Composition and method for administering parzsotin to patients with liver dysfunction

Abstract

A composition and method are provided for administering parzsotin or a pharmaceutically acceptable salt thereof to patients with hepatic impairment.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 455,193, filed on 28 March 2023, which is incorporated herein by reference in its entirety.

[0002] A composition and method are provided for administering parzsotin or a pharmaceutically acceptable salt thereof to patients with hepatic impairment. [Background technology]

[0003] Somatostatin is a peptide hormone that modulates the endocrine system and influences neurotransmission and cell proliferation through interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Six subtypes of somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5), encoded by five different somatostatin receptor genes. Modulation of specific subtypes of somatostatin receptors or combinations thereof is attractive for the treatment of medical conditions, diseases, or disorders that would benefit from modulating somatostatin activity.

[0004] Despite the progress made in this field, there remains a need for novel therapeutic products useful for treating conditions, diseases, or disorders that would benefit from modulating somatostatin activity. One such drug is palzsotin, an SST2 agonist with the following chemical structure.

[0005] [ka]

[0006] Parzsotin is an orally administered non-peptide somatostatin agonist currently undergoing clinical trials for the treatment of acromegaly and carcinoid syndrome.

[0007] Liver damage is a condition in which the normal function of the liver is impaired. Liver damage can be acute, rapidly developing, or chronic. Chronic liver damage or cirrhosis can result from many causes, including excessive alcohol consumption, hepatitis, autoimmune diseases, genetic factors, or metabolic disorders, or it can be idiopathic. Liver damage is generally irreversible, and treatment consists of preventing progression and treating symptoms. In severe cases, liver transplantation is the only option. Liver damage may not present with significant symptoms, or it may be characterized by symptoms such as reduced blood clotting ability (coagulation disorders) and impaired brain function (encephalopathy), intraperitoneal fluid retention, increased risk of infection, hypogonadism, changes in liver size, jaundice, and increased sensitivity to drugs.

[0008] AUC and C12C of drugs and / or their metabolites in patients with hepatic impairment max , and t 1 / 2 Changes in systemic drug exposure, quantified by pharmacokinetic parameters such as these, can lead to numerous problems, including physician complexity in prescribing due to the need for dose adjustments, the need for liver function tests, the lack of availability of suitable doses and / or the lack of availability of certain drugs to patients with liver impairment, as well as unintentional overdoses.

[0009] A method for administering an SST2 agonist, such as parzsotin or a pharmaceutically acceptable salt thereof, to a patient in need, the patient having hepatic impairment, and having a significant, unmet need for the method. This disclosure satisfies these and other needs, which are evident by reference to the following disclosures. [Overview of the Initiative]

[0010] A method is provided for administering parzsotin or a pharmaceutically acceptable salt thereof to a patient, wherein the patient has liver impairment.

[0011] Also provided is a method of administering to a patient a therapeutically effective amount of palbociclib or a pharmaceutically acceptable salt thereof, wherein the patient has liver impairment and the therapeutically effective amount of palbociclib or a pharmaceutically acceptable salt thereof is the same amount as that administered to a patient without liver impairment.

[0012] Also provided is a method of administering to a patient a therapeutically effective amount of palbociclib or a pharmaceutically acceptable salt thereof, and then determining that the patient has liver impairment and administering to the patient the same therapeutically effective amount of palbociclib or a pharmaceutically acceptable salt thereof.

[0013] Also provided is a pharmaceutical composition for use in treating a patient with palbociclib, wherein the patient has liver impairment and the composition comprises palbociclib or a pharmaceutically acceptable salt thereof.

[0014] Also provided is a pharmaceutical composition for use in treating a patient with palbociclib, wherein the patient has liver impairment and the composition comprises a therapeutically effective amount of palbociclib or a pharmaceutically acceptable salt thereof and the composition comprises the same amount of palbociclib or a pharmaceutically acceptable salt thereof as that used for treating a patient without liver impairment with palbociclib.

[0015] Also included is the use of palbociclib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a patient with liver impairment.

[0016] Also included is palbociclib or a pharmaceutically acceptable salt thereof for use in a method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of palbociclib or a pharmaceutically acceptable salt thereof, then determining that the patient has liver impairment, and administering to the patient the same therapeutically effective amount of palbociclib or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] [Figure 1][14C] This shows parzsotin metabolites detected in human excretions after administration of parzsotin. [Figure 2] This shows an overview of the recovery percentages of parzsotin and its excreted metabolites in humans after oral administration of a single dose of [14C]parzsotin. [Figure 3A] Figure 3A shows the mean plasma concentration of parzsotin versus time in patients with mild hepatic impairment. [Figure 3B] Figure 3B shows the mean plasma concentration of parzsotin versus time for patients with moderate hepatic impairment. [Figure 3C] Figure 3C shows the mean plasma concentration of parzsotin versus time for patients with severe hepatic impairment. [Figure 3D] Figure 3D shows the mean plasma concentration of parzsotin versus time for patients, and for patients without liver impairment (i.e., normal patients). [Figure 4] The graphs show the mean plasma concentration of parzsotin versus time for patients. (A) shows the mean plasma concentration of parzsotin versus time for patients with mild hepatic impairment, (B) shows the mean plasma concentration of parzsotin versus time for patients with moderate hepatic impairment, (C) shows the mean plasma concentration of parzsotin versus time for patients with severe hepatic impairment, and (D) shows the mean plasma concentration of parzsotin versus time for patients without hepatic impairment (i.e., normal patients). [Figure 5] The box plots of AUC0-t for each liver function group are shown. [Figure 6] The box plots for AUC0-∞ for each liver function group are shown. [Figure 7] The box plots for Cmax for each liver function group are shown. [Modes for carrying out the invention]

[0018] The following description includes specific details to provide a complete understanding of various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other examples, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of embodiments. Unless the context requires otherwise, the word “comprise” and its variations, e.g., “comprises” and “comprising,” throughout this specification and the following claims should be interpreted in an open, comprehensive sense, i.e., “includes but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute an interpretation of the scope or meaning of the claimed invention.

[0019] Throughout this specification, any reference to “one embodiment,” “an embodiment,” “several embodiments,” or “a particular embodiment” means that a particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment. Therefore, the occurrence of the phrases “in one embodiment,” “in an embodiment,” “in several embodiments,” or “in a particular embodiment” in various places throughout this specification does not necessarily refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any preferred manner in one or more embodiments.

[0020] Furthermore, as used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context clearly indicates otherwise.

[0021] As used herein, “Partzsotin” may be referred to as partzsotin free base, partzsotin HCl, 3-[4-(4-amino-1-piperidyl)-3-(3,5-difluorophenyl)-6-quinolyl]-2-hydroxybenzonitrile, 3-[4-(4-amino-1-piperidyl)-3-(3,5-difluorophenyl)-6-quinolyl]-2-hydroxybenzonitrile hydrochloride, 3-[4-(4-amino-1-piperidyl)-3-(3,5-difluorophenyl)-6-quinolyl]-2-hydroxybenzonitrile monohydrochloride, and 3-[4-(4-amino-1-piperidyl)-3-(3,5-difluorophenyl)-6-quinolyl]-2-hydroxybenzonitrile dihydrochloride. Additional parzsotin salts are disclosed in U.S. Patent Publication No. 2022 / 0267295, which are incorporated by reference in their entirety.

[0022] As used herein, “liver impairment” means impaired liver function.

[0023] As used herein, the Childpugh score is a score based on five clinical measures of liver impairment, including bilirubin, serum albumin, prothrombin time international normalized ratio (PT INR), ascites, and hepatic encephalopathy levels. Each measure is assigned a rank of 1, 2, or 3, and the sum of the five ranks is the Childpugh score. The Childpugh score can be used to classify liver impairment by placing subjects in the Childpugh group.

[0024] As used herein, “mild liver impairment” refers to a liver impairment rank level based on a Childpues score of 5–6.

