Fonetupitant for administration by intravenous bolus

Abstract

An improved method of administering a neurokinin-1 receptor antagonist, preferably defortupitant, by intravenous injection, preferably for a shortened period of time.

Description

Technical Field

[0001] This disclosure relates to an improved method of administering a neurokinin-1 receptor antagonist, specifically fosnetupitant, via intravenous bolus injection. Background Technology

[0002] Netupitant is a substance P neurokinin 1 receptor antagonist (NK-1 RA) that, in combination with other antiemetics, is part of a guideline-recommended regimen for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in cancer patients receiving highly emetogenic (HEC) or moderately emetogenic chemotherapy (MEC). The oral fixed-dose combination (FDC) of netupitant and palonosetron is currently approved in the United States, Europe, and several other countries worldwide under the name Akynzeo®. This drug is approved for the prevention of acute and delayed nausea and vomiting associated with initial and repeated chemotherapy cycles, including but not limited to HEC.

[0003] Because netupitant itself is insoluble in water, its phosphorylated prodrug (“netupitant”) is typically administered intravenously (IV). In 2018, the United States approved a fixed-dose IV combination of netupitant and palonosetron for the prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of highly emetogenic chemotherapy for cancers. Akynzeo® for injection is a lyophilized powder, reconstituted in 5% glucose injection or 0.9% sodium chloride injection and further diluted to 50 mL, administered as a 30-minute IV infusion starting 30 minutes before chemotherapy. A liquid formulation of IV NEPA was subsequently approved, with indications and instructions for use substantially the same as the lyophilized form.

[0004] What is needed is a more convenient administration protocol for NK-1 receptor antagonists that can be completed in a shorter time without causing adverse events such as injection site reactions. Invention Overview

[0005] A safe, effective, and efficient method for administering fonetopitant has been unexpectedly discovered. In one embodiment, this disclosure provides a method for safely administering fonetopitant to a subject in need of it, the method comprising administering a liquid solution of fonetopitant to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0006] In another embodiment, this disclosure provides a method for treating or preventing vomiting in a subject in need of it, the method comprising administering a therapeutically effective amount of dissolved fornetotipant to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0007] In another embodiment, this disclosure provides a method for treating or preventing nausea or vomiting in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of dissolved fornetotipant to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0008] In another embodiment, this disclosure provides a method for treating or preventing chemotherapy-induced nausea and vomiting in a subject in need of such treatment, the method comprising administering, by intravenous bolus, 235 mg of formetupitant (based on the weight of the free base) (equivalent to 260 mg of formetupitant chloride hydrochloride) in a ready-to-use solution for intravenous administration to the subject over a duration of 2-15 minutes.

[0009] Other advantages of this disclosure are partially described in the following description, and these other advantages will be partially apparent from the description, or may be learned by practicing the present disclosure. The advantages of this disclosure will be realized and obtained through the elements and combinations specifically pointed out in the appended claims. It should be understood that both the foregoing general description and the following detailed description are exemplary and illustrative only and are not intended to limit the scope of the claimed disclosure. Detailed description

[0010] Definitions and Terms Unless the context clearly specifies otherwise, the singular forms “a” and “said” as used in this specification and in the following claims include the plural objects.

[0011] As used herein and in the following claims, “comprising” and its variations mean “including (but not limited to)” and are not intended to exclude, for example, other additives, components, wholes or steps. When an element is described as comprising multiple components, steps or conditions, it will be understood that the element may also be described as comprising any combination of such multiple components, steps or conditions or “consisting of the multiple components, steps or conditions or a combination of components, steps or conditions” or “consisting substantially of the multiple components, steps or conditions or a combination of components, steps or conditions.”

[0012] "Therapeutic effective amount" refers to the amount that, when administered to a person to support or influence metabolic processes, or to treat or prevent a disease, is sufficient to cause the treatment or prevention of that disease, or to support or influence metabolic processes.

[0013] When a range is provided by specifying either the lower limit of the range separately from the upper limit or by specifying a concrete value, it will be understood that a range can be defined by selectively combining any lower limit variable, upper limit variable, and mathematically possible concrete value. Similarly, when a range is defined as covering from one endpoint to another, the range will be understood to also cover the area between the two endpoints but excluding the two endpoints themselves.

