not adjusted for absolute bioavailability. AUC∞ is AUC last +C last / λ z It can be calculated as, in the formula, C last This represents the last observed measurable (non-BQl) plasma analyte concentration. Statistics included sample size (n), mean, standard deviation (SD), %CV, arithmetic mean, geometric mean, median, minimum, and maximum.

[0217] To compare mild and moderate liver impairment (Cohorts 2 and 3) with normal liver function (Cohort 1), an analysis of variance (ANOVA) model was used, with logarithmically transformed AUC(AUC∞ and AUC last ) and C maxThe group was then fitted using the liver impairment group as a factor. The mean PK parameters AUC and C10 were compared between participants with mild and moderate liver impairment (Cohorts 2 and 3) and participants with normal liver function (Cohort 1). max A 90 percent confidence interval for the ratio was constructed using the estimated least squares mean and between-participant variance from the ANOVA model.

[0218] Plasma and urine samples of certrexant, M12 (JNJ-49388599) and M16 (JNJ-51963964) were analyzed using effective bioanalytical methods employing LC-MS / MS for analysis. Plasma concentrations of certrexant, M12, and M16 were determined using a lower limit of quantification (LLOQ) of 1.00 ng / mL. The quantification range for certrexant, M12, and M16 was 1.00–2000 ng / mL.

[0219] Pharmacokinetics of certrexant Figure 1a shows the linear mean plasma concentration-time profile of certrexant after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3. Figure 1b shows the data from Figure 1a on a semi-logarithmic scale. As shown in Figures 1a and 1b, the mean plasma concentration-time profile of certrexant after a single oral administration of 20 mg of certrexant (normal liver function and mild hepatic impairment) or 10 mg of certrexant (moderate hepatic impairment) is t max After reaching that point, it decreased exponentially.

[0220] For all cohorts, unbound plasma concentrations were derived using the 2-hour fraction unbound values, and these unbound concentrations were used to derive unbound PK parameters. The mean fraction unbound values ​​of certrexant at 2 hours for normal liver function, mild hepatic impairment, and moderate hepatic impairment were 1.50%, 2.02%, and 3.39%, respectively. Figure 2a shows the linear mean plasma concentration-time profiles of unbound certrexant after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3. Figure 2b shows the data from Figure 2b on a semi-logarithmic scale. The mean plasma concentration-time profile of unbound certrexant after a single oral administration of 20 mg of certrexant (normal liver function and mild hepatic impairment) or 10 mg of certrexant (moderate hepatic impairment) was t max After reaching that point, it decreased exponentially.

[0221] Table 3 presents a summary list of the major pharmacokinetic parameters of certrexant for all cohorts, including dose-normalized PK parameters.

[0222] [Table 3] Note: Dose normalized to 20 mg for Cohort 3.

[0223] Mean PK parameter C for mild liver damage max AUC last , and AUC∞ was 547 ng / mL, 3718h * ng / mL, and 3750h * The values ​​are ng / mL, and for normal liver function, they are 542 ng / mL and 2714 h, respectively. * ng / mL, and 2720h * The value is ng / mL. Mean PK parameter C for mild liver damage. max The AUC of certrexant was equivalent, but last And AUC∞ was 1.37 times and 1.38 times higher compared to normal liver function. The clearance half-life (t) of normal liver function and mild liver impairment was also higher. 1 / 2 ) and median tmax These were 2.68 hours, 3.87 hours, and 1.50 hours and 4.00 hours, respectively.

[0224] Participants in Cohort 3 (moderate hepatic impairment) received a lower dose of 10 mg of certrexant, and therefore, their PK parameters were dose-normalized to 20 mg so that they could be compared to the group with normal liver function (Cohort 1). Mean PK parameter C for moderate hepatic impairment max AUC last , and AUC∞ were 287 ng / mL and 1383 h, respectively. * ng / mL, and 1397h * The value is ng / mL. Mean PK parameter C for dose-normalized moderate hepatic impairment with certrexant. max AUC last , and AUC∞ (574 ng / mL, 2765 h, respectively) * ng / mL, and 2794h * ng / mL) indicates normal liver function (C max AUC last , and AUC∞ were 542 ng / mL and 2714 h, respectively. * ng / mL, and 2720h * It was comparable to (ng / mL).

[0225] Table 4 shows the plasma protein binding of certrexant to α-1-AGP, total protein, and albumin per cohort in participants with varying degrees of liver function at 2 hours on day 1.

[0226] [Table 4]

[0227] Albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, and α-1-AGP and total celtrexant PK parameters (C max AUC last The relationship between AUC∞(C) and CL / F) is expressed as the total cellular PK parameter (C) as the dependent variable.max AUC last AUC∞ and CL / F were evaluated by fitting a linear regression model using one of the following as a linear predictor: albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, or α-1-AGP (using baseline values). last The slopes of the regression lines for and AUC∞ were found to be statistically significant for α-1-AGP (p values ​​were 0.0262 and 0.0283, respectively), and CL / F was found to be statistically significant for both total protein and α-1-AGP (p values ​​were 0.0451 and 0.0025, respectively).