[0025] As used herein, “moderate hepatic impairment” refers to a rank level of hepatic impairment based on a Childpues score of 7–9.

[0026] As used herein, “severe hepatic impairment” refers to a rank level of hepatic impairment based on a Childpues score of 10–15.

[0027] As used herein, "about" means ±10% of the recited value, and more specifically includes values of ±5%, ±2%, and ±1% of the recited value.

[0028] As used herein, "AUC" refers to the curve or area under the curve of the plasma concentration of paroxetine or a pharmaceutically acceptable salt thereof over time after a dosing event.

[0029] As used herein, "AUC 0-t " refers to the area under the curve of the plasma concentration of paroxetine or a pharmaceutically acceptable salt thereof with respect to the time from 0 to the last quantifiable concentration.

[0030] As used herein, "AUC 0-24 " refers to the area under the curve of the plasma concentration of paroxetine or a pharmaceutically acceptable salt thereof with respect to the time extrapolated from 0 to 24 hours.

[0031] As used herein, "AUC 0-∞ " or "AUC 0-inf " refers to the area under the curve of the plasma concentration of paroxetine or a pharmaceutically acceptable salt thereof with respect to the time from 0 to infinity.

[0032] As used herein, "C[[ID=3l]] max " is a pharmacokinetic parameter indicating the maximum plasma concentration observed after the delivery of paroxetine or a pharmaceutically acceptable salt thereof.

[0033] As used herein, "t max " refers to the time to C max after the delivery of paroxetine or a pharmaceutically acceptable salt thereof.

[0034] As used herein, "t lag " refers to the time delay between the administration time of paroxetine or a pharmaceutically acceptable salt thereof and the appearance time of the measurable test substance.

[0035] When used herein, "t 1 / 2 "Plasma half-life" or "elimination half-life" refers to the apparent terminal phase half-life of parzsotin or its pharmaceutically acceptable salt after delivery.

[0036] As used herein, “MRT” refers to the apparent mean residence time of parzsotin or its pharmaceutically acceptable salt.

[0037] As used herein, "CL / F" refers to the apparent systemic clearance of parzsotin or a pharmaceutically acceptable salt thereof.

[0038] When used herein, "V z " / F" refers to the apparent distribution volume of parzsotin or its pharmaceutically acceptable salt.

[0039] When used herein, "λ z This refers to the apparent terminal rate constant.

[0040] As used herein, "BMI" refers to a patient's body size index.

[0041] As used herein, "ECG" refers to an electrocardiogram.

[0042] As used herein, "QTcF" refers to the QT interval corrected using the Fridericia formula.

[0043] As used herein, "IGF-1" refers to insulin-like growth factor 1.

[0044] As used herein, "AE" refers to an adverse event, and "TEAE" refers to an adverse event under investigational treatment.

[0045] As used herein, "PK" refers to pharmacokinetics, and "PD" refers to pharmacodynamics.

[0046] As used herein, "GH" refers to growth hormone.

[0047] As used herein, “administering to a patient” means the process of introducing a composition or dosage form to a patient via means of introduction recognized in the art.

[0048] As used herein, “adjusting the dosage,” “changing the dosage,” “adjusting the medication,” or “changing the medication” are all synonymous and mean gradually reducing, decreasing, or increasing the dose of a substance, or discontinuing the administration of a substance to a patient.

[0049] As used herein, the term “disorder” is intended to be used interchangeably with the terms “disease,” “syndrome,” and “condition” (as in medical conditions), all in that they reflect an abnormal medical condition of the body or part thereof of a human or animal that impairs normal function, and are typically expressed by distinguishing between signs and symptoms.

[0050] As used herein, “dose” means the measured amount of the activator taken by a patient at one time. In certain embodiments where the activator is not parzsotin free base, the amount is the molar equivalent of the corresponding amount of parzsotin free base. For example, drugs are often packaged in a pharmaceutically acceptable salt form, e.g., parzsotin monohydrochloride, and the dosage strength refers to the mass of the molar equivalent of parzsotin, which is the corresponding free base. As an example, 21.6 mg of parzsotin monohydrochloride is the molar equivalent of 20 mg of parzsotin free base.

[0051] As used herein, “effective dose” and “therapeutic dose” of a drug, compound, medicine, or composition are amounts that are non-toxic and effective in producing several desired therapeutic effects when administered to a subject or patient (e.g., a human subject or patient). The exact therapeutic dose for a subject may depend, for example, on the size and health of the subject, the nature and severity of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those skilled in the art. The effective dose for a given situation is determined by ordinary experimentation and is within the scope of clinician judgment.

[0052] As used herein, “patient,” “individual,” or “subject” means a mammal, including humans, in which therapy is desired, and generally refers to the recipient of therapy.

[0053] As used herein, “pharmaceutically acceptable” means a material that is biologically or otherwise undesirable, i.e., a material that can be incorporated into a pharmaceutical composition for a patient without causing an undesirable biological effect or without interacting in a harmful manner with any of the other components of the composition containing it. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutically acceptable carrier or excipient, it is implied that the carrier or excipient meets the necessary standards of toxicity and manufacturing testing, or that it is included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration. “Pharmacologically active” (or “active”) derivative or analogue means a derivative or analogue that has the same type and degree of pharmacological activity as the parent compound. The term “pharmaceutically acceptable salt” includes acid addition salts formed with a suitable inorganic acid, inorganic base, or organic base.

[0054] As used herein, “risk” means the probability or opportunity of an adverse reaction, injury, or other undesirable outcome arising from a medical procedure. “Acceptable risk” means the measure of the risk of harm, injury, or disease arising from a medical procedure that is acceptable to an individual or group. Whether a risk is “acceptable” depends on the benefits that the individual or group perceives to be obtainable in exchange for taking the risk, whether they accept the scientific and other advice provided about the magnitude of the risk, and many other factors, both political and social. “Acceptable risk” of an adverse reaction means that the probability of the adverse reaction occurring is small, or the consequences are very minor, or the benefits (perceived or actual) of the activator are very large, so that an individual or group in society is willing to take on or accept the risk of an adverse reaction. “Unacceptable risk” of an adverse reaction means that an individual or group in society, after weighing the likelihood of an adverse reaction occurring, the consequences of the adverse reaction, and the benefits (perceived or actual) of the activator, is unwilling to take on or accept the risk of an adverse reaction. "Being at risk" means being in a condition or illness characterized by a high level of risk or susceptibility. Risk assessment involves identifying and characterizing the nature, frequency, and severity of risks associated with the use of a product.

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

[0056] As used herein, “to treat” or “treatment” refers to a therapeutic use for the purpose of slowing or stopping the progression of a disorder and / or alleviating its symptoms.

[0057] Treatment method A method is provided for administering parzsotin or a pharmaceutically acceptable salt thereof to a patient, wherein the patient has liver impairment, and the method includes administering parzsotin free base or a pharmaceutically acceptable salt thereof to the patient.

[0058] In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective dose.

[0059] Furthermore, a method is provided for administering parzsotin or a pharmaceutically acceptable salt thereof to a patient, wherein the patient has liver impairment, and the therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof is administered to the patient having liver impairment, wherein the therapeutically effective dose is the same as the dose administered to a patient without liver impairment.

[0060] Also provided is a method for administering parzsotin or a pharmaceutically acceptable salt thereof to a patient, comprising: administering a therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof to the patient; subsequently determining that the patient has liver impairment; and administering the same therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof.

[0061] In certain embodiments, patients with hepatic impairment are exposed to an amount of parzsotin free base equivalent to that in patients with normal liver function who are administered the same amount of parzsotin or a pharmaceutically acceptable salt thereof.

[0062] In certain embodiments, the patient has mild, moderate, or severe liver impairment.

[0063] In certain embodiments, the patient has a ChildPull score of 5-6, 7-9, or 10-15.

[0064] In certain embodiments, the patient has mild liver impairment.

[0065] In certain embodiments, the patient has a ChildPull score of 5-6.