[0014] When used herein, the term “about” will compensate for the variability permitted in the pharmaceutical industry and inherent in products within the industry, such as differences in product strength due to manufacturing variations and time-related degradation. The term allows for any variations that, in accordance with good manufacturing practices, would permit the evaluated product to be considered therapeutically or bioequivalent in humans to the strengths claimed by the product.

[0015] In the context of this disclosure, which pertains to any of the disease conditions listed herein, the term “treatment” means reducing the occurrence of symptoms or conditions, or alleviating or reducing at least one symptom associated with such condition, or slowing or reversing the development of such condition, or controlling or influencing the underlying metabolic processes of such condition. Within the meaning of this disclosure, the term also means preventing, delaying the onset (i.e., the period prior to the clinical manifestation of the disease), and / or reducing the risk of developing or worsening the disease.

[0016] The phrase “acceptable” used in conjunction with the compositions of this disclosure means the molecular entity and other components of these compositions that are physiologically tolerable and generally do not produce adverse effects when administered to a subject (e.g., a mammal, such as a human).

[0017] The known chemical name of flonetupitant is 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropionamide)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonoyloxy)methyl)piperazine-1-onium. This compound, in its free form, has the following chemical structure:

[0018] The molecular weight of the free form of this compound is 688.6 g / mol. The molecular weight of its chloride hydrochloride is 761.53 g / mol. A method for preparing frinetopitant is described in WO 2013 / 082102.

[0019] Unless otherwise specified, when used herein, the term "formetupitant" includes both the free form of formetupitant and its pharmaceutically acceptable salts. When the term formetupitant is followed by an equivalent of a salt in parentheses, such as "(equivalent to xx mg of a specific salt)," it means that formetupitant is contained in the formulation in the form of the listed salt, and that the listed salt is added in an equivalent amount. If a solution containing a salt, such as formetupitant chloride hydrochloride, is referred to as formetupitant chloride hydrochloride according to the terminology conventions of medicinal chemists, regardless of any ionic dissociation of formetupitant chloride hydrochloride in solution, it is still referred to as formetupitant chloride hydrochloride.

[0020] “Vomiting” is a technical term used in the field of cancer supportive care and, as used herein and in the field of cancer supportive care, refers to the act of vomiting or retching (i.e., the action of the stomach and esophagus attempting to vomit (expel some or all of the contents of the stomach), including retching without vomiting, also known as dry heaving). Similarly, “chemotherapy-induced nausea and vomiting” or “CINV” is a technical term in this field. Therefore, in this document and in the field of cancer supportive care, treatment or prevention of CINV is defined as a “complete response,” which means a response to chemotherapy administration typically within a defined time period without vomiting episodes and without the need for emergency medications. The term “nausea” is a subjective feeling of illness or discomfort in the stomach that may begin with the urge to vomit rather than an element of vomiting or CINV. All methods disclosed herein can be used to treat or prevent vomiting, nausea, and / or CINV.

[0021] "CINV" can also be referred to as "nausea and vomiting associated with cancer chemotherapy," or similar terms can be used, and it can be further defined as: (1) CINV occurring in the "acute" phase (i.e., during the first 24 hours after chemotherapy administration) and / or the "delayed" phase (i.e., during the period of 25–120 hours after chemotherapy administration), and / or (2) CINV occurring in the initial or repeated courses of chemotherapy, and / or (3) CINV occurring in response to low-emetic (LEC), moderate-emetic (MEC), or high-emetic (HEC) chemotherapy, as defined in various references, including Hesketh PJ, J Clin Oncol 2016; 34:381. Therefore, any method of this disclosure can be practiced to treat or prevent acute and delayed nausea and vomiting associated with the initial and repeated courses of moderate- or high-emetic cancer chemotherapy.

[0022] As used herein, the term "solution" refers to a liquid mixture in which the minor component (solubilized) is dissolved and uniformly distributed within the major component (solvent). Therefore, a "liquid solution" of fornetotipant refers to a liquid in which fornetotipant is completely dissolved and uniformly distributed. The terms "dissolved" and "solubilized" are used interchangeably herein. In all embodiments of this disclosure, fornetotipant is administered in the form of a liquid solution in which it is dissolved.