[0228] Figure 3a shows the certrexant AUC relative to α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last Figure 3d shows the scatter plots of the following: Figure 3b shows the scatter plot of certrexant AUC∞ against α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. Figure 3c shows the scatter plot of certrexant CL / F against total protein levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. Figure 3e shows the total certrexant C2 level relative to α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. max The scatter plot is shown below.

[0229] Table 5 presents a summary list of the key PK parameters of unbound sertorexant for all cohorts, including dose-normalized PK parameters.

[0230] [Table 5] Note: Dose normalization for cohort 3 at 20 mg

[0231] The mean PK parameters C max,unbound , AUC last,unbound , and AUC∞ ,unbound for mild liver impairment are 10.6 ng / mL, 60.2 h * ng / mL, and 60.6 h * ng / mL, while for normal liver function, they are 7.32 ng / mL, 34.1 h * ng / mL, and 34.2 h * ng / mL, respectively. The mean PK parameters C max,unbound , AUC last,unbound , and AUC∞ ,unbound of unbound sertorexant for mild liver impairment were 1.45-fold, 1.77-fold, and 1.77-fold higher, respectively, compared to normal liver function.

[0232] Participants in cohort 3 (moderate liver impairment) received a lower dose of 10 mg of sertorexant, and thus, the PK parameters were dose-normalized to 20 mg so that they could be compared to the normal liver function group (cohort 1). The mean PK parameters C max,unbound , AUC [[ID=​​​​​​​​​​​​​​​​ng / mL) indicates normal liver function (C max,unbound AUC last,unbound , and AUC∞ ,unbound These values ​​are 7.32 ng / mL and 34.1 h, respectively. * ng / mL, and 34.2h * Compared to ng / mL, these values ​​were 2.81 times, 2.77 times, and 2.79 times higher, respectively.

[0233] Albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, and α-1-AGP and unbound certrexant PK parameters (C max,unbound AUC last,unbound , and AUC∞ ,unbound The relationship between () and the unbound cell trexant PK parameter (C) is used as the dependent variable. max,unbound AUC last,unbound , and AUC∞ ,unbound ), and evaluation was performed by fitting a linear regression model using one of the following as a linear predictor: albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, or α-1-AGP (using baseline values). max,unbound The slopes of the regression lines were found to be statistically significant for albumin, prothrombin time, and α-1-AGP (p-values ​​were 0.0099, 0.0005, and 0.0009, respectively), and AUC last,unbound and AUC∞ ,unbound The effects were significant for albumin, prothrombin time, ALP, and α-1-AGP (p values ​​were 0.0006, 0.0025, 0.0248, 0.0006, and 0.0005, 0.0025, 0.0238, and 0.0006, respectively).

[0234] Figure 4a shows the relationship between unbound certrexant C and albumin levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. max,unboundThe scatter plot is shown. Figure 4b shows the relationship between unbound certrexant C2 and prothrombin time after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. max,unbound The scatter plot is shown. Figure 4c shows the α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3, relative to unbound certrexant C max,unbound The scatter plot is shown. Figure 4d shows the AUC of albumin levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last,unbound The scatter plot is shown. Figure 4e shows the AUC as a function of prothrombin time after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last,unbound The scatter plot is shown. Figure 4f shows the AUC against ALP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last,unbound The scatter plot is shown. Figure 4g shows the AUC of α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last,unbound The scatter plot is shown. Figure 4h shows the AUC∞ of albumin levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. ,unbound The scatter plot is shown. Figure 4i shows the AUC∞ as a function of prothrombin time after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. ,unboundThe scatter plot is shown. Figure 4j shows the AUC∞ of ALP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. ,unbound The scatter plot is shown. Figure 4k shows the AUC∞ of α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. ,unbound The scatter plot is shown below.

[0235] Table 6 presents a summary of the statistical results for certrexant in mild liver impairment versus normal liver function. In particular, Table 6 shows summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of certrexant exposure parameters after oral administration of 20 mg of certrexant in Cohort 1 and Cohort 2.

[0236] [Table 6] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0237] Based on the geometric mean ratio (GMR) of certrexant, mild hepatic impairment Cmax and AUC (AUC last %CV (and AUC∞) were approximately 1.07 times and 1.40 times higher, respectively, compared to normal liver function. max Regarding this, 30.5%, AUC(AUC last The C15% and AUC∞ values ​​were 45.5% and 45.6%, respectively. The C15% of certrexant in patients with mild liver impairment versus those with normal liver function was also observed.max AUC last The point estimate ratios (90% CI) for , and AUC∞ were 106.63% (82.50%~137.81%), 139.89% (96.35%~203.10%), and 140.44% (96.65%~204.08%), respectively.

[0238] Participants in Cohort 3 received a lower dose of 10 mg of certrexant, and therefore, the PK parameters were dose-normalized to 20 mg so that they could be compared to those with normal liver function (Cohort 1). A summary of the statistical results for certrexant in dose-normalized moderate hepatic impairment versus normal liver function is presented in Table 7. In particular, Table 7 shows summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of certrexant exposure parameters after oral administration of 20 mg of certrexant in Cohort 1 and 10 mg of certrexant in the Cohort 3 dose normalized to 20 mg.