[0066] In certain embodiments, the patient has moderate liver impairment.

[0067] In certain embodiments, the patient has a ChildPull score of 7 to 9.

[0068] In certain embodiments, the patient has severe liver impairment.

[0069] In certain embodiments, the patient has a ChildPue score of 10 to 15.

[0070] In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 10 mg to about 120 mg of parzsotin free base. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg to about 120 mg of parzsotin free base. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg to about 60 mg of parzsotin free base.

[0071] In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in amounts equivalent to about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg of parzsotin free base.

[0072] In certain embodiments, the patient has acromegaly, carcinoid syndrome, and / or neuroendocrine tumors (NETs).

[0073] In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered to a patient to treat acromegaly, carcinoid syndrome, and / or NETs.

[0074] In certain embodiments, the patient has acromegaly.

[0075] In certain embodiments, the patient has acromegaly, and parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg to about 60 mg of parzsotin free base. In certain embodiments, the patient has acromegaly, and parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg of parzsotin free base. In certain embodiments, the patient has acromegaly, and parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 60 mg of parzsotin free base.

[0076] In certain embodiments, the patient has acromegaly, and to treat the acromegaly, the patient is administered parzsotin or a pharmaceutically acceptable salt thereof.

[0077] In certain embodiments, the patient has carcinoid syndrome and / or NET. In certain embodiments, the patient has carcinoid syndrome.

[0078] In certain embodiments, the patient has carcinoid syndrome and / or NET, and parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg to about 120 mg of parzsotin free base. In certain embodiments, the patient has carcinoid syndrome and / or NET, and parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg of parzsotin free base. In certain embodiments, the patient has carcinoid syndrome and / or NET, and parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 60 mg of parzsotin free base. In certain embodiments, the patient has carcinoid syndrome and / or NET, and parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg of parzsotin free base. In certain embodiments, the patient has carcinoid syndrome and / or NET, and parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 100 mg of parzsotin free base. In certain embodiments, the patient has carcinoid syndrome and / or NET, and parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 120 mg of parzsotin free base.

[0079] In certain embodiments, the patient has carcinoid syndrome and / or NET, and parzsotin or a pharmaceutically acceptable salt thereof is administered to the patient to treat the carcinoid syndrome and / or NET.

[0080] In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in one or more dosage forms. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in two or more dosage forms. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in three or more dosage forms. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in four or more dosage forms. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in five or more dosage forms.

[0081] In certain embodiments, the dosage form contains an amount of parzsotin equivalent to about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, or about 80 mg of parzsotin free base. In certain embodiments, the dosage form contains an amount of parzsotin equivalent to about 20 mg of parzsotin free base. In certain embodiments, the dosage form contains an amount of parzsotin equivalent to about 30 mg of parzsotin free base. In certain embodiments, the dosage form contains an amount of parzsotin equivalent to about 40 mg of parzsotin free base. In certain embodiments, the dosage form contains an amount of parzsotin equivalent to about 50 mg of parzsotin free base. In certain embodiments, the dosage form contains an amount of parzsotin equivalent to about 60 mg of parzsotin free base. In certain embodiments, the dosage form contains an amount of parzsotin equivalent to about 80 mg of parzsotin free base.

[0082] In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in one dosage form containing an amount of parzsotin equivalent to about 40 mg, about 60 mg, or about 80 mg of parzsotin free base. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in two dosage forms, each dosage form containing an amount of parzsotin equivalent to about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of parzsotin free base. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in three dosage forms, each dosage form containing an amount of parzsotin equivalent to about 20 mg or about 40 mg of parzsotin free base. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in four dosage forms, each dosage form containing an amount of parzsotin equivalent to about 20 mg or about 30 mg of parzsotin free base. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in five dosage forms, each dosage form containing an amount of parzsotin equivalent to about 20 mg of parzsotin free base. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered in six dosage forms, each dosage form containing an amount of parzsotin equivalent to about 20 mg of parzsotin free base.

[0083] In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered orally. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered orally via an oral dosage form. Oral dosage forms include tablets. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered orally via an oral dosage form of tablets.

[0084] In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is parzsotin hydrochloride. In certain embodiments, parzsotin hydrochloride is monohydrochloride or dihydrochloride. In preferred embodiments, parzsotin hydrochloride is monohydrochloride.

[0085] In certain embodiments, the hydrochloride salt of parzsotin is amorphous.

[0086] In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered daily. In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is administered once daily.

[0087] Pharmaceutical composition Also provided is a pharmaceutical composition for use in treating a patient with parzsotin, characterized in that the patient has liver impairment, and the composition contains parzsotin or a pharmaceutically acceptable salt thereof.

[0088] In certain embodiments, the composition contains a therapeutically effective amount of parzsotin or a pharmaceutically acceptable salt thereof.

[0089] Also provided is a pharmaceutical composition for use in treating a patient with parzsotin, characterized in that the patient has liver impairment, the composition contains a therapeutically effective amount of parzsotin or a pharmaceutically acceptable salt thereof, and the composition contains the same amount of parzsotin or a pharmaceutically acceptable salt thereof as would be contained in the compound for use in treating a patient without liver impairment with parzsotin.

[0090] Also provided is a parzsotin or a pharmaceutically acceptable salt thereof for use in a method of treating a patient, wherein the method comprises administering to a patient a therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof, determining thereafter that the patient has liver damage, and administering to the patient the same therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof.

[0091] Furthermore, the use of parzsotin or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the treatment of a patient is also provided, in which case the patient has liver impairment.

[0092] In certain embodiments, the pharmaceutical composition provides patients with liver impairment with equivalent exposure to parzsotin free base compared to patients with normal liver function who are administered the same composition.

[0093] In certain embodiments, the patient has mild, moderate, or severe liver impairment.

[0094] In certain embodiments, the patient has a ChildPull score of 5-6, 7-9, or 10-15.

[0095] In certain embodiments, the patient has mild liver impairment.

[0096] In certain embodiments, the patient has a ChildPull score of 5-6.

[0097] In certain embodiments, the patient has moderate liver impairment.

[0098] In certain embodiments, the patient has a ChildPull score of 7 to 9.

[0099] In certain embodiments, the patient has severe liver impairment.

[0100] In certain embodiments, the patient has a ChildPue score of 10 to 15.

[0101] In certain embodiments, the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 10 mg to about 120 mg of parzsotin free base. In certain embodiments, the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 40 mg to about 120 mg of parzsotin free base. In certain embodiments, the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 40 mg to about 60 mg of parzsotin free base.

[0102] In certain embodiments, the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg of parzsotin free base.

[0103] In certain embodiments, the patient has acromegaly, carcinoid syndrome, and / or NET.

[0104] In certain embodiments, the pharmaceutical composition is intended for use in treating acromegaly, carcinoid syndrome, and / or NETs.

[0105] In certain embodiments, the patient has acromegaly.

[0106] In certain embodiments, the patient has acromegaly, and the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 40 mg to about 60 mg of parzsotin free base. In certain embodiments, the patient has acromegaly, and the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 40 mg of parzsotin free base. In certain embodiments, the patient has acromegaly, and the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 60 mg of parzsotin free base.

[0107] In certain embodiments, the pharmaceutical composition is intended for use in treating patients with acromegaly.

[0108] In certain embodiments, the patient has carcinoid syndrome and / or NET. In certain embodiments, the patient has carcinoid syndrome.

[0109] In certain embodiments, the patient has carcinoid syndrome and / or NET, and the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 40 mg to about 120 mg of parzsotin free base. In certain embodiments, the patient has carcinoid syndrome and / or NET, and the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 40 mg of parzsotin free base. In certain embodiments, the patient has carcinoid syndrome and / or NET, and the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 60 mg of parzsotin free base. In certain embodiments, the patient has carcinoid syndrome and / or NET, and the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 80 mg of parzsotin free base. In certain embodiments, the patient has carcinoid syndrome and / or NET, and the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 100 mg of parzsotin free base. In a particular embodiment, the patient has carcinoid syndrome and / or NET, and the pharmaceutical composition contains an amount of parzsotin or a pharmaceutically acceptable salt thereof equivalent to about 120 mg of parzsotin free base.