[0023] As used herein, “intravenous bolus” refers to a single dose of drug delivered over a short period of time by injection into a blood vessel. This term does not include forced injection, such as “IV bolus” administration.

[0024] "Ready-to-use" or "RTU" solutions are solutions that can be administered directly to a patient without further dilution and are supplied by the manufacturer accordingly, typically in sealed containers such as vials, bags, or ampoules. Any of the methods disclosed herein may be practiced using ready-to-use solutions.

[0025] discuss In one embodiment, this disclosure provides a method for safely administering funtopitan to a subject who requires it, the method comprising administering a liquid solution of funtopitan to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0026] In another embodiment, this disclosure provides a method for treating or preventing vomiting in a subject in need of it, the method comprising administering a therapeutically effective amount of dissolved fornetotipant to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0027] In another embodiment, this disclosure provides a method for treating or preventing nausea or vomiting in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of dissolved fornetotipant to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0028] In another embodiment, this disclosure provides a method for treating or preventing chemotherapy-induced nausea and vomiting in a subject in need, the method comprising administering, by intravenous bolus, to the subject 235 mg of formnetupitant (based on the weight of the free base) (equivalent to 260 mg of formnetupitant chloride hydrochloride) in the form of a ready-to-use solution for intravenous administration over a duration of 2-15 minutes. That is, the solution contains 260 mg of formnetupitant chloride hydrochloride dissolved therein, corresponding to 235 mg of formnetupitant free base.

[0029] A method for safely administering funtopitan to a subject in need of it, the method comprising administering a liquid solution of funtopitan to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0030] A method for treating or preventing vomiting in a subject in need of it, the method comprising administering a therapeutically effective amount of dissolved fornetotipant to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0031] A method for treating or preventing nausea and vomiting in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of dissolved fornetotipant to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0032] A method for treating or preventing chemotherapy-induced nausea and vomiting in a subject in need of such treatment, the method comprising administering 235 mg of formetupitant (based on the weight of the free base) (equivalent to 260 mg of formetupitant chloride hydrochloride) to the subject by intravenous bolus over a duration of 2–15 minutes.

[0033] Preferably, any method of this disclosure is implemented for the treatment or prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of highly emetogenic cancer chemotherapy.

[0034] In any embodiment of this disclosure, formetupitant is administered via a peripheral vein before or after the administration of a chemotherapeutic agent, and optionally in the same peripheral line as the chemotherapeutic agent, preferably undiluted. Formetupitant is preferably administered as a ready-to-use solution without the need for additional dilution or reconstitution from a lyophilized dose. In a particularly preferred embodiment, formetupitant is administered as a ready-to-use solution for intravenous bolus administration.

[0035] Preferably, any method of this disclosure is carried out without causing adverse reactions at the injection site. In one embodiment, the method is free from clinically significant adverse reactions selected from thrombophlebitis, necrosis, and vasculitis. In other embodiments, the method is free from clinically significant adverse reactions selected from application site erythema, ecchymosis, edema, pain, papules, paresthesia, swelling, and wheezing.

[0036] In some embodiments, the administration occurs over a duration ranging from 2 to 15 minutes. In other embodiments, the duration is approximately 2, 5, 10, or 15 minutes, or any interval defined between and including any of the aforementioned values. In other embodiments, administration is performed via intravenous bolus over a duration of 2 to 15 minutes. In other embodiments, administration is performed via intravenous bolus over a duration of 2, 5, 10, or 15 minutes, or any interval defined between and including any of the aforementioned values.

[0037] When implementing the methods of this disclosure, the amount of fornettopitant administered, the volume of administration, and the formulation used are all factors to consider. In some embodiments, fornettopitant is administered in the form of chloride hydrochloride. In some embodiments, about 235 mg of fornettopitant is administered (based on the weight of the free base) (equivalent to 260 mg of fornettopitant chloride hydrochloride).

[0038] In some embodiments, fornetutant is dissolved in about 10-30 mL of water, preferably 20 mL of water. The pH is preferably alkaline or slightly acidic. Therefore, in several embodiments, fornetutant is dissolved at a pH of 6-11, 7-10, or 8.5-9.5. In other embodiments, fornetutant is administered in an aqueous solution containing a chelating agent. In other embodiments, fornetutant is administered in an aqueous solution containing disodium ethylenediaminetetraacetate.

