WO2025036703A1

WO2025036703A1 - Fosnetupitant for administration via intravenous bolus

Info

Publication number: WO2025036703A1
Application number: PCT/EP2024/071640
Authority: WO
Inventors: Flavio Fabiani; Marco GUANCI; Stefano FRIZZARIN; Fabio Trento
Original assignee: Helsinn Healthcare SA
Current assignee: Helsinn Healthcare SA
Priority date: 2023-08-13
Filing date: 2024-07-31
Publication date: 2025-02-20
Anticipated expiration: 2026-02-13

Abstract

Improved methods of administering neurokinin-1 receptor antagonists, preferably fosnetupitant, via intravenous bolus, preferably over reduced periods of time.

Description

FOSNETUPITANT FOR ADMINISTRATION VIA INTRAVENOUS BOLUS

FIELD

The current disclosure relates to improved methods of administering neurokinin-1 receptor antagonists, particularly fosnetupitant, via intravenous bolus.

BACKGROUND

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

Because netupitant is insoluble in water as such, its phosphorylated prodrug (“fosnetupitant”) is commonly employed for intravenous (IV) administration. An IV fixed dose combination of fosnetupitant and palonosetron was approved in the United States in 2018 as Akynzeo® for injection, indicated in prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Akynzeo® for injection is a lyophilized powder to be reconstituted and further diluted to 50 mL, in either 5% dextrose injection or 0.9% sodium chloride injection, to be administered as a 30 min IV infusion, starting 30 min before chemotherapy. A liquid formulation of IV NEPA was subsequently approved with substantially the same indication and directions of use as the lyophilized form.

What is needed are more convenient administration regimens for NK-1 receptor antagonists, that can be accomplished in shorter time frames, without causing adverse events such as injection site reactions. SUMMARY OF DISCLOSURE

Methods of administering fosnetupitant have unexpectedly been discovered that are safe, efficient, and highly effective. In one embodiment the disclosure provides a method of safely administering fosnetupitant to a human subject in need thereof comprising administering to the subject a liquid solution of fosnetupitant over a duration of 2-15 minutes via an intravenous bolus.

In another embodiment the disclosure provides a method of treating or preventing emesis in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of solubilized fosnetupitant over a duration of 2-15 minutes via an intravenous bolus.

In another embodiment the disclosure provides a method of treating or preventing nausea or vomiting in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of solubilized fosnetupitant over a duration of 2-15 minutes via an intravenous bolus.

In still another embodiment the disclosure provides a method of treating or preventing chemotherapy induced nausea and vomiting in a human subject in need thereof, comprising administering to the subject 235 mg of fosnetupitant (based on the weight of the free base) (equivalent to 260 mg fosnetupitant chloride hydrochloride) in a ready to use solution for intravenous administration over a duration of 2-15 minutes via an intravenous bolus.

Additional advantages of the disclosure are set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the disclosure. The advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed.

DETAILED DESCRIPTION

Definitions and Use of Terms

As used in this specification and in the claims which follow, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. As used in this specification and in the claims which follow, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. When an element is described as comprising a plurality components, steps or conditions, it will be understood that the element can also be described as comprising any combination of such plurality, or “consisting of’ or “consisting essentially of’ the plurality or combination of components, steps or conditions.

“Therapeutically effective amount” means that amount which, when administered to a human for supporting or affecting a metabolic process, or for treating or preventing a disease, is sufficient to cause such treatment or prevention of the disease, or supporting or affecting the metabolic process.

When ranges are given by specifying the lower end of a range separately from the upper end of the range, or specifying particular numerical values, it will be understood that a range can be defined by selectively combining any of the lower end variables, upper end variables, and particular numerical values that is mathematically possible. In like manner, when a range is defined as spanning from one endpoint to another, the range will be understood also to encompass a span between and excluding the two endpoints.

When used herein the term “about” will compensate for variability allowed for in the pharmaceutical industry and inherent in products in this industry, such as differences in product strength due to manufacturing variation and time-induced product degradation. The term allows for any variation which in the practice of good manufacturing practices would allow the product being evaluated to be considered therapeutically equivalent or bioequivalent in humans to the recited strength of a claimed product.