[0239] [Table 7] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0240] Based on the GMR of certrexant, dose-normalized moderate hepatic impairment C max AUC last , and AUC∞ were approximately 1.07 times, 1.15 times, and 1.16 times higher, respectively, compared to normal liver function. max AUC lastThe %CV of certrexant for dose-normalized moderate hepatic impairment versus normal hepatic function was 30.5%, 45.5%, and 45.6%, respectively. max AUC last The point estimate ratios (90% CI) for , and AUC∞ were 107.28% (83.00%~138.65%), 114.79% (79.06%~166.66%), and 115.66% (79.59%~168.06%), respectively.

[0241] Table 8 presents a summary of the statistical results for unbound certrexant in mild hepatic impairment versus normal hepatic function. In particular, Table 8 provides summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of unbound certrexant exposure parameters after oral administration of 20 mg of certrexant in cohorts 1 and 2.

[0242] [Table 8] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0243] Based on the GMR of unbound certrexant, mild liver damage C max,unbound AUC last,unbound , and AUC∞ ,unbound These values ​​were approximately 1.28 times, 1.68 times, and 1.69 times higher, respectively, compared to normal liver function. %CV is C max,unbound Regarding 54.8%, AUC(AUC last,unbound and AUC∞ ,unbound The percentages for ) were 40.7% and 40.6%. C of unbound certrexant for mild liver impairment versus normal liver function. max,unboundAUC last,unbound , and AUC∞ ,unbound The point estimate ratios (90% CI) for each were 128.24% (82.49%~199.35%), 168.24% (120.10%~235.67%), and 168.91% (120.67%~236.43%), respectively.

[0244] Participants in Cohort 3 received a lower dose of 10 mg of certrexant, and therefore, the PK parameters were dose-normalized to 20 mg so that they could be compared to those with normal liver function (Cohort 1). A summary of the statistical results for unbound certrexant for dose-normalized moderate hepatic impairment versus normal liver function is presented in Table 9. In particular, Table 9 provides summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of unbound certrexant exposure parameters after oral administration of 20 mg of certrexant in Cohort 1 and 10 mg of certrexant (dose-normalized to 20 mg) in Cohort 3.

[0245] [Table 9] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0246] Based on the GMR of unbound certrexant, dose-normalized moderate hepatic impairment C max,unbound AUC last,unbound , and AUC∞ ,unbound These values ​​were approximately 2.48 times, 2.65 times, and 2.67 times higher, respectively, compared to normal liver function. %CV was calculated as Cmax, 54.8% for unbound, and AUC(AUC) last,unbound and AUC∞ ,unboundThe rates for unbound certrexant were 40.7% and 40.6% for dose-normalized moderate hepatic impairment versus normal hepatic function. max,unbound AUC last,unbound , and AUC∞ ,unbound The point estimate ratios (90% CI) for each were 247.61% (159.29%~384.93%), 264.95% (189.14%~371.13%), and 266.96% (190.71%~373.68%), respectively.

[0247] Pharmacokinetics of M12 Figure 5a shows the linear mean plasma concentration-time profiles of M12 after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3. Figure 5b shows the data from Figure 5a on a semi-logarithmic scale. As shown in Figures 1a and 1b, the mean plasma concentration-time profiles of M12 after a single oral administration of 20 mg of certrexant (normal liver function and mild hepatic impairment) or 10 mg of certrexant (moderate hepatic impairment) were t max After reaching that point, it decreased exponentially.

[0248] For all cohorts, unbound plasma concentrations were derived using the 2-hour fraction unbound values, and these unbound concentrations were used to derive unbound PK parameters. The mean fraction unbound values ​​of M12 at 2 hours for normal liver function, mild hepatic impairment, and moderate hepatic impairment were 5.45%, 7.07%, and 11.4%, respectively. Figure 6a shows the linear mean plasma concentration-time profiles of unbound M12 after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3. Figure 6b shows the data from Figure 6a on a semi-logarithmic scale. After a single oral administration of 20 mg of certrexant (normal liver function and mild hepatic impairment) or 10 mg of certrexant (moderate hepatic impairment), the mean plasma concentration-time profiles of unbound M12 were t max After reaching that point, it decreased exponentially.

[0249] Table 10 presents a summary list of the primary PK parameters of M12 for all cohorts, including dose-normalized PK parameters.

[0250] [Table 10] Note: Dose normalized to 20 mg for Cohort 3.

[0251] Mean M12PK parameter C for mild liver damage max AUC last , and AUC∞ was 368 ng / mL, 4833h * ng / mL, and 4857h * The values ​​are ng / mL. Normal liver function is 336 ng / mL and 2689 h, respectively. * ng / mL, and 2703h * The value is ng / mL. Mean PK parameter C for mild liver damage. max They were equivalent, but the AUC of M12 last Both AUC∞ and elimination half-life were 1.80 times higher compared to normal liver function. t1 / 2 ) and median t max These were 3.44 hours, 4.99 hours, and 2.00 hours and 5.00 hours, respectively.