[0039] In some embodiments, the solution is isotonic. Therefore, it is preferably administered as an isotonic aqueous solution with a tensile strength of 270-330 mOsm / kg. In some embodiments, it is administered in an aqueous solution containing a tensile agent, preferably mannitol.

[0040] In one specific embodiment, floctopitan is dissolved in about 20 mL of water at a pH of 6 to 11 in the absence of any surfactants, antioxidants, or preservatives.

[0041] In another embodiment, funatetopitan is administered in an aqueous solution as a single agent containing no other active ingredients.

[0042] In another embodiment, fonetopitant is administered in an aqueous solution in combination with one or more other active ingredients. Preferred other active ingredients include 5-HT3 antagonists such as palonosetron, ondansetron, granisetron, and dolasetron.

[0043] In another specific embodiment, the method includes administering about 20 mL of a liquid solution comprising: about 235 mg of fornettopitan (based on the weight of the free base) (equivalent to 260 mg of fornettopitan chloride hydrochloride); about 3.2 mg of disodium ethylenediaminetetraacetate; about 760 mg of mannitol; sodium hydroxide and optionally hydrochloric acid to adjust the pH to about 8.5-9.5; and water measured to 20 mL.

[0044] The method is preferably followed by the administration of one or more chemotherapeutic agents. Therefore, in some embodiments, the method further includes intravenous chemotherapy administered approximately 60 minutes, 45 minutes, 30 minutes, or 15 minutes after an intravenous bolus injection. In one embodiment, the method further includes intravenous chemotherapy 30 minutes after an intravenous bolus injection.

[0045] Since NK1 and 5HT3 antagonists are typically administered intravenously after dilution, the method disclosed herein offers particular advantages when considering the possibility of insufficient solution for dilution. Furthermore, this method simplifies and reduces potential medication errors associated with product use. Additionally, the short bolus injection, rather than a 30-minute infusion, is far more effective, and the short bolus simplifies the management of patients who typically undergo complex cancer treatment regimens. More specifically, shortened infusion periods of less than 30 minutes, such as 15, 10, 5, or 2 minutes, improve the product's usability and benefits.

[0046] Shorter infusion times are highly beneficial for several reasons. For example, shorter infusion times lead to reduced seat occupancy, which in turn provides improved patient compliance and comfort, resulting in a better patient experience. Reduced seat occupancy is also beneficial for hospital and nurse management of patients, leading to overall optimization of procedures in terms of time and patient compliance.

[0047] In addition, given the shortage of solutions for dilution, ready-to-use solutions are advantageous; ready-to-use formulations do not require further dilution before application.

[0048] Other implementation methods

[0049] As an example of this disclosure, the following implementation methods are further provided.

[0050] [Embodiment 1] A method for safely administering funtopitan to a subject who requires it, the method comprising administering a liquid solution of funtopitan to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0051] [Embodiment 2] A method for treating or preventing vomiting in a subject who requires it, the method comprising administering a therapeutically effective amount of dissolved fornetotipant to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0052] [Embodiment 3] In another embodiment, this disclosure provides a method for treating or preventing nausea or vomiting in a subject who has a need for it, the method comprising administering a therapeutically effective amount of dissolved fornetotipant to the subject by intravenous bolus injection over a duration of 2-15 minutes.

[0053] [Embodiment 4] A method for treating or preventing chemotherapy-induced nausea and vomiting in a subject in need of such treatment, the method comprising administering, by intravenous bolus, 235 mg of formetupitant (based on the weight of the free base) (equivalent to 260 mg of formetupitant chloride hydrochloride) in a ready-to-use solution for intravenous administration to the subject over a duration of 2-15 minutes.

[0054] [Embodiment 5] The method according to any one of Embodiments 1-4 is performed without causing adverse reactions at the injection site.

[0055] [Embodiment 6] The method according to any one of Embodiments 1-5, wherein the duration is about 2, 5, 10 or 15 minutes.

[0056] [Embodiment 7] The method according to any one of Embodiments 1, 2, 3, 5 or 6, wherein fornetotitan is administered as chloride hydrochloride.

[0057] [Effective Method 8] The method according to any one of Embodiments 1, 2, 3, 5 or 6, wherein about 235 mg of fornetotipant (based on the weight of the free base) is administered (equivalent to 260 mg of chloride hydrochloride).