In the context of the present disclosure insofar as it relates to any of the disease conditions recited herein, the term “treatment” means to reduce the occurrence of a symptom or condition, or to relieve or alleviate at least one symptom associated with such condition, or to slow or reverse the progression of such condition, or to manage or affect the metabolic processes underlying such condition. Within the meaning of the present disclosure, the terms also denote to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease. The phrase “acceptable” as used in connection with compositions of the disclosure, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a subject (e.g., a mammal such as a human).

Fosnetupitant is known chemically as 4-(5-(2-(3,5-bis(trifhroromethyl)phenyl)-N,2- dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-l -methyl-1 -((phosphonooxy)methyl) piperazin-1 - ium. The compound has the following chemical structure in its free form:

The molecular weight of the compound in its free form is 688.6 g/mol. The molecular weight of the chloride hydrochloride salt is 761.53 g/mol. A method of preparing fosnetupitant is described in WO 2013/082102.

The term “fosnetupitant,” when used herein, includes both the free form of fosnetupitant and pharmaceutically acceptable salts thereof unless specifically recited otherwise. When the term fosnetupitant is succeeded in parentheses by an equivalence to a salt, e.g. “(equivalent to xx mg of a particular salt)”, it is meant that the fosnetupitant is included in the formulation as the recited salt, and that the recited salt has been added in the equivalent amount. If reference is made to a solution comprising a salt such as fosnetupitant chloride hydrochloride, consistent with terminology employed by pharmaceutical chemists, the fosnetupitant chloride hydrochloride can be in solution and still be referred to as fosnetupitant chloride hydrochloride despite any disassociation of counter-ions.

“Emesis,” is a term of art used in the field of cancer supportive care and, as used in the current document and the field of cancer supportive care, refers to the act of vomiting or retching (i.e. the action of the stomach and esophagus to try to vomit (eject some or all of the contents of the stomach), including retching that does not cause vomiting which is also known as dry heaves). In like manner, “chemotherapy induced nausea and vomiting” or “CINV” is a technical term of art. The treatment or prevention of CINV is thus defined herein and in the field of cancer supportive care as “complete response,” meaning no emetic episodes, and no rescue medication, in response to the administration of chemotherapy, typically over a defined period. The term “nausea” is a subjective feeling of sickness or discomfort in the stomach that may come with an urge to vomit and is not an element of emesis or CINV. All of the methods of the current disclosure can be used to treat or prevent emesis, nausea, and/or CINV.

“CINV” may also be referred to as “nausea and vomiting associated with cancer chemotherapy,” or using words of like import, which can further be defined as: (1) CINV occurring during the “acute” phase (i.e. during the first 24 hours after chemotherapy administration) and/or the “delayed” phase (i.e. during the time period 25-120 hours after chemotherapy administration), and/or (2) CINV occurring during an initial course of chemotherapy or multiple (i. e. repeat) courses of chemotherapy, and/or (3) CINV occurring in response to low emetogenic (LEC), moderately emetogenic (MEC), or highly emetogenic (HEC) chemotherapy, as defined in various references including Hesketh PJ, J Clin Oncol 2016; 34:381. Thus, any of the methods of the current disclosure can be practiced to treat or prevent acute and delayed nausea and vomiting associated with initial and repeat courses of moderately or highly emetogenic cancer chemotherapy.

The term “solution” as used herein refers to a liquid mixture in which the minor component (the solute) is dissolved / solubilized and uniformly distributed within the major component (the solvent). Thus, a “liquid solution” of fosnetupitant refers to a liquid in which the fosnetupitant is fully dissolved and uniformly distributed. The terms “dissolved” and “solubilized” are used interchangeably herein. In all of the embodiments of the current disclosure, the fosnetupitant is administered as a liquid solution, solubilized therein.

An “intravenous bolus” as used herein refers to a single dose of a drug given over a short period of time by injection into a blood vessel. The term excludes forced injections such as “push IV” administration.

A “ready to use” or “RTU” solution refers to a solution which can be administered directly to a patient without further dilution, and is supplied by the manufacturer as such, commonly in a sealed container such as a vial, bag or ampule. Any of the methods of the current disclosure can be practiced using a ready to use solution. Discussion

In one embodiment the disclosure provides a method of safely administering fosnetupitant to a human subject in need thereof comprising administering to the subject a liquid solution of fosnetupitant over a duration of 2-15 minutes via an intravenous bolus.