[0252] Participants in Cohort 3 (moderate hepatic impairment) received a lower dose of 10 mg of certrexant, and therefore, their PK parameters were dose-normalized to 20 mg so that they could be compared to the group with normal liver function (Cohort 1). Mean M12 PK parameter C for moderate hepatic impairment. max AUC last , and AUC∞ were 131 ng / mL and 1277 h, respectively. * ng / mL, and 1292h * The value is ng / mL. Mean PK parameter C for dose-normalized moderate hepatic impairment. max The AUC of M12 was 0.78 times, but last and AUC∞ (261 ng / mL, 2553 h, respectively) * ng / mL, and 2584h* ng / mL) indicates normal liver function (C max AUC last The values ​​for , and AUC∞ were 336 ng / mL and 2689 h, respectively. * ng / mL, and 2703h * This was comparable to (ng / mL). The elimination half-life (t) was observed in individuals with normal liver function and moderate liver impairment. 1 / 2 ) and median t max These were 3.44 hours, 4.07 hours, and 2.00 hours and 2.25 hours, respectively.

[0253] Table 11 shows the plasma protein binding of M12 to α-1-AGP, total protein, and albumin per cohort in participants with varying degrees of liver function at 2 hours on day 1.

[0254] [Table 11]

[0255] Albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, and α-1-AGP and M12PK parameters (C max AUC last The relationship between , and AUC∞) is expressed using the M12PK parameter (C) as the dependent variable. max AUC last AUC∞ was evaluated by fitting a linear regression model using albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, or α-1-AGP as linear predictors (using baseline values). last The slopes of the regression lines for and AUC∞ were found to be statistically significant for α-1-AGP (p values ​​were 0.0491 and 0.0489, respectively), C max The results were found to be statistically significant for both total protein and α-1-AGP (p-values ​​were 0.0038 and 0.0011, respectively).

[0256] Figure 7a shows the M12 C levels in relation to total protein levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. max A scatter plot is shown. Figure 7b shows the M12 C levels in response to oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. max The scatter plot is shown. Figure 7c shows the M12 AUC of α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last The scatter plots are shown. Figure 7d shows the scatter plots of M12 AUC∞ against α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3.

[0257] Table 12 presents a summary list of the primary PK parameters of unbound M12 for all cohorts, including dose-normalized PK parameters.

[0258] [Table 12] Note: Dose normalized to 20 mg for Cohort 3.

[0259] Mean PK parameter C for mild liver damage max,unbound AUC last,unbound , and AUC∞ ,unbound The concentration was 24.4 ng / mL, 268h * ng / mL, and 270h * The values ​​are ng / mL. Normal liver function is 16.7 ng / mL and 123h, respectively. * ng / mL, and 123h * The value is ng / mL. Unbound M12 C max,unbound AUC last,unbound , and AUC∞ ,unboundThe mean PK parameters in patients with mild liver impairment were 1.46 times, 2.18 times, and 2.20 times higher, respectively, compared to patients with normal liver function.

[0260] Participants in Cohort 3 (moderate hepatic impairment) received a lower dose of 10 mg of certrexant, and therefore, their PK parameters were dose-normalized to 20 mg so that they could be compared to the group with normal liver function (Cohort 1). Mean PK parameter C for moderate hepatic impairment max,unbound AUC last,unbound , and AUC∞ ,unbound These values ​​are 14.2 ng / mL and 134h, respectively. * ng / mL, and 136h * The value is ng / mL. The mean PK parameter C is C, which is dose-normalized for unbound M12 with moderate hepatic impairment. max,unbound AUC last,unbound , and AUC∞ ,unbound (28.5 ng / mL, 268h respectively) * ng / mL, and 271h * ng / mL) indicates normal liver function (C max,unbound AUC last,unbound , and AUC∞ ,unbound These values ​​are 16.7 ng / mL and 123h respectively. * ng / mL, and 123h * Compared to ng / mL, these values ​​were 1.71 times, 2.18 times, and 2.20 times higher, respectively.

[0261] Albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, and α-1-AGP, and unbound M12PK parameters. Cmax,unbound AUC last,unbound , and AUC∞ ,unbound The relationship between () and the unjointed M12PK parameter (C) is used as the dependent variable. max,unbound AUC last,unbound , and AUC∞ ,unbound AUC was evaluated by fitting a linear regression model using albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, or α-1-AGP as linear predictors (using baseline values).last,unbound and AUC∞ ,unbound The slopes of the regression lines were found to be statistically significant for ALP and α-1-AGP (p values ​​were 0.0165, 0.0248, 0.0163, and 0.0238, respectively), C max,unbound The results were found to be statistically significant for both prothrombin time and α-1-AGP (p-values ​​were 0.0154 and 0.0014, respectively).

[0262] Figure 8a shows the response of unbound M12 C to prothrombin time after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. max,unbound The scatter plot is shown. Figure 8b shows the unbound M12 C levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. max,unbound The scatter plot is shown. Figure 8c shows the unbound M12 AUC against ALP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last,unbound The scatter plot is shown. Figure 8d shows the unbound M12 AUC relative to α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last,unbound The scatter plot is shown. Figure 8e shows the unbound M12 AUC∞ of ALP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. ,unbound The scatter plot is shown. Figure 8f shows the unbound M12 AUC C∞ of α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. ,unbound The scatter plot is shown below.