[0058] [Effective Method 9] The method according to any one of Embodiments 1-8, wherein funtopitan is dissolved in about 10-30 mL or 20 mL of water.

[0059] [Effective Method 10] The method according to any one of Embodiments 1-9, wherein floctopitan is dissolved at pH 6-11, 7-10 or 8.5-9.5.

[0060] [Embodiment 11] The method according to any one of Embodiments 1-10, wherein fornetotitan is administered in an aqueous solution containing a chelating agent.

[0061] [Embodiment 12] The method according to any one of Embodiments 1-11, wherein floctopitan is administered in an aqueous solution containing disodium ethylenediaminetetraacetate.

[0062] [Embodiment 13] The method according to any one of Embodiments 1-12, wherein formetalitol is administered as an isotonic aqueous solution having a tensile strength of 270-330 mOsm / kg.

[0063] [Embodiment 14] The method according to any one of Embodiments 1-13, wherein fornetotitan is administered in an aqueous solution containing a tensioning agent, preferably mannitol.

[0064] [Embodiment 15] The method according to any one of Embodiments 1-14, wherein fornetotitan is administered in an aqueous solution containing mannitol.

[0065] [Effective Method 16] The method according to any one of Embodiments 1-15, wherein floctopitan is dissolved in about 10-30 mL or 20 mL of water with a pH of 6 to 11 in the absence of any surfactant, antioxidant or preservative.

[0066] [Embodiment 17] The method according to any one of Embodiments 1-16, wherein fornetotipant is administered in an aqueous solution as a single reagent containing no other active ingredients.

[0067] [Embodiment 18] The method according to any one of Embodiments 1-16, wherein funtopitant is administered in combination with one or more other active ingredients in an aqueous solution.

[0068] [Embodiment 19] The method according to any one of Embodiments 1-18, the method comprising administering about 20 mL of a liquid solution comprising: (a) about 235 mg of fornetotitan (based on the weight of the free base) (equivalent to 260 mg of chloride hydrochloride); (b) about 3.2 mg of disodium ethylenediaminetetraacetate; (c) about 760 mg of mannitol; (d) sodium hydroxide and optionally hydrochloric acid to adjust the pH to about 8.5-9.5; and (e) water measured to 20 mL.

[0069] [Embodiment 20] The method according to any one of Embodiments 1-19 further includes intravenous chemotherapy administered less than or equal to about 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes or 2 minutes after the start or completion of intravenous bolus injection.

[0070] [Embodiment 21] The method according to any one of Embodiments 1-20 further includes intravenous chemotherapy at least 30 minutes after the start or completion of intravenous bolus injection.

[0071] [Embodiment 22] According to any one of Embodiments 1-21, wherein after intravenous bolus injection, less than or equal to about 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes or 2 minutes, fonetupitant is administered at the injection site and intravenous chemotherapy is administered at the same injection site.

[0072] [Effective Method 23] The method according to any one of Embodiments 1-22, wherein the administration does not have any clinically significant adverse reactions selected from thrombophlebitis, necrosis and vasculitis.

[0073] [Effective Method 24] The method according to any one of Embodiments 1-22, wherein the application does not have any clinically significant adverse reactions selected from the application site, such as erythema, ecchymosis, edema, pain, papules, paresthesia, swelling and wheezing.

[0074] [Embodiment 25] The method according to any one of Embodiments 1-22, wherein frinetopitant is administered as a ready-to-use solution.

[0075] [Effective Method 26] The method according to any one of Embodiments 1-25, wherein funtopitan is administered in undiluted form.

[0076] [Embodiment 27] The method according to any one of Embodiments 1-26, wherein fonetopitant is administered as a ready-to-use solution for intravenous bolus administration.

[0077] [Embodiment 28] The method according to any one of Embodiment 27 is used to treat or prevent acute and delayed nausea and vomiting associated with initial and repeated courses of highly emetogenic cancer chemotherapy.

[0078] [Embodiment 29] The method according to any one of Embodiments 1-28, wherein fornettopic tannin is administered via a peripheral vascular system without dilution.