In still another embodiment the disclosure provides a method of treating or preventing chemotherapy induced nausea and vomiting in a human subject in need thereof, comprising administering to the subject 235 mg of fosnetupitant (based on the weight of the free base) (equivalent to 260 mg fosnetupitant chloride hydrochloride) in a ready to use solution for intravenous administration over a duration of 2-15 minutes via an intravenous bolus. I.e., the solution comprises 260 mg of fosnetupitant chloride hydrochloride salt solubilized therein, corresponding to 235 mg of fosnetupitant free base.

A method of safely administering fosnetupitant to a human subject in need thereof comprising administering to the subject a liquid solution of fosnetupitant over a duration of 2-15 minutes via an intravenous bolus.

A method of treating or preventing emesis in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of solubilized fosnetupitant over a duration of 2-15 minutes via an intravenous bolus.

A method of treating or preventing nausea and vomiting in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of solubilized fosnetupitant over a duration of 2-15 minutes via an intravenous bolus.

A method of treating or preventing chemotherapy induced nausea and vomiting in a human subject in need thereof, comprising administering to the subject 235 mg fosnetupitant (based on the weight of the free base) (equivalent to 260 mg fosnetupitant chloride hydrochloride) over a duration of 2-15 minutes via an intravenous bolus.

Any of the method of the current disclosure are preferably performed for treating or preventing of acute and delayed nausea and vomiting associated with initial and repeated courses of highly emetogenic cancer chemotherapy.

In any of the embodiments of the current disclosure, the fosnetupitant is administered via a peripheral line, preferably without dilution, either before or after administration of the chemotherapy agent and optionally in the same peripheral line as the chemotherapy agent. The fosnetupitant is preferably administered as a ready to use solution, not requiring additional dilutions or reconstituted from a lyophilized dosage form. In a particularly preferred embodiment, the fosnetupitant is administered as a ready to use solution for intravenous bolus administration.

Any of the methods of the current disclosure are preferably undertaken without causing injection site adverse reactions. In one embodiment the methods are free of clinically significant adverse reactions selected from thrombophlebitis, necrosis and vasculitis. In other embodiments the methods are free of clinically significant adverse reactions selected from administration-site erythema, bruising, edema, pain, papule, paresthesia, swelling, and dyspnea.

In some embodiments the duration of the administration occurs in the range of 2-15 minutes. In other embodiments, the duration is about 2, 5, 10, or 15 minutes, or any interval defined between and including any of the foregoing values. In other embodiments the administration occurs over a duration of 2-15 minutes via an intravenous bolus. In other embodiments the administration occurs over a duration of 2, 5, 10, or 15 minutes, or any interval defined between and including any of the foregoing values, via an intravenous bolus.

The amount of fosnetupitant administered, the volume of administration, and the formulation administered are all factors to be considered when performing the methods of the disclosure. In some embodiments, the fosnetupitant is administered as the chloride hydrochloride salt. In some embodiments about 235 mg fosnetupitant (based on the weight of the free base) (equivalent to 260 mg fosnetupitant chloride hydrochloride) is administered.

In some embodiments the fosnetupitant is solubilized in about from 10-30 mL of water, preferably 20 mL of water. The pH is preferably basic or slightly acidic. Thus, in various embodiments the fosnetupitant is solubilized at a pH of 6-11, 7-10, or 8.5-9.5. In other embodiments the fosnetupitant is administered in an aqueous solution comprising a chelating agent. In still other embodiments the fosnetupitant is administered in an aqueous solution comprising disodium edetate.

In some embodiments the solution will be isotonic. Thus, the fosnetupitant is preferably administered as an aqueous isotonic solution having a tonicity of 270-330 mOsm/kg. In some embodiments the fosnetupitant is administered in an aqueous solution comprising a tonicity agent, preferably mannitol.

In one particular embodiment the fosnetupitant is solubilized in about 20 mL of water at a pH of from 6 to 11, in the absence of any surfactants, antioxidants, or preservatives.

In another embodiment the fosnetupitant is administered in an aqueous solution as a single agent free of any other active ingredients.

In still another embodiment, the fosnetupitant is administered in an aqueous solution in combination with one or more additional active ingredients. Preferred additional active ingredients include 5-HT3 antagonists such as palonosetron, ondansetron, granisetron, and dolasetron.