[0110] In a particular embodiment, the patient has carcinoid syndrome and / or NET, and the pharmaceutical composition is for use in treating carcinoid syndrome and / or NET. In a particular embodiment, the patient has carcinoid syndrome, and the pharmaceutical composition is for use in treating carcinoid syndrome.

[0111] In certain embodiments, the pharmaceutical composition is formulated as an oral dosage form. Oral dosage forms include tablets. In certain embodiments, the pharmaceutical composition is a tablet.

[0112] In certain embodiments, the pharmaceutical compositions provided herein may be provided in unit dosage forms or multi-dose dosage forms. As used herein, a unit dosage form refers to a physically distinct unit that is suitable for administration to a subject and is individually packaged as known in the art. Each unit dose contains a predetermined amount of the active ingredient in association with the necessary pharmaceutical carrier or excipients, sufficient to produce the desired therapeutic effect. Examples of unit dosage forms include individually packaged tablets. A unit dosage form may be administered in fractions or in multiple doses. A multi-dose dosage form is a fraction of an isolated unit. This refers to multiple identical unit dosage forms packaged in a single container, administered in a single dose form. An example of a multi-dose dosage form is a bottle of tablets.

[0113] In certain embodiments, the unit dosage form contains an amount of parzsotin equivalent to about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, or about 80 mg of parzsotin free base. In certain embodiments, the unit dosage form contains an amount of parzsotin equivalent to about 20 mg of parzsotin free base. In certain embodiments, the unit dosage form contains an amount of parzsotin equivalent to about 30 mg of parzsotin free base. In certain embodiments, the unit dosage form contains an amount of parzsotin equivalent to about 40 mg of parzsotin free base. In certain embodiments, the unit dosage form contains an amount of parzsotin equivalent to about 50 mg of parzsotin free base. In certain embodiments, the unit dosage form contains an amount of parzsotin equivalent to about 60 mg of parzsotin free base. In certain embodiments, the unit dosage form contains an amount of parzsotin equivalent to about 80 mg of parzsotin free base.

[0114] In certain embodiments, parzsotin or a pharmaceutically acceptable salt thereof is parzsotin hydrochloride. In certain embodiments, parzsotin hydrochloride is monohydrochloride or dihydrochloride. In preferred embodiments, parzsotin hydrochloride is monohydrochloride.

[0115] In certain embodiments, the hydrochloride salt of parzsotin is amorphous.

[0116] In certain embodiments, the pharmaceutical composition is administered daily. In certain embodiments, the pharmaceutical composition is administered once daily.

[0117] In certain embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients. Examples of pharmaceutically acceptable carriers or excipients include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow promoters, colorants, dye migration inhibitors, sweeteners, and flavoring agents.

[0118] Parzsotin Parzsotin is an orally administered non-peptide SST2 agonist having the structure shown below.

[0119] [ka]

[0120] In vitro, parzsotin showed a 50% response rate of 0.25 nmol / L (EC2). 50 At average drug (agonist) concentrations resulting in ), it inhibits cyclic adenosine monophosphate (cAMP) accumulation via human somatostatin receptor 2 (SST2) activation, exhibiting >4000-fold selectivity over other human somatostatin receptors. Parzsotin is >2000-fold selective to SST2 than a large panel of other known receptors, channels, and enzymes known to be targets of other drugs, thus reducing the risk of undesirable off-target activity or toxicity. Parzsotin exhibited a 75-fold bias for G protein activation and subsequent reduction of intracellular cAMP levels compared to β-alarestin activation and subsequent receptor internalization. This 75-fold bias suggests the possibility of reduced receptor desensitization by parzsotin at pharmacologically appropriate concentrations, potentially reducing the risk of tachyphylaxis.

[0121] The in vivo pharmacological efficacy of parzsotin has been studied in rats and dogs. In rats, acute efficacy was evaluated by examining the suppression of plasma GH in response to rat growth hormone-releasing hormone (rGHRH) challenge. Orally administered parzsotin significantly and dose-dependently suppressed GH compared to rats vehicle-treated with doses of ≥3 mg / kg. Plasma EC for GH suppression 50 It was estimated to be 11 ng / mL. The effect of chronic oral administration of parzsotin for 14 days was evaluated by measuring the sustained suppression of IGF-1 in rats. Parzsotin (≥10 mg / kg / day) was effective in suppressing plasma IGF-1 for up to 14 days. In rats, at a dose of 10 mg / kg / day, parzsotin on the final day resulted in the mean plasma C12. max and AUC 0-24 The levels were 127 ng / mL and 975 ng × h / mL, respectively. Octreotide, an injectable peptide SST2 agonist approved for the treatment of acromegaly, was evaluated as a positive control in rat studies and demonstrated a maximal effect similar to orally administered parzsotin. The sustained effect of parzsotin on IGF-1 suppression was also demonstrated in beagle dogs at an oral dose of ≥6 mg / kg / day over 7 days. The oral efficacy of parzsotin in vivo provides strong evidence for its use as an oral treatment for acromegaly.

[0122] The synthesis of parzsotin is disclosed in U.S. Patent No. 10,597,377, which is incorporated by reference in its entirety.

[0123] Acromegaly Acromegaly is a serious disorder generally caused by benign growth hormone (GH) secretion from the pituitary gland, with a reported prevalence of up to 8.8 per 100,000 people in the United States. Excessive GH secretion leads to increased secretion of insulin-like growth factor-1 (IGF-1) from the liver, which causes overgrowth of bones and cartilage, organ enlargement, and alterations in glucose and lipid metabolism. Symptoms of acromegaly include abnormal growth of the limbs and changes in the shape of bones and cartilage that result in altered facial features. Overgrowth of bones and cartilage, as well as thickening of tissues, can lead to arthritis, carpal tunnel syndrome, joint pain, enlargement of the lips, nose, and tongue, lowering of the voice due to enlargement of the vocal cords, sleep apnea due to airway obstruction, and enlargement of the heart, liver, and other organs. Additional symptoms include thickened skin, rough skin texture, oily skin, skin tags, excessive sweating, body odor, fatigue and weakness, headaches, vision problems, goiter, decreased libido, menstrual irregularities in women, and erectile dysfunction in men.

[0124] The primary therapeutic goals of acromegaly are to normalize serum GH and IGF-1 levels to reduce mortality, restore or reduce signs and symptoms, control tumor volume, and maintain pituitary function. Surgical removal of the pituitary adenoma, whenever possible, is the preferred initial treatment for most patients with acromegaly. Pharmacological interventions are used in patients who are not candidates for surgical removal of the tumor, or when surgery is only partially successful or unsuccessful in achieving the therapeutic goals. Approximately 50% of patients with acromegaly are candidates for pharmacological intervention. Somatostatin, secreted by neuroendocrine cells in the hypothalamus, inhibits GH release from both the normal pituitary gland and pituitary adenomas by stimulating somatostatin receptors. Therefore, somatostatin receptor agonists may be effective in lowering serum GH and IGF-1 levels. Somatostatin analogs are typically the first pharmacological treatment used; however, these drugs have limitations, as they are injectable and produce an incomplete response in approximately 50% of patients. Additional pharmacological treatment options include dopamine agonists or GH receptor antagonists, which may be used in combination with somatostatin agonists.

[0125] Parzsotin has been designated as a minor drug by the Food and Drug Administration for the treatment of acromegaly (DRU-2017-5766).

[0126] A protocol for the treatment of acromegaly with parzsotin is disclosed in U.S. Patent Publication No. 2022 / 0387420, which is incorporated in its entirety by reference.