[0263] Table 13 presents a summary of the statistical results for M12 regarding mild liver impairment versus normal liver function. In particular, Table 13 shows summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of the M12 exposure parameter after oral administration of 20 mg of certrexant in Cohort 1 and Cohort 2.

[0264] [Table 13] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0265] Based on the GMR of M12, mild liver damage C max and AUC(AUC last %CV (and AUC∞) were approximately 1.11 times and 1.71 times higher, respectively, compared to normal liver function. max Regarding this, 31.3%, AUC(AUC last The percentages for M12 (and AUC∞) were 60.0% and 59.8%, respectively. max AUC last The point estimate ratios (90% CI) for , and AUC∞ were 111.23% (85.48%~144.72%), 171.17% (106.25%~275.75%), and 171.38% (106.50%~275.79%), respectively.

[0266] Participants in Cohort 3 received a lower dose of 10 mg of certrexant, and therefore, the PK parameters were dose-normalized to 20 mg so that they could be compared to those with normal liver function (Cohort 1). A summary of the statistical results for M12 for dose-normalized moderate hepatic impairment versus normal liver function is presented in Table 14. In particular, Table 14 provides summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of the M12 exposure parameters after oral administration of 20 mg of certrexant in Cohort 1 and 10 mg of certrexant at the 20 mg normalized Cohort 3 dose.

[0267] [Table 14] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0268] Based on the GMR of M12, dose-normalized moderate hepatic impairment C max While the ratio is 0.79, the AUC last AUC∞ and %CV were approximately 1.03 times and 1.04 times higher, respectively, compared to normal liver function. max Regarding this, 31.3%, AUC(AUC last The percentages for M12 (and AUC∞) were 60.0% and 59.8%. max AUC last The point estimate ratios (90% CI) for , and AUC∞ were 79.13% (60.82%~102.96%), 102.84% (63.84%~165.67%), and 103.51% (64.32%~166.56%), respectively.

[0269] Table 15 presents a summary of the statistical results for unbound M12 in mild hepatic impairment versus normal hepatic function. In particular, Table 15 shows summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of the unbound M12 exposure parameter after oral administration of 20 mg of certrexant in Cohort 1 and Cohort 2.

[0270] [Table 15] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0271] Based on GMR of unbound M12, mild liver damage C max,unbound AUC last,unbound , and AUC∞ ,unbound These values ​​were approximately 1.29 times, 1.98 times, and 1.99 times higher, respectively, compared to normal liver function. %CV is C max,unbound Regarding 40.0%, AUC(AUC last,unbound and AUC∞ ,unbound The percentages for ) were 43.6% and 43.3%. C of unbound M12 for mild liver damage versus normal liver function. max,unbound AUC last,unbound , and AUC∞ ,unbound The point estimate ratios (90% CI) for each were 128.83% (92.51%~179.42%), 198.26% (138.46%~283.90%), and 198.51% (139.01%~283.48%), respectively.

[0272] Table 16 presents a summary of the statistical results for unbound M12 in dose-normalized moderate hepatic impairment versus normal hepatic function. In particular, Table 16 provides summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of the unbound M12 exposure parameter after oral administration of 20 mg of certrexant in Cohort 1 and 10 mg of certrexant (dose-normalized to 20 mg) in Cohort 3.

[0273] [Table 16] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0274] Based on the GMR of unbound M12, dose-normalized moderate hepatic impairment C max,unbound AUC last,unbound , and AUC∞ ,unbound These values ​​were approximately 1.68 times, 2.19 times, and 2.20 times higher, respectively, compared to normal liver function. max,unbound AUC last,unbound , and AUC∞ ,unbound The %CVs were 40.0%, 43.6%, and 43.3%, respectively. C of unbound M12 for dose-normalized moderate hepatic impairment versus normal hepatic function. max,unbound AUC last,unbound , and AUC∞ ,unbound The point estimate ratios (90% CI) for each were 168.44% (120.95%~234.58%), 218.90% (152.87%~313.46%), and 220.33% (154.29%~314.63%), respectively.

[0275] Pharmacokinetics of M16 Figure 9a shows the linear mean plasma concentration-time profiles of M16 after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3. Figure 9b shows the data from Figure 9b on a semi-logarithmic scale. As shown in Figures 9a and 9b, after a single oral administration of 20 mg of certrexant (normal liver function and mild hepatic impairment) or 10 mg of certrexant (moderate hepatic impairment), the mean plasma concentration-time profile of certrexant was t max After reaching that point, it decreased exponentially.