In another particular embodiment, the methods comprise administering about 20 mL of a liquid solution comprising: about235 mg ofthe fosnetupitant (based on the weight ofthe free base) (equivalent to 260 mg fosnetupitant chloride hydrochloride); about 3.2 mg disodium edetate; about 760 mg mannitol; sodium hydroxide and optionally hydrochloric acid to a pH of about 8.5 -9.5; and water q.s. to 20 mL.

The methods are preferably followed by the administration of one or more chemotherapy agents. Thus, in some embodiments the method further intravenous chemotherapy administered about 60 minutes, 45 minutes, 30 minutes, or 15 minutes after the intravenous bolus. In one embodiment the methods further comprise intravenous chemotherapy 30 minutes after the intravenous bolus.

As NK1 and 5HT3 antagonists are conventionally administered after dilution via an intravenous drip, the methods of the current disclosure offer particular advantages when considering the possibility of shortages of solutions used for dilution. In addition, the methods simplify and reduce potential medication errors associated with the use of the product. Additionally, a short bolus injection instead of a 30 min infusion is much more efficient and simplifies the management of patients who are commonly undergoing complex treatment regimens for cancer. More particularly, a shortened period of infusion time less than 30 minutes, such as 15, 10, 5 or 2 minutes, improves the utility and advantages of the product. A shortened infusion time is significantly advantageous for several reasons. For example, a shortened infusion time leads to a reduced chair occupancy providing improved compliance and comfort for the patient leading to a better patient experience. A reduced chair occupancy is also advantageous for the management of the patient by the hospital and the nurse, leading to an overall optimization of the procedures in terms of time and patient compliance.

In addition to that, a ready to use solution is advantageous considering the shortage of solutions used for dilution; a ready to use formulation has no need of further dilution before administration.

ADDITIONAL EMBODIMENTS

The following embodiments are further provided as exemplary of the current disclosure.

[Embodiment 1] A method of safely administering fosnetupitant to a human subject in need thereof comprising administering to the subject a liquid solution of fosnetupitant over a duration of 2-15 minutes via an intravenous bolus.

[Embodiment 2] A method of treating or preventing emesis in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of solubilized fosnetupitant over a duration of 2-15 minutes via an intravenous bolus.

[Embodiment 3] In another embodiment the disclosure provides a method of treating or preventing nausea or vomiting in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of solubilized fosnetupitant over a duration of 2-15 minutes via an intravenous bolus.

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

[Embodiment 5] The method of any of embodiments 1-4, undertaken without causing injection site adverse reactions.

[Embodiment 6] The method of any of embodiments 1-5, wherein the duration is about 2, 5, 10, or 15 minutes. [Embodiment 7] The method of any of embodiments 1, 2, 3, 5, or 6, wherein the fosnetupitant is administered as the chloride hydrochloride salt.

[Embodiment 8] The method of any of embodiments 1, 2, 3, 5, or 6, wherein about 235 mg of the fosnetupitant (based on the weight of the free base) (equivalent to 260 mg chloride hydrochloride) is administered.

[Embodiment 9] The method of any of embodiments 1-8, wherein the fosnetupitant is solubilized in about 10-30 mL or 20 mL of water.

[Embodiment 10] The method of any of embodiments 1-9, wherein the fosnetupitant is solubilized at a pH of 6-11, 7-10, or 8.5-9.5.

[Embodiment 11] The method of any of embodiments 1-10, wherein the fosnetupitant is administered in an aqueous solution comprising a chelating agent.

[Embodiment 12] The method of any of embodiments 1-11, wherein the fosnetupitant is administered in an aqueous solution comprising disodium edetate.

[Embodiment 13] The method of any of embodiments 1-12, wherein the fosnetupitant is administered as an aqueous isotonic solution having a tonicity of 270-330 mOsm/kg.

[Embodiment 14] The method of any of embodiments 1-13, wherein the fosnetupitant is administered in an aqueous solution comprising a tonicity agent, preferably mannitol.

[Embodiment 15] The method of any of embodiments 1-14, wherein the fosnetupitant is administered in an aqueous solution comprising mannitol.

[Embodiment 16] The method of any of embodiments 1-15, wherein the fosnetupitant is solubilized in about 10-30 mL or 20 mL of water at a pH of from 6 to 11, in the absence of any surfactants, antioxidants, or preservatives.