[0127] Neuroendocrine tumors (NETs) and carcinoid syndromes Neuroendocrine tumors (NETs) arise from cells in the gastrointestinal (GI) tract (approximately 70% of cases), the lung (approximately 25% of cases), and more rarely, the pancreatic enterocrine system. As of January 1, 2014, the estimated 20-year time-limited prevalence of NETs in the United States was 171,321. Approximately 48% of these tumors are locally advanced or metastatic at the time of diagnosis.

[0128] NETs may clinically present with symptoms of tumor growth (abdominal pain and occasionally bowel obstruction) or may be incidentally detected during imaging or endoscopic procedures performed for unrelated reasons. Approximately 10%–20% of these tumors may present with symptoms including skin flushing and diarrhea, known as carcinoid syndrome. Carcinoid syndrome is caused by the direct secretion of serotonin and other vasoactive substances by the tumor into the systemic circulation, usually from liver metastases of midgut NETs.

[0129] Excess serotonin and other hormonal active products (including histamine, tachykinin, kallikrein, and prostaglandins) produced by some neurofibromatosis (NETs) are responsible for the symptoms collectively known as carcinoid syndrome. These symptoms most commonly include skin flushing (seen in 85%), recurrent watery diarrhea, and seizures (seen in 75-85%). Bronchospasm, venous telangiectasia, right-sided heart valve disease, and mesenteric and retroperitoneal fibrosis may also be present. Serotonin is a significant contributor to diarrhea and mesenteric, retroperitoneal, and cardiac fibrosis seen in this disorder, but it does not cause skin flushing.

[0130] Carcinoid syndrome is most common in patients when NETs originating from the distal small intestine or proximal colon (midgut) metastasize to the liver. It is thought that the excess serotonin secreted by liver metastases bypass first-pass liver inactivation and reach the circulation directly, mediating the symptoms. Rarely, NETs in the lungs or ovaries can release hormones directly into the systemic circulation, causing symptoms without metastasis. Carcinoid syndrome associated with bronchial NETs is often atypical and presents with episodes of skin flushing and / or sweating, which may be accompanied by additional symptoms such as tremor, periorbital edema, tearing, salivation, and edema.

[0131] Carcinoid syndrome usually arises from intestinal NETs with liver metastases, making surgical intervention very difficult for most patients. Hepatectomy or ablation may be beneficial in patients where at least 90% of the disease bulk can be removed. Somatostatin receptor ligand therapy with octreotide or lanreotide has been shown to improve the symptoms of carcinoid syndrome and slow the growth of underlying NETs.

[0132] For patients with persistent symptoms on somatostatin receptor ligand therapy, treatment options include local therapy for liver metastases, tetrotristat, interferon-alpha, antidiarrheal medication, everolimus, or adjuvant therapy with peptide receptor radioligand therapy (PPRT).

[0133] Daily oral treatment with parzsotin can achieve higher drug concentrations in the liver, which is the most common source of vasoactive substances that cause the symptoms of carcinoid syndrome. Therefore, parzsotin has the potential to improve treatment outcomes by eliminating painful injections while simultaneously achieving symptom control.

[0134] Palzsotin preparations Capsules: Parzsotin is available as a 10 mg (Swedish orange size 2) solid dose capsule. Dose strength is expressed as the free base equivalent of parzsotin. Pharmacologically acceptable excipients used in the preparation of capsule formulations include mannitol, microcrystalline cellulose, croscarmellose sodium, vitamin E polyethylene glycol succinate, colloidal silicon dioxide, sodium stearyl fumarate, and Swedish orange opaque capsules (red iron oxide, titanium dioxide, and gelatin). These excipients are common in solid oral formulations and are generally considered safe (GRAS) in the US and EU, below the maximum permissible limits provided in the FDA's Inactive Ingredients Database (IID).

[0135] Tablets: Parzsotin is available as an immediate-release tablet containing an amorphous spray-dried dispersion of parzsotin in a water-soluble polymer, copovidone. The tablets are coated with a water-soluble pink film. The formulation is supplied as a single-strength 20 mg tablet. Dose strength is expressed as the free base equivalent of parzsotin. Excipients used in the manufacture of parzsotin tablets include copovidone (for spray-dried dispersion), mannitol, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, and OpaDry Pink coating (hypromellose, titanium dioxide, triacetin, iron oxide - yellow, and iron oxide - red). Excipients are common in solid oral formulations and are considered GRAS in the US and EU, below the maximum permissible limits provided in the FDA's IID. Parzsotin 20 mg tablets are packaged in 36 high-density polyethylene (HDPE) bottles containing a desiccant, capped with a child-resistant closure, and sealed with a heat-induction seal. Paltzosotin tablets should be stored at temperatures between 15 and 30 degrees Celsius.

[0136] A paltzsotin formulation including the above is disclosed in U.S. Patent No. 11,266,641, which is incorporated by reference in its entirety. [Examples]

[0137] Example 1: In healthy male volunteers [ 14 A Phase 1 open-label single-dose study (ADME study) to evaluate the mass balance, elimination pathway, and metabolic profile of [C]-labeled parzsotin. This is a study in healthy men involving 3.0 MBq (80 μCi) [ 14 This was a Phase I open-label single-dose study with the primary objective of characterizing the absorption, distribution, metabolism, excretion, and mass balance of a single oral dose of 20 mg of parzsotin containing [C]-labeled parzsotin.

[0138] Radiolabeled molecules (usually [ 14The use of [C]) is a common method used to confirm information regarding the elimination pathways and metabolic fate of compounds in the early stages of development. This assessment provides estimation of basic PK parameters, evaluation of the pathways and rates of radioactivity elimination, and identification of metabolites and metabolic pathways. These data can be compared with similar data obtained from nonclinical studies, both from a PK and metabolic perspective.

[0139] Dosage selection In the ADME trial, a dose of 20 mg of parzsotin was selected for oral administration as the possible therapeutic dose estimated by the PD activity of growth hormone-releasing hormone (GHRH)-stimulated GH secretion suppression. In healthy adult males, the AUC of parzsotin increased in a dose-dependent manner after oral administration within the dose ranges of 1.25–20 mg (SAD) and 5–30 mg (repeated dose escalation [MAD]).

[0140] To ensure the success of metabolite profiling (and identification), the dose administered is [ 14 I selected C (approximately 3.0 MBq).

[0141] Patient group The sample size of six male subjects is a number of subjects that is generally acceptable for ADME tests and is considered sufficient to achieve the objectives of the test.

[0142] Test design On day 1, the subjects received a single oral dose of 20 mg of parzsotin as an oral solution containing 3.0 MBq (80 μCi) of radioactivity. For oral administration, the total volume ingested by the subjects was 240 mL, including the test drug (10 mL), rinse solution (100 mL total, 50 mL of water per rinse, for two drug vial rinses), and tap water (130 mL). Subjects had to ingest all solutions in an upright position within 2 minutes between 8:00 AM and 11:00 AM, after fasting for at least 10 hours overnight. Fasting was maintained for 4 hours after oral drug administration. The time of oral administration was recorded, and the residual radioactivity of the empty test drug vial was measured.

[0143] If at least 90% of the administered radioactivity since drug administration (day 1) was recovered in urine and feces, and the total radioactivity in urine and feces was less than 1% of the total administered dose over a 24-hour period between two consecutive pharmacokinetic (PK) sample collection days, as determined by QuickCount, a rapid method for measuring radioactivity in urine and feces, subjects were discharged on day 8 (approximately 168 hours after drug administration). If the discharge criteria were not met on day 8, subjects had to remain hospitalized for up to an additional 13 days (days 9-21) until the criteria were met (daily checks using QuickCount). If the discharge criteria were still not met on day 21, subjects were discharged and asked to continue collecting urine and feces at home, bringing these samples to the clinical research center every 2-3 days until day 28, or until the discharge criteria were met, whichever came first.

[0144] Blood sample Unlabeled parzsotin and [ 14 Blood samples were collected for the analysis of [C]-parzsotin concentrations and metabolite profiling. Blood samples were collected before administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 120, and 168 hours after administration for the analysis of parzsotin pharmacokinetic parameters, quantification of total radioactivity in blood and plasma, and metabolite profiling (and thereafter every 48 hours, radioactivity was assessed as needed).