[0079] Example In the following embodiments, work has been done to ensure accuracy relative to numerical values ​​(e.g., quantities, temperatures, etc.), but some errors and deviations may exist. The following embodiments are intended to provide a complete disclosure and illustration to those skilled in the art, illustrating the preparation and evaluation methods of the methods claimed in this disclosure, and the following embodiments are merely examples of this disclosure and are not intended to limit the scope of the inventors' belief that it falls within their invention.

[0080] Example 1. A Phase I, open-label, single-dose, two-part study in healthy male and female volunteers to evaluate the safety and pharmacokinetics of an IV bolus administration of 235 mg netupitant, as well as the derived netupitant and its metabolites.

[0081] Research Design: Open-label, single-dose, two-part (Part A and Part B) Phase I study of safety and pharmacokinetics. Part B will be conducted using a randomized crossover design.

[0082] Research products: The test product (T) was an intravenous (IV) solution of 235 mg free base of formetupitant, 20 mL ready-to-use solution manufactured by Patheon Italia SpA, Italy. The reference product was Akynzeo (235 mg formetupitant / 0.25 mg palonosetron) in an intravenous (IV) form of 20 mL injectable solution manufactured by Baxter Oncology GmbH, Germany. Optional, the placebo (P) product was a 0.9% sodium chloride injection solution of the same strength as the ready-to-use solution of IV formetupitant for intravenous administration (placebo), a commercially available product.

[0083] Dosage regimen / Part A: In Part A of the study, in cohort 1, following a randomized parallel group design, 10 healthy volunteers (HVs) will receive the T dose as a single 30-minute IV infusion, while another 10 subjects will receive a single IV dose of undiluted R (therapeutic Rα) as a single 30-minute IV infusion of 20 mL. In each of the three consecutive cohorts (cohorts 2, 3, and 4), 10 healthy volunteers (HVs) will receive a single IV dose of T. In cohorts 2, 3, and 4, the T infusion will be administered using an alternating approach that reduces the infusion duration. Therefore, the duration of the T infusion will vary in each cohort as follows: Group 1: 30 min (T or Rα) Group 2: 15 min (T) Group 3: 5 min (T) Group 4: 2 min(T) At the end of each cohort, safety and tolerability results will be evaluated. Pre-defined stopping rules will be considered to determine whether to proceed to the next cohort and for a shorter injection duration. Following cohort 1, if a 30-minute injection duration at T is proven safe and well-to-be-tolerated, a 15-minute duration will be tested in cohort 2. Following cohort 2, if a 15-minute injection duration is proven safe and well-to-be-tolerated, a 5-minute duration will be tested in cohort 3. Following cohort 3, if a 5-minute injection duration is proven safe and well-to-be-tolerated, a 2-minute duration will be tested in cohort 4. At the end of Part A of Study A, the organizers will make a final decision on whether to proceed to Part B based on the shortest injection duration determined in Part A and deemed appropriate in terms of safety.

[0084] Part B of the study will employ a two-way crossover randomized design and will include 40 male and female participants. Prior to the crossover phase, each participant will receive P for the shortest infusion duration determined in Part A of the study. Subsequently, over two consecutive crossover periods, each participant will receive T for the shortest infusion duration deemed safe and well-tolerated as determined in Part A, with 20 mL of R solution diluted to 50 mL with 0.9% sodium chloride injection over 30 min.

[0085] The main objectives of Part A: The shortest, safe, and tolerable duration of IV injection T was determined from four test durations arranged in descending order: 30, 15, 5, and 2 min. The selected shortest (safe and tolerable) injection duration determined in Part A will be considered for testing in Part B.

[0086] Secondary objectives of Part A: The pharmacokinetic profiles of funeptetin, netupeptetin, and netupeptetin metabolites M1, M2, and M3 in plasma were characterized at the relevant injection durations following injection T and injection of undiluted R (defined as Rα).

[0087] Determine the safety and tolerability of administering T at the relevant injection duration.

[0088] The main objectives of Part B are: The study in Part A defines the exposure equivalence between the minimum safe injection duration (T) and the exposure rate (R) as a 30-minute diluted infusion. This will be based on the level of netupitant exposure (AUC). 0-∞ and AUC 0-t Estimate exposure equivalence.