[Embodiment 17] The method of any of embodiments 1-16, wherein the fosnetupitant is administered in an aqueous solution as a single agent free of any other active ingredients

[Embodiment 18] The method of any of embodiments 1-16, wherein the fosnetupitant is administered in an aqueous solution in combination with one or more additional active ingredients.

[Embodiment 19] The method of any of embodiments 1-18, comprising administering about 20 mL of a liquid solution comprising: (a) about 235 mg of the fosnetupitant (based on the weight of the free base) (equivalent to 260 mg of the chloride hydrochloride salt); (b) about 3.2 mg disodium edetate; (c) about 760 mg mannitol; (d) sodium hydroxide and optionally hydrochloric acid to a pH of about 8.5-9.5; and (e) water q.s. to 20 mL. [Embodiment 20] The method of any of embodiments 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 initiating or completing intravenous bolus.

[Embodiment 21 ] The method of any of embodiments 1 -20, further comprising intravenous chemotherapy less than or equal to 30 minutes after initiating or completing intravenous bolus.

[Embodiment 22] The method of any of embodiments 1-21, wherein the fosnetupitant is administered at an 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 intravenous bolus.

[Embodiment 23] The method of any of embodiments 1-22, wherein the administration is free of clinically significant adverse reactions selected from thrombophlebitis, necrosis and vasculitis.

[Embodiment 24] The method of any of embodiments 1 -22, wherein the administration is free of clinically significant adverse reactions selected from administration-site erythema, bruising, edema, pain, papule, paresthesia, swelling, and dyspnea.

[Embodiment 25] The method of any of embodiments 1-22, wherein the fosnetupitant is administered as a ready to use solution.

[Embodiment 26] The method of any of embodiments 1-25, wherein the fosnetupitant is administered in undiluted form.

[Embodiment 27] The method of any of embodiments 1-26, wherein fosnetupitant is administered as a ready to use solution for intravenous bolus administration.

[Embodiment 28] The method of any of embodiments 27, for treating or preventing of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.

[Embodiment 29] The method of any of embodiments 1-28, wherein the fosnetupitant is administered via a peripheral line without dilution.

EXAMPLES

In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their invention.

Example 1. A phase I, open label, single dose, two parts study in male and female healthy volunteers to assess the safety and pharmacokinetics of Fosnetupitant 235 mg administered as IV bolus and of derived Netupitant and Netupitant metabolites.

Study design: Open label, single dose, two parts (part A and part B), safety and pharmacokinetics phase I study. Study Part B will be conducted according to a randomized crossover design.

Investigational products: The test (T) product is an intravenous (IV) solution of fosnetupitant 235 mg free base 20 m ready to use solution manufactured by Patheon Italia S.p. A., Italy. The reference product is an intravenous (IV) version of Akynzeo (235 mg fosnetupitant/0.25 mg palonosetron) in 20 mL injectable solution manufactured by Baxter Oncology GmbH, Germany. The placebo (P) product, which is optional, is a 0.9% sodium chloride injection solution matching IV fosnetupitant 20 mL ready to use solution for intravenous administration (placebo), commercially available product purchased from the market.

Dose regimens / Part A: In Part A of the study, cohort 1, 10 healthy volunteers (HV) will receive a dose of T as a one single 30-min IV infusion and additional 10 subjects will receive a single IV dose of undiluted R (treatment Ra) as a one single 30-min IV infusion of 20 mL, according to a randomized parallel group design. In each of 3 consecutive cohorts - 2, 3 and 4, - 10 healthy volunteers (HV) will receive a single IV dose of T. A staggered approach with decreasing infusion time duration will be applied to the injection of T in cohorts 2, 3 and 4. Therefore, in each cohort, the T injection duration will vary as follows:

• Cohort 1: 30 min (T or Ra)

• Cohort 2: 15 min (T)

• Cohort 3 : 5 min (T)

• Cohort 4: 2 min (T)

At the end of each cohort, safety and tolerability results will be evaluated. Predefined stopping rules will be considered for deciding whether to with the next cohort and a shorter injection duration. After cohort 1, if the injection duration of 30 min of T proves to be safe and well tolerated, 15 min will be tested in cohort 2. After cohort 2, if the injection duration of 15 min proves to be safe and well-tolerated, 5 min will be tested in cohort 3. After cohort 3, if the injection duration of 5 min proves to be safe and well-tolerated, 2 min will be tested in cohort 4. At the end of study Part A, the Sponsor will take a final decision whether to proceed with study Part B with the resulting shortest injection duration considered as adequate in terms of safety determined in study Part A.