[0276] For all cohorts, unbound plasma concentrations were derived using the 2-hour fraction unbound values, and these unbound concentrations were used to derive unbound PK parameters. The mean fraction unbound values ​​of M16 at 2 hours for normal liver function, mild hepatic impairment, and moderate hepatic impairment were 4.0%, 5.68%, and 9.01%, respectively. Figure 10a shows the linear mean plasma concentration-time profiles of unbound M16 after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant in cohort 3. Figure 10a shows the data from Figure 10b on a semi-logarithmic scale. After a single oral administration of 20 mg of certrexant (normal liver function and mild hepatic impairment) or 10 mg of certrexant (moderate hepatic impairment), the mean plasma concentration-time profiles of unbound M16 were t max After reaching that point, it decreased exponentially.

[0277] Table 17 presents a summary list of the primary PK parameters of M16 for all cohorts, including dose-normalized PK parameters.

[0278] [Table 17] Note: Dose normalized to 20 mg for Cohort 3.

[0279] Mean M16PK parameter C for mild liver damage max AUC last, and AUC∞ was 51.5 ng / mL, 827h * ng / mL, and 851h * The values ​​are ng / mL, and for normal liver function, they are 69.0 ng / mL and 885h, respectively. * ng / mL, and 924h * The value is ng / mL. Mean PK parameter C for mild liver damage. max It was 0.75 times, but the AUC of M16 last And AUC∞ was comparable to that of normal liver function. Normal liver function, mild liver impairment: elimination half-life (t 1 / 2 ) and median t max These were 13.4 hours, 10.2 hours, and 2.00 hours and 4.00 hours, respectively.

[0280] Participants in Cohort 3 (moderate hepatic impairment) received a lower dose of 10 mg of certrexant, and therefore, the PK parameters were dose-normalized to 20 mg so that they could be compared to those with normal liver function (Cohort 1). Mean M16 PK parameter C for moderate hepatic impairment. max AUC last The values ​​for , and AUC∞ were 21.5 ng / mL and 315 h, respectively. * ng / mL, and 342h * The value is ng / mL. The mean PK parameter C for dose-normalized moderate hepatic impairment in M16. max AUC last , and AUC∞ (43.0 ng / mL, 631h respectively) * ng / mL, and 683h * ng / mL) indicates normal liver function (C max AUC last The values ​​for , and AUC∞ were 69.0 ng / mL and 885h, respectively. * ng / mL, and 924h * Compared to (ng / mL), the levels were 0.62 times, 0.71 times, and 0.74 times. The elimination half-life (t) in individuals with normal liver function and moderate liver impairment was also observed. 1 / 2 ) and median t max These were 13.4 hours, 10.2 hours, and 2.00 hours and 2.50 hours, respectively.

[0281] Table 18 shows the plasma protein binding of M16 to α-1-AGP, total protein, and albumin per cohort in participants with varying degrees of liver function at 2 hours on day 1.

[0282] [Table 18]

[0283] Albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, and α-1-AGP and M16PK parameters (C max AUC last The relationship between , and AUC∞) is expressed using the M16PK parameter (C) as the dependent variable. max AUC last This was evaluated by fitting a linear regression model using albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, or α-1-AGP (using baseline values) as linear predictors. max AUC last The slopes of the regression lines for α-1-AGP and AUC∞ were found to be statistically significant (p values ​​were 0.0004, 0.0003, and 0.0003, respectively).

[0284] Figure 11a shows the M16 C response to α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. max The scatter plot is shown. Figure 11b shows the M16 AUC against α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. lastThe scatter plots are shown. Figure 11c shows the scatter plots of M16 AUC∞ against α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3.

[0285] Table 19 presents a summary list of the primary PK parameters of unbound M16 for all cohorts, including dose-normalized PK parameters.

[0286] [Table 19] Note: Dose normalized to 20 mg for Cohort 3.

[0287] Mean PK parameter C for mild liver damage max,unbound AUC last,unbound , and AUC∞ ,unbound The result was 2.77 ng / mL, 41.9 h * ng / mL, and 43.2h * The values ​​are ng / mL. Normal liver function is 2.55 ng / mL and 30.7 h, respectively. * ng / mL, and 31.9h * It is ng / mL. max,unbound The mean PK parameters for mild hepatic impairment were comparable, and the AUC of unbound M16 was similar. last,unbound and AUC∞ ,unbound These levels were 1.36 times and 1.35 times higher compared to normal liver function.

[0288] Participants in Cohort 3 (moderate hepatic impairment) received a lower dose of 10 mg of certrexant, and therefore, the PK parameters were dose-normalized to 20 mg so that they could be compared to those with normal liver function (Cohort 1). Mean PK parameter C for moderate hepatic impairment max,unbound AUC last,unbound , and AUC∞ ,unbound These values ​​are 2.01 ng / mL and 28.1 h, respectively. * ng / mL, and 30.4h *The value is ng / mL. The mean PK parameter C for dose-normalized moderate hepatic impairment of unbound M16. max,unbound AUC last,unbound , and AUC∞ ,unbound (4.02 ng / mL, 56.1 h, respectively) * ng / mL, and 60.8h * ng / mL) indicates normal liver function (C max,unbound AUC last,unbound , and AUC∞ ,unbound These values ​​are 2.55 ng / mL and 30.7 h, respectively. * ng / mL, and 31.9h * Compared to ng / mL, the levels were 1.58 times, 1.83 times, and 1.91 times higher.