[0089] Secondary objectives of Part B: The pharmacokinetic profiles of funeptetin, netupitant, and netupitant metabolites M1, M2, and M3 in plasma were characterized in Part A as the shortest safe injection duration of administration (T) and as a 30-minute dilution infusion (R).

[0090] The safety and tolerability of T administered at the shortest injection duration defined as safe in Part A were confirmed compared to R administered as a 30-minute diluted infusion.

[0091] Evaluate the effect of T on ECG parameters (heart rate, QT, QTcF, QTcB, PR, and QRS interval).

[0092] In healthy male and female subjects, evaluate the effect of administration of fonetopipant at the shortest infusion time (as defined in Part A) on the QT interval compared with placebo.

[0093] The main endpoint of Part A: The type, number, and frequency of treatment-emergent adverse events were collected 24 hours after administration.

[0094] The main endpoint of Part B: The area under the plasma concentration-time curve (AUC) of netutopistane from time 0 to the last measurable concentration or to infinity was calculated after administration of netutopistane at the infusion duration selected in Part A (T) and after administration of netutopistane as a 30-minute dilution infusion (R). 0-t and AUC 0-∞ .

[0095] Secondary safety endpoints in Part A: Vital signs (blood pressure, pulse rate), 12-lead ECG, clinical laboratory tests (blood chemistry, hematology and urine analysis), weight and physical examination.

[0096] Secondary safety endpoints in Part B: Safety and tolerability parameters of T relative to R (treatment-induced adverse events, vital signs [blood pressure, pulse rate], 12-lead ECG, clinical laboratory tests (blood chemistry, hematology and urine analysis), weight and physical examination).

[0097] Cardiac evaluation.

[0098] Secondary PK endpoints for Part A and Part B: For plasma fonetipantan, netupitantan, and its major metabolites M1, M2, and M3, when applicable: C0, C max t max C 最终 t 最终 AUC 0-t(For all analytes, the AUC of netupitant in Part B) 0-t Except for the primary endpoint), AUC 0-24 lz t 1 / 2 , CL, Vz, MRT.

[0099] Secondary PK endpoint for Part B only: For plasma fnettopitant, nettopitant, and its major metabolites M1, M2, and M3, when applicable: AUC 0-120 AUC 0-∞ (Netopitane AUC) 0-∞ Except, this is the primary endpoint. For plasma fonetipantin: R AUC fos / netu For plasma M1:R AUC M1 / netu For plasma M2:R AUC M2 / netu For plasma M3:R AUC M3 / netu The sample size for the netutopeptide exposure equivalence (netutopeptide AUC) evaluation in Part B of this study was 40 healthy male and female participants, with 34 participants completing the study. No replacements will be made for those who drop out. Inclusion criteria included healthy male / female volunteers, aged 18–55 years (inclusive), and a body mass index (BMI) of 18.5–30 kg / m². 2 (inclusive).

[0100] * * * * * * * * Several publications have been referenced in this application. The entire contents of these publications are incorporated herein by reference to provide a more complete description of the prior art to which this disclosure pertains. It will be apparent to those skilled in the art that various modifications and alterations can be made to this disclosure without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art upon consideration of this specification and practice of the disclosure herein. This specification and embodiments are provided as exemplary only, and the true scope and spirit of this disclosure are defined by the following claims.

Claims

1. A solution of fonetopitant for use in a method of safe administration to a subject in need thereof, wherein the subject is administered a liquid solution of fonetopitant by intravenous bolus over a duration of 2-15 minutes.

2. For use in a method of treating or preventing vomiting in a subject in need of such treatment, wherein a therapeutically effective amount of dissolved fornettopitan is administered to the subject by intravenous bolus over a duration of 2-15 minutes.

3. For use in a method of treating or preventing nausea or vomiting in a subject in need of such treatment, wherein a therapeutically effective amount of dissolved fornetutant is administered to the subject by intravenous bolus over a duration of 2-15 minutes.

4. For use in a method of treating or preventing chemotherapy-induced nausea and vomiting in a subject in need thereof, wherein 235 mg of fornettopitan in a ready-to-use solution for intravenous administration, which is equivalent to 260 mg of fornettopitan chloride hydrochloride based on the weight of the free base, is administered to the subject by intravenous bolus over a duration of 2–15 minutes.