[0145] Urine sample Urine was collected for total radioactivity analysis, quick count of total radioactivity, and metabolite profiling. Participants were instructed to completely empty their bladder before administration of the study drug and at the end of each collection interval. Baseline urine samples were collected within 12 hours prior to each administration of the study drug. For quantification of total radioactivity and metabolite profiling, urine was collected before administration, at three intervals on day 1 (0–4 hours, 4–8 hours, and 8–24 hours post-administration), and then every 24 hours thereafter until discharge criteria were met.

[0146] Stool collection All fecal excrement was collected for total radioactivity analysis, quick count of total radioactivity, and metabolite profiling. Baseline fecal samples were collected within 48 hours prior to administration of the study drug and could be collected at home. Baseline samples were taken from the last bowel movement before study drug intake. Fecal samples were collected pre-administration and at 24-hour intervals for quantification of total radioactivity and metabolite profiling until discharge criteria were met.

[0147] analysis Analysis of partzsotin in plasma was performed by Q2 Solutions (IQVIA, Itaca, NY, USA) using a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. The lower limit of quantification (LLOQ) for partzsotin in plasma was 0.5 ng / mL.

[0148] Total blood count in plasma, whole blood, urine, and feces via validated liquid scintillation counting method 14 The radioactivity of ¹¹C was analyzed in the bioanalysis laboratory at PRA Heath Sciences. The total reactivity LLOQ was 3.36 ng-eq / mL in plasma and 5.6 ng-eq / mL in whole blood.

[0149] Metabolite profiling of plasma, urine, and feces was performed at WuXi AppTec (Cranbury, NJ, USA). For plasma, samples were pooled at time points (0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post-administration) for metabolite profiling. In addition, plasma samples were pooled by participants over time points (0–48 hours) using Hamilton's method and analyzed to determine the quantitative profiles of radiolabeled components. Prior to radioprofiling, plasma samples were extracted using solid-phase extraction.

[0150] Urine and fecal samples were pooled at different time points (0–8 hours, 8–24 hours, and 24–72 hours after administration). Prior to radioprofiling, urine samples were centrifuged to remove solids, and fecal homogenates were extracted with acetonitrile. Plasma and fecal extracts and urine supernatant were subjected to LC separation and fractionation. Metabolite characterization was performed using LC-MS / MS with appropriate radioactivity monitors. Metabolite structures were characterized through interpretation of mass spectral fragmentation patterns and, where possible, comparison with reference standards.

[0151] conclusion 20 mg (80 μCi) administered to healthy male volunteers 14 Following a single oral administration of [C]-partzsotin, partzsotin was the only drug-related component detected in human plasma (0–48 hours). The absence of detectable metabolites in human plasma suggests that measurement of partzsotin alone is sufficient to characterize the pharmacokinetic and pharmacokinetic effects of partzsotin.

[0152] 20 mg (80 μCi) administered to healthy male volunteers 14 Following a single oral dose of [C]-parzsotin, the overall mean recovery rate of administered radioactivity was 94%, with 90% recovered in feces and 3.9% in urine. This suggested that the primary route of excretion was feces. The majority of the total radioactivity (88% of the administered dose) was excreted over 120 hours.

[0153] Metabolic profiling of excretions determined that approximately 84% of the dose was excreted in human feces, with unvariant partzotin being the most abundant component, accounting for 39.7%. M632 / 1 was the major metabolite, accounting for 20.4% of the dose, while M676 / 1, M472 / 1, and M648 / 1 accounted for 2.53%, 7.92%, and 4.26% respectively (see Figure 1). The extent of excretion of unvariant partzotin or its metabolites in human bile is unknown. Metabolites found in feces may have been secreted into the bile.

[0154] The amount of unchanged parzsotin and its metabolites excreted in human urine after a single oral dose of radiolabeled parzsotin was low, representing <4% of the total radioactive material administered. In human urine, M632 / 1 and parzsotin were the two major components, accounting for 1.44% and 1.33% of the dose, respectively, while the other metabolites M472 / 1, M648 / 1, and M676 / 1 were minority components, accounting for 0.15% to 0.2% of the dose.

[0155] In vitro and in vivo studies of parzsotin in humans suggest that CYP-mediated oxidation and uridine glucuronidyltransferase (UGT)-mediated glucuronidation are the major pathways involved in the metabolic clearance of parzsotin (see Figure 1). 14 Scaling of parzsotin and its excreted metabolites to estimate the overall metabolic clearance pathway in humans after parzsotin administration suggests that glucuronidation is the major metabolic pathway, accounting for 27.9% of the dose, with oxidation pathways accounting for a total of 14.3% (see Figure 2). This is consistent with in vitro studies suggesting that CYP-mediated metabolism contributes approximately 16.8%.

[0156] CYP phenotyping studies using human liver microsomes and recombinant CYP450 have shown that CYP3A4 / 5 catalyzes the oxidative metabolism of parzsotin with a small contribution from CYP2D6, while studies of parzsotin with recombinant uridine diphosphate glucuronosyltransferase (UGT), with or without 2% BSA, suggest that M632 / 1 formation is catalyzed by UGT1A1, UGT1A3, UGT1A8, UGT1A9, and UGT1A10.

[0157] Since parzsotin is metabolized in the human liver, patients with hepatic impairment are expected to show increased parzsotin PK exposure compared to patients with normal liver function receiving the same therapeutic dosage. Therefore, it is expected that liver function should be assessed before or during treatment to reduce risk and ensure patient safety. To reduce risk and ensure safety, it is expected that parzsotin dose adjustments will be necessary for patients with hepatic impairment compared to patients with normal liver function.

[0158] Example 2: A Phase 1 open-label single-dose study to evaluate the safety, tolerability, and pharmacokinetics of parzsotin in subjects with varying degrees of hepatic impairment. This was a Phase 1 open-label single-dose trial whose primary objective was to compare the PK profile of a single dose of parzsotin in subjects with varying degrees of liver impairment with the PK profile of healthy, matched controls.

[0159] The second objective of the study was to evaluate the safety and tolerability of a single dose of parzsotin in subjects with varying degrees of liver impairment.

[0160] Dosage selection A dose-exposure response analysis of the Phase 2 trial of parzsotin in patients with acromegaly identified that oral parzsotin in the 40–60 mg dosing range was expected to produce IGF-1 suppression similar to that of injected long-acting somatostatin receptor ligands. A 20 mg dose was available to Phase 3 trial patients who could not tolerate higher doses. The 20 mg dose was used in this trial due to the expected increased PK exposure from parzsotin in subjects with hepatic impairment.

[0161] Patients were administered immediate-release palzsotin tablets containing 20 mg of palzsotin in a spray-dried dispersion and the following inactive excipients: copovidone (for spray-dried dispersion), mannitol, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, and opa-dry pink coating (hypromellose, titanium dioxide, triacetin, iron oxide - yellow, and iron oxide - red).

[0162] The single oral dose of 20 mg of parzsotin administered in this study was evaluated according to the recommendations provided in the U.S. FDA's "Guidance for Industry, Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling."

[0163] Patient group In total, 36 male and female subjects were enrolled, including 14 subjects with normal liver function, 8 subjects with mild, stable liver impairment (Group 1), 8 subjects with moderate, stable liver impairment (Group 2), and 6 subjects with severe, stable liver impairment (Group 3). Healthy subjects with normal liver function (Group 4) were matched with subjects with liver impairment according to sex, age (±10 years), and BMI (±20%). Reasonable attempts were made to match healthy subjects with subjects with liver impairment from a racial perspective. Healthy subjects were matched to two or more subjects in different liver impairment groups, but in some cases, they were matched to one or fewer subjects within each liver impairment group. After enrolling a sufficient number of subjects with liver impairment in Groups 1, 2, and 3, healthy subjects were recruited for the trial.