[0289] Albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, and α-1-AGP, and unbound M16PK parameters. Cmax,unbound AUC last,unbound , and AUC∞ ,unbound The relationship between () and the unjointed M16PK parameter (C) is used as the dependent variable. max,unbound AUC last,unbound , and AUC∞ ,unbound AUC was evaluated by fitting a linear regression model using albumin, bilirubin, prothrombin time, ALP, ALT, AST, total protein, or α-1-AGP as linear predictors (using baseline values). last,unbound and AUC∞ ,unbound The slopes of the regression lines were found to be statistically significant for albumin, prothrombin time, and α-1-AGP (p values ​​were 0.0465, 0.0190, 0.0041, and 0.0295, 0.0158, and 0.0026, respectively), C max,unbound The results were found to be statistically significant for both prothrombin time and α-1-AGP (p-values ​​were 0.0169 and 0.0077, respectively).

[0290] Figure 12a shows the response of unbound M16 C to prothrombin time after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. max,unbound The scatter plot is shown. Figure 12b shows the relationship between unbound M16 C and α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. max,unbound The scatter plot is shown. Figure 12c shows the unbound M16 AUC against albumin levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last,unbound The scatter plot is shown. Figure 12d shows the unbound M16 AUC as a function of prothrombin time after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last,unbound The scatter plot is shown. Figure 12e shows the unbound M16 AUC C of α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last,unbound The scatter plot is shown. Figure 12f shows the unbound M16 AUC against albumin levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. last,unbound The scatter plot is shown. Figure 12g shows the unbound M16 AUC∞ as a function of prothrombin time after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. ,unbound The scatter plot is shown. Figure 12h shows the unbound M16 AUC C∞ of α-1-AGP levels after oral administration of 20 mg of certrexant in cohorts 1 and 2, and 10 mg of certrexant (dose-normalized to 20 mg) in cohort 3. ,unboundThe scatter plot is shown below.

[0291] Table 20 presents a summary of the statistical results for M16 regarding mild liver impairment versus normal liver function. In particular, Table 20 shows summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of M16 exposure parameters after oral administration of 20 mg of certrexant in Cohort 1 and Cohort 2.

[0292] [Table 20] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0293] Based on the GMR of M16, mild liver impairment C max AUC last , and AUC∞ were approximately 0.77 times, 1.01 times, and 0.99 times, respectively, compared to normal liver function. %CV is C max Regarding this, 32.2%, AUC(AUC last The percentages for C16 (and AUC∞) are 38.9% and 38.2%, respectively. max AUC last The point estimate ratios (90% CI) for , and AUC∞ were 77.40% (59.08%~101.39%), 100.62% (72.87%~138.94%), and 99.38% (72.35%~136.51%), respectively.

[0294] Participants in Cohort 3 received a lower dose of 10 mg of certrexant, and therefore, the PK parameters were dose-normalized to 20 mg so that they could be compared to those with normal liver function (Cohort 1). A summary of the M16 statistical results for dose-normalized moderate hepatic impairment versus normal liver function is presented in Table 21.

[0295] [Table 21] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0296] Based on the GMR of M16, dose-normalized moderate hepatic impairment C max AUC last , and AUC∞ were approximately 0.65 times, 0.80 times, and 0.83 times, respectively, compared to normal liver function. %CV is C max Regarding this, 32.2%, AUC(AUC last The percentages for C16 (and AUC∞) are 38.9% and 38.2%, respectively. max AUC last The point estimate ratios (90% CI) for , and AUC∞ were 64.69% (49.38%~84.74%), 79.68% (57.71%~110.03%), and 83.00% (60.42%~114.01%), respectively.

[0297] Table 22 presents a summary of the statistical results for unbound M16 in mild hepatic impairment versus normal hepatic function. In particular, Table 22 provides summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of the unbound M16 exposure parameter after oral administration of 20 mg of certrexant in Cohort 1 and Cohort 2.

[0298] [Table 22] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0299] Based on GMR of unbound M16, mild liver damage C max,unbound This is 0.96 times compared to normal liver function, and AUC last,unbound and AUC∞ ,unbound These were approximately 1.25 times and 1.23 times higher, respectively. %CV is C max,unbound Regarding 56.6%, AUC(AUC last,unbound and AUC∞ ,unbound The percentages for ) were 46.5% and 45.9%. C of unbound M16 for mild liver damage versus normal liver function. max,unbound AUC last,unbound , and AUC∞ ,unbound The point estimate ratios (90% CI) for each were 96.12% (61.06%~151.31%), 124.96% (85.37%~182.90%), and 123.42% (84.74%~179.76%), respectively.

[0300] Table 23 presents a summary of the statistical results for unbound M16 for dose-normalized moderate hepatic impairment versus normal hepatic function. In particular, Table 23 provides summarized statistical results for the estimated geometric mean ratios and 90% confidence intervals of the unbound M16 exposure parameter after oral administration of 20 mg of certrexant in Cohort 1 and 10 mg of certrexant (dose-normalized to 20 mg) in Cohort 3.