5. The use of fonetostilbene according to any one of claims 1-4, wherein it is administered without causing adverse reactions at the injection site.

6. Formetopistan for use according to any one of claims 1-5, wherein the duration is about 2, 5, 10 or 15 minutes.

7. Fornettopitan for use according to any one of claims 1, 2, 3, 5 or 6, wherein fornettopitan is administered as a chloride hydrochloride salt.

8. The formetupitant for use according to any one of claims 1, 2, 3, 5 or 6, wherein about 235 mg of formetupitant is administered, which, based on the weight of the free base, is equivalent to 260 mg of formetupitant chloride hydrochloride.

9. The formetalitol for use according to any one of claims 1-8, wherein the formetalitol is dissolved in about 10-30 mL or 20 mL of water.

10. The formetalitol for use according to any one of claims 1-9, wherein the formetalitol is dissolved at pH 6-11, 7-10 or 8.5-9.

5.

11. The formetalitant for use according to any one of claims 1-10, wherein formetalitant is administered in an aqueous solution containing a chelating agent.

12. The formetalitant for use according to any one of claims 1-11, wherein formetalitant is administered in an aqueous solution containing disodium ethylenediaminetetraacetate.

13. Fornettopitan for use according to any one of claims 1-12, wherein fornettopitan is administered as an isotonic aqueous solution having a tensile strength of 270-330 mOsm / kg.

14. Fornettopant for use according to any one of claims 1-13, wherein fornettopant is administered in an aqueous solution containing a tonic agent, preferably mannitol.

15. Fornettopic tandem for use according to any one of claims 1-14, wherein fornettopic tandem is administered in an aqueous solution containing mannitol.

16. The formetalitol for use according to any one of claims 1-15, wherein formetalitol is dissolved in about 10-30 mL or 20 mL of water at a pH of 6-11 in the absence of any surfactant, antioxidant or preservative.

17. The formetalitol for use according to any one of claims 1-16, wherein formetalitol is administered in an aqueous solution as a single agent free of any other active ingredients.

18. The formetalitol for use according to any one of claims 1-16, wherein formetalitol is administered in combination with one or more other active ingredients in an aqueous solution.

19. The fonetostitol for use according to any one of claims 1-18, comprising administering about 20 mL of a liquid solution, said liquid solution comprising: a) Approximately 235 mg of formetupitant, which, based on the weight of the free base, is equivalent to 260 mg of formetupitant chloride hydrochloride; b) Approximately 3.2 mg of disodium ethylenediaminetetraacetate; c) Approximately 760 mg of mannitol; d) Sodium hydroxide and optionally hydrochloric acid to adjust the pH to approximately 8.5-9.5; and e) Quantify to 20 mL of water.

20. The fonetopitant for use according to any one of claims 1-19, further comprising intravenous chemotherapy administered less than or equal to about 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes, or 2 minutes after the start or completion of an intravenous bolus injection.

21. The fonetupitant for use according to any one of claims 1-20, further comprising intravenous chemotherapy less than or equal to about 30 minutes after the start or completion of the intravenous bolus injection.

22. The fonetopitant for use according to any one of claims 1-21, wherein fonetopitant is administered at the injection site and intravenous chemotherapy is administered at the same injection site less than or equal to about 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes, or 2 minutes after the start or completion of intravenous bolus injection.

23. The use of fonetopitol according to any one of claims 1-22, wherein the administration is free from clinically significant adverse reactions selected from thrombophlebitis, necrosis, and vasculitis.

24. Fornettopitan for use according to any one of claims 1-22, wherein the administration is free from clinically significant adverse reactions selected from erythema, ecchymosis, edema, pain, papules, paresthesia, swelling and wheezing at the site of application.

25. The formetalitant for use according to any one of claims 1-24, wherein formetalitant is administered as an ready-to-use solution.

26. The use of formetupitant according to any one of claims 1-25, wherein formetupitant is administered in undiluted form.

27. The formetalitant for use according to any one of claims 1-26, wherein formetalitant is administered as a ready-to-use solution for intravenous bolus administration.

28. The fonetupitant for use according to any one of claims 27, for the treatment or prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of highly emetogenic cancer chemotherapy.

29. Fornettopic tan for use according to any one of claims 1-28, wherein fornettopic tan is administered via a peripheral vein without dilution.

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