[0164] A total of 36 participants were enrolled in the study, and all participants completed the study. All 36 enrolled participants (100.0%) were included in the safety and PK analysis populations.

[0165] Methods for assigning patients to treatment groups The ChildePew Scale was used to classify the severity of liver impairment into three categories: mild (scores of 5–6), moderate (scores of 7–9), and severe (scores of 10–15).

[0166] Test design Written informed consent in accordance with US Title 21 CFR Part 50 was obtained from each participant before they participated in the study and before any study-related procedures involving risk to the participant were performed. Participants received a signed and dated copy of the informed consent form.

[0167] The study included a screening period (days 28-2), a check-in period (day 1), and a treatment period (days 1-7). On day 1, all subjects received a single oral dose of 20 mg of parzsotin (1 x 20 mg tablet) administered with 240 mL of room temperature water, after fasting for at least 10 hours overnight (no food or beverages except water). Subjects remained fasting and upright (sitting or standing) for 4 hours after administration. Water was permitted as desired, except 1 hour before and 1 hour after administration of the study drug. Subjects consumed a standard meal scheduled at the same time each day throughout the study.

[0168] Participants were discharged from the clinical facility on the 7th day after completing the trial procedure. Excluding screening, the trial period was approximately 8 days.

[0169] Drug concentration measurement Serial blood samples for PK analysis of parzsotin were collected before administration (0 hours) and up to 144 hours after parzsotin administration.

[0170] Blood samples for analysis of parzsotin concentrations in plasma were collected at the following time points: before administration (0 hours), and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, and 144 hours after parzsotin administration.

[0171] The blood sample collection window was as follows: ±5 minutes for blood samples collected up to 1 hour, ±15 minutes for blood samples collected up to 12 hours, ±1 hour for blood samples collected at 24 hours, and ±4 hours for blood samples collected after 24 hours.

[0172] Pharmacokinetic samples were analyzed using validated liquid chromatography coupled to a tandem mass spectrometry assay for parzsotin in human plasma.

[0173] Plasma concentration-time data were analyzed by non-compartmental analysis using Phoenix® WinNonlin® Version 8.3 (Certara USA, Inc., Princeton, NJ).

[0174] The PK assessment used in this study is an acceptable standard for describing the PK profile of drugs in plasma. The safety assessment performed is considered standard and is recognized as reliable, accurate, and relevant.

[0175] Adverse events (AEs) The principal investigator was responsible for reporting all adverse events (AEs) observed or reported during the study, regardless of their relationship to the investigational drug or their clinical significance, from the time the subject signed the Informed Consent Form (ICF) until the end of the study (EOS). Serious adverse events (SAEs) occurring after the ICF was signed and within four weeks of the last parzsotin dose were to be reported. If there was any suspicion that a clinical observation was an AE, the event was to be reported.

[0176] Clinical Laboratory Evaluation Blood and urine samples for hematology, serology, urinalysis, and screening tests were collected at screening, check-in (day 1), day 3, and at the end of the tests.

[0177] The following clinical laboratory evaluations were conducted.

[0178] Hematology: Absolute number and difference of neutrophils, hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, white blood cells (basophils, eosinophils, lymphocytes, monocytes, neutrophils), mean corpuscular volume, platelet count, red blood cell count, and red blood cell distribution width.

[0179] Coagulation: Activated partial thromboplastin time and / or partial thromboplastin time, international normalized ratio, and prothrombin time.

[0180] Serum chemistry: Alanine aminotransferase, albumin, alkaline phosphatase, amylase, aspartate aminotransferase, bilirubin (total), blood urea nitrogen, calcium, carbon dioxide, chloride, cholesterol (total, high-density lipoprotein, and calculated low-density lipoprotein), creatinine, gamma-glutamyltransferase, globulin, glucose, lactate dehydrogenase, lipase, phosphorus, potassium, sodium, total protein, triglycerides, and uric acid.

[0181] Urine test: Appearance, bilirubin, color, glucose, ketones, white blood cells, reflex microscopy (performed if the dipstick is positive for protein or blood levels are 1+ or higher, and includes bacteria, urinary casts, crystals, epithelial cells, red blood cells, and white blood cells), nitrite, occult blood, pH, protein, specific gravity, and urobilinogen.

[0182] Serology: Hepatitis B surface antigen, hepatitis C virus antibody, and HIV antibody types 1 and 2 (screening only).

[0183] Other analyses (for all subjects): urinary drug screening (amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, methamphetamine, methylenedioxymethamphetamine, and opioids [including heroin, codeine, and oxycodone]), and alcohol breath testing (screening and check-in).

[0184] Other analyses (in women): follicle-stimulating hormone (administered at screening to confirm postmenopausal status), serum human chorionic gonadotropin pregnancy test (screening only), and urine human chorionic gonadotropin pregnancy test (check-in and end of test).

[0185] Vital signs measurement Vital signs were measured during screening, check-in, within 1.5 hours before parzsotin administration, within 4, 8, and 12 hours after parzsotin administration, on days 2-6 (morning), and at the end of the study after the subject had been seated for at least 5 minutes. Post-administration vital signs were measured within ±15 minutes of the nominal administration time.

[0186] Vital signs included systolic and diastolic blood pressure, pulse rate, respiratory rate, and oral (or equivalent) body temperature.

[0187] Physical examination Participants underwent a physical examination at the time specified in the event schedule. A complete physical examination included at least an assessment of the skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, heart, cardiovascular system, abdomen, lymph nodes, and musculoskeletal system / limbs. A brief physical examination included at least an assessment of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Ad-hoc physical examinations were performed at the discretion of the principal investigator as needed to assess adverse events or abnormal laboratory findings.

[0188] 12-lead electrocardiogram After subjects were in a supine position for at least 10 minutes, three 12-lead ECGs (at approximately 1-minute intervals) were obtained at screening, check-in (day 1), 2 (±1) hours after administration of parzsotin, and at the end of the study.

[0189] The electrocardiogram evaluation included whether the trace was normal or abnormal, the presence of rhythm, arrhythmia or conduction disturbance, morphology, evidence of myocardial infarction, or comments regarding ST segment, T wave, and U wave abnormalities. In addition, measurements were taken and reported at the following intervals: RR interval, PR interval, QRS width, QT interval, and QTcF.

[0190] Genetics On the first day, blood samples were collected for genotyping to determine the UGT1A1 genotype.

[0191] For subjects whose UGT1A1 genotype classification was "low metabolic" (PM), it was not possible to determine PM classification through direct comparison with different groups; therefore, the PM classification versus non-PM classification is also shown.

[0192] Pharmacokinetic parameters and analysis The following pharmacokinetic parameters were calculated: Area under the curve (AUC) of plasma concentration from time 0 to the last quantifiable concentration. 0-t ), Area under the time curve (AUC) of plasma concentration from 0 to 24 hours. 0-24 ), Area under the plasma concentration-time curve (AUC) from time 0 to infinity. 0-∞ ), Observed maximum plasma concentration (C max ), Time to observed maximum plasma concentration (T max ), Delay time between administration time and the appearance time of the measurable test substance (T lag ), Apparent terminal phase half-life (t 1 / 2 ), Apparent terminal rate constant (λ z ), Apparent mean dwell time (MRT), Apparent overall clearance (CL / F), and Apparent distribution volume (V z / F).

[0193] The plasma PK parameters of paltzsotin are summarized in Table 1 below.

[0194] [Table 1]

[0195] Table 2 below shows the results of a sensitivity analysis investigating potential imbalances across the liver impairment group in the distribution of baseline covariates used in target matching (age and BMI).

[0196] [Table 2]

[0197] As shown in Figures 3 and 4, after a single oral administration of 20 mg of parzsotin tablets to subjects with mild, moderate, or severe hepatic impairment and normal hepatic function, the mean plasma concentration of parzsotin rapidly peaked, reaching its maximum concentration 1.6 to 3 hours after administration. Subsequently, plasma concentrations decreased in a similar manner across all treatment groups, and parzsotin concentrations remained measurable in systemic circulation throughout 144 hours after administration.