[0301] [Table 23] N = 8 participants per cohort Note: The log-transformed PK parameters were analyzed using an analysis of variance (ANOVA) model of the cohort as a factor, and the results were inversely transformed using the inverse logarithm. N: This includes the number of participants who completed at least one treatment and were able to obtain evaluable PK parameters. %CV=100 * (sqrt(exp(MSE)-1).

[0302] Based on the GMR of unbound M16, dose-normalized moderate hepatic impairment C max,unbound AUC last,unbound , and AUC∞ ,unbound These values ​​were approximately 1.48 times, 1.82 times, and 1.90 times higher, respectively, compared to normal liver function. max,unbound AUC last,unbound , and AUC∞ ,unbound The %CVs were 56.6%, 46.5%, and 45.9%, respectively. C of unbound M16 for dose-normalized moderate hepatic impairment versus normal hepatic function. max,unbound AUC last,unbound , and AUC∞ ,unbound The point estimate ratios (90% CI) for each were 148.13% (94.10%~233.18%), 182.46% (124.66%~267.08%), and 190.05% (130.49%~276.81%), respectively.

[0303] The specific embodiments disclosed herein are intended to illustrate some aspects of the invention, and the invention described and claimed herein is not limited in scope by these embodiments. Any equivalent embodiments are intended to fall within the scope of the invention. Indeed, various modifications of the invention, in addition to those illustrated and described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All publications cited herein are incorporated in their entirety by reference.

Claims

1. A method for treating orexin-2 mediated disorder in a human subject requiring treatment for orexin-2 mediated disorder, wherein the subject has moderate hepatic impairment, and the method is A method comprising administering certrexant or a pharmaceutically acceptable salt or hydrate thereof at a reduced dose less than the therapeutically effective daily dose suitable for treatment in humans with normal liver function.

2. A method for treating orexin-2 mediated disorder in human subjects requiring treatment for orexin-2 mediated disorder, If the subject has moderate hepatic impairment, administer certrexant or a pharmaceutically acceptable salt or hydrate thereof at a reduced dose less than the therapeutically effective daily dose suitable for human subjects with normal liver function. If the subject has severe liver impairment, do not administer certrexant or its pharmaceutically acceptable salt or hydrate to the subject. A method comprising administering certrexant or a pharmaceutically acceptable salt or hydrate thereof to the subject in the daily dose, provided that the subject does not have moderate to severe liver impairment.

3. The method according to claim 1 or 2, wherein the subject having moderate liver impairment has a Child's Puer score of 7 to 9.

4. The method according to any one of claims 1 to 3, wherein certrexant is administered as a free base.

5. The method according to any one of claims 1 to 3, wherein certrexant hydrochloride is administered.

6. The method according to any one of claims 1 to 5, wherein the orexin-2 mediated disorder is depression or insomnia.

7. The method according to claim 6, wherein the orexin-2 mediated disorder is depression.

8. The method according to claim 7, wherein the depression is major depressive disorder.

9. The method according to claim 7, wherein the depression is bipolar depression.

10. The method according to any one of claims 7 to 9, wherein the subject has concomitant symptoms of insomnia.

11. The method according to claim 10, wherein the subject has an ISI score of 15 or more.

12. The method according to claim 6, wherein the orexin-2 mediated disorder is insomnia.

13. The method according to any one of claims 1 to 12, wherein certrexant is administered orally.

14. The method according to claim 13, wherein the daily dose is approximately 20 mg / day to approximately 60 mg / day.

15. The method according to claim 14, wherein the reduced dose is approximately 5 mg / day to approximately 20 mg / day.

16. The method according to claim 15, wherein the reduced dose is approximately 20 mg / day.

17. The method according to claim 15, wherein the reduced dose is approximately 15 mg / day.

18. The method according to claim 15, wherein the reduced dose is approximately 10 mg / day.

19. The method according to claim 15, wherein the reduced dose is approximately 5 mg / day.

20. The method according to claim 14, wherein the daily dose is selected to provide an unbound mean plasma concentration of certrexant of about 0.75 ng / mL to about 1.5 ng / mL when administered to a human subject having normal liver function.

21. The method according to claim 20, wherein administration of certrexant or a pharmaceutically acceptable salt or hydrate thereof at the reduced dose to a subject having moderate hepatic impairment provides an effective therapeutic range of unbound mean plasma concentration of certrexant.

22. The method according to any one of claims 1 to 21, wherein the subject has an insufficient response to an antidepressant other than certrexant or a pharmaceutically acceptable salt or hydrate thereof.

23. The method according to claim 22, wherein the subject has an insufficient response to a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI).

24. The method according to any one of claims 1 to 23, wherein certrexant or a pharmaceutically acceptable salt or hydrate thereof is administered adjunctly with a second pharmaceutically active agent.

25. The method according to claim 24, wherein the second pharmaceutically active agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI).

26. The method according to claim 2, wherein the subject having mild liver impairment has a Child's Puer score of 5 to 6.

27. The method according to claim 2, wherein the subject having severe liver impairment has 10 or more Child's Puer scores.

28. The method according to any one of claims 1 to 3 or 6 to 27, wherein hydrate of certrexant hydrochloride is administered.

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