Part B of the study will follow a 2-way, cross-over randomized design and will include 40 male and female subjects. Before entering the crossover phase, each subject will receive P at the shortest infusion duration determined in study Part A. Afterwards, in 2 consecutive crossover periods, each subject will receive T at the shortest injection duration considered as safe and well tolerated, determined in study part A, and 20 mL of solution of R diluted to 50 mL with 0.9% sodium chloride injection solution and infused in 30 min.

Primary objective of Part A: To define the shortest safe and tolerable duration of IV injection of T among 4 durations tested in decreasing order: 30, 15, 5 and 2 min, respectively. The selected shortest (safe and tolerable) injection duration determined in part A will be considered for testing in study Part B.

Secondary objectives of Part A:

• to characterize the pharmacokinetic profile in plasma of fosnetupitant, netupitant and netupitant metabolites Ml, M2 and M3 after injection of T administered at the relevant injection duration and after injection of undiluted R (defined as Ra).

• to determine the safety and tolerability of T administered at the relevant injection duration.

Primary objective of Part B: To investigate the exposure equivalence of T, at the shortest injection duration defined as safe in Part A, and R, administered as a 30 min diluted infusion. The equivalence in exposure will be estimated in terms of extent of exposure to netupitant (AUCo-oo and AUCo-t).

Secondary objectives of Part B:

• To characterize the pharmacokinetic profile in plasma of fosnetupitant, netupitant and netupitant metabolites Ml, M2 and M3 after administration of T at the shortest injection duration defined as safe in Part A and R administered as 30 min diluted infusion.

• To confirm the safety and tolerability of T administered at the shortest injection duration defined as safe in Part A in comparison to R, administered as a 30 min diluted infusion.

• To assess the effect of T on ECG parameters (heart rate, QT, QTcF, QTcB, PR and QRS intervals).

• To assess the effects of the administration of fosnetupitant on the QT interval in the shortest infusion time (defined in Part A) compared to placebo, in male and female healthy subjects.

Primary endpoint of Part A: Type, number and frequency of treatment-emergent adverse events collected up to 24 h post-dose.

Primary endpoint of Part B: Area under the plasma concentration-time curve of netupitant from time zero to the time of last measurable concentration or to infinity, AUCo-t and AUCo-oo following administration of T, at the infusion duration selected in Part A, and R administered as 30 min diluted infusion.

Secondary safety endpoints of Part A: Vital signs (blood pressure, pulse rate), 12-lead ECG, clinical laboratory tests (blood chemistry, hematology and urinalysis), body weight and physical examination.

Secondary safety endpoints of Part B:

• Safety and tolerability parameters of T versus R (treatment-emergent adverse events, vital signs [blood pressure, pulse rate], 12-lead ECG, clinical laboratory tests (blood chemistry, hematology and urinalysis), body weight and physical examination.

• Cardiac evaluations.

Secondary PK endpoints of Part A and B: For plasma fosnetupitant, netupitant and its main metabolites Ml, M2 and M3, when applicable: Co, C_max, t_max, Ci_ast, ti_ast, AUCo-t (for all analytes with exception of netupitant AUCo-t in Part B, which is the primary endpoint), AUC0-24, lz, ty₂, CL, Vz, MRT.

Secondary PK endpoints of Part B only: For plasma fosnetupitant, netupitant and its main metabolites Ml, M2 and M3, when applicable: AUC0-120, AUCo-00 (with exception of netupitant AUCo-00, which is the primary endpoint) For plasma fosnetupitant: RAucfos/netu

For plasma Ml : RAucMl/netu

For plasma M2: RAucM2/netu

For plasma M3: RAucM3/netu The sample size for the netupitant exposure equivalence (netupitant AUC) assessment in

Part B of the study will be 40 healthy male and female subjects in order to have 34 completed subjects. Drop-outs will not be replaced. Select inclusion criteria include healthy men/women volunteers, 18-55 years old (inclusive) and Body Mass Index (BMI) 18.5-30 kg/m² inclusive