[0198] Box plots of PK parameters for each liver function group are shown in Figures 5-7. Compared to the normal liver function group, the total plasma exposure to parzsotin (area under the curve [AUC] of plasma concentration from time 0 to the last quantifiable concentration) is shown. 0-t ] and the area under the concentration-time curve extrapolated from time 0 to infinity [AUC 0-inf The AUCs of parzsotin were similar for subjects with mild and severe hepatic impairment, respectively, with geometric mean ratios of 1.00 and 0.90. 0-t and AUC 0-inf This was approximately 25% lower compared to the normal liver function group (geometric mean ratio [GMR] of 0.74 and 0.75). Overall, no trends were observed, and whole plasma exposure to parzsotin appeared to be similar across all liver function groups compared to the normal group.

[0199] Compared to the group with normal liver function, the peak plasma exposure (C) of parzsotin was higher. max ) was similar for subjects with severe hepatic impairment having a GMR of 1.05. For subjects with mild hepatic impairment, parzsotin C max Compared to the group with normal liver function, the C of parzsotin was 35% higher (1.35 GMR), and in subjects with moderate liver impairment, max It was 24% lower (0.76 GMR). Overall, no trends were observed, and it can be concluded that parzsotin peak plasma exposure is similar across all liver function groups compared to the normal group.

[0200] Apparent terminal phase half-life (t 1 / 2 The mean estimated values ​​of ) were similar across all groups. For the mild and severe hepatic impairment groups, the mean apparent systemic clearance (CL / F) after oral administration and the apparent volume of distribution (V) in the terminal phase after oral administration were similar. z The CL / F value was similar to that of the normal group, but the mean CL / F and V z The / F values ​​were 1.8 times and 1.6 times higher in the moderate liver impairment group compared to the normal group; however, the variability of exposure parameters was generally highest in the moderate liver impairment group.

[0201] Since the GMR was similar in both analyses, it appears there was no imbalance in the distribution of baseline covariates used for target matching (age and BMI).

[0202] Safety evaluation Safety and tolerability were evaluated using the following endpoints: reported adverse events (AEs), laboratory results (hematology, coagulation, serology, and urinalysis), vital signs, and 12-lead electrocardiogram results.

[0203] All 36 subjects enrolled in the trial received all planned single doses of paltzsotin 20 mg (1 x 20 mg tablets) and were included in the safety and PK analysis population.

[0204] Table 3 provides an overall summary of TEAEs. Table 4 provides summaries of TEAEs by system organ class (SOC) and basic term (PT). Table 5 provides summaries of TEAEs by PT. Table 6 provides summaries of related TEAEs by PT.

[0205] [Table 3]

[0206] [Table 4]

[0207] [Table 5]

[0208] [Table 6]

[0209] Overall, 17 TEAEs were experienced by 10 subjects (27.8%). The number of TEAEs reported in the study was similar across all four groups. Overall, 9 subjects (25.0%) reported 13 TEAEs that the principal investigator considered to be related to parzsotin. No subjects discontinued the study due to TEAEs. All TEAEs resolved by the end of the study, with the exception of a mild hematuria TEAE that was reported as ongoing.

[0210] One participant (12.5%) from the group with mild liver impairment died spontaneously on day 27. The death was deemed unrelated to parzsotin by the principal investigator.

[0211] conclusion After a single oral administration of 20 mg of parzsotin tablets to subjects with varying degrees of hepatic impairment, parzsotin peak and systemic exposure were similar across all hepatic impairment groups compared to subjects with normal liver function. Overall, there were no changes in parzsotin plasma exposure considered clinically significant or sufficient to justify dose adjustments in patients with mild, moderate, or severe hepatic impairment.

[0212] A single oral dose of 20 mg of parzsotin was safe and was generally well-tolerated in subjects with varying degrees of hepatic impairment and those with normal hepatic function in this study.

Claims

1. A method comprising administering to a patient a therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof, wherein the patient has hepatic impairment.

2. A method comprising administering to a patient a therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof, wherein the patient has liver impairment, and the therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof is the same amount as that administered to a patient without liver impairment.

3. (a) administering to the patient a therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof, (b) Subsequently, it is determined that the patient has liver damage, (c) A method comprising administering to the patient the same therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof.

4. The method according to any one of claims 1 to 3, wherein the patient has mild, moderate, or severe liver impairment.

5. The method according to claim 4, wherein the patient has mild liver dysfunction.

6. The method according to claim 4, wherein the patient has moderate liver impairment.

7. The method according to claim 4, wherein the patient has severe liver dysfunction.

8. The method according to any one of claims 1 to 4, wherein the patient has a Childpus score of 5-6, 7-9, or 10-15.

9. The method according to claim 8, wherein the patient has a ChildPuth score of 5 to 6.

10. The method according to claim 8, wherein the patient has a ChildPull score of 7 to 9.

11. The method according to claim 8, wherein the patient has a ChildPuth score of 10 to 15.

12. The method according to any one of claims 1 to 11, wherein the patient has acromegaly, carcinoid syndrome, and / or neuroendocrine tumor (NET).

13. The method according to any one of claims 1 to 12, wherein the patient has acromegaly.

14. The method according to claim 13, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg of parzsotin free base.

15. The method according to claim 13, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 60 mg of parzsotin free base.

16. The method according to any one of claims 1 to 15, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered to the patient for the treatment of acromegaly.

17. The method according to any one of claims 1 to 12, wherein the patient has carcinoid syndrome and / or NET.

18. The method according to claim 17, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg of parzsotin free base.

19. The method according to claim 17, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg of parzsotin free base.

20. The method according to claim 17, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 120 mg of parzsotin free base.

21. The method according to any one of claims 1 to 12 and 17 to 20, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered to the patient for the treatment of carcinoid syndrome and / or NET.

22. The method according to any one of claims 1 to 21, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered daily.

23. The method according to any one of claims 1 to 22, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered once daily.

24. The method according to any one of claims 1 to 23, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered orally.

25. The method according to any one of claims 1 to 24, wherein the parzsotin or a pharmaceutically acceptable salt thereof is administered in one or more oral dosage forms.

26. The method according to claim 25, wherein the oral dosage form is a tablet.

27. The method according to any one of claims 1 to 25, wherein the parzsotin or a pharmaceutically acceptable salt thereof is parzsotin hydrochloride.

28. The method according to claim 27, wherein the hydrochloride salt of parzsotin is amorphous.

29. The method according to any one of claims 1 to 28, wherein the patient having liver impairment is exposed to an amount of parzsotin free base equivalent to the amount administered to a patient with normal liver function who is administered the same amount of parzsotin or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition for use in treating a patient having acromegaly, carcinoid syndrome, and / or neuroendocrine tumor (NET), wherein the patient has liver impairment, and the composition comprises a therapeutically effective amount of parzsotin or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition for use in treating a patient having acromegaly, carcinoid syndrome, and / or neuroendocrine tumors (NETs), wherein the patient has liver impairment, the composition comprises a therapeutically effective amount of parzsotin or a pharmaceutically acceptable salt thereof, and the composition comprises the same amount of parzsotin or a pharmaceutically acceptable salt thereof as for use in treating a patient without liver impairment.

32. The use of parzsotin or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the treatment of a patient having acromegaly, carcinoid syndrome, and / or neuroendocrine tumors (NETs), wherein the patient has hepatic impairment.

33. Parzsotin or a pharmaceutically acceptable salt thereof for use in a method of treating patients with acromegaly, carcinoid syndrome, and / or neuroendocrine tumors (NETs), wherein the method is (a) administering to the patient a therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof, (b) Subsequently, it is determined that the patient has liver damage, (c) administering to the patient the same therapeutically effective dose of parzsotin or a pharmaceutically acceptable salt thereof, comprising parzsotin or a pharmaceutically acceptable salt thereof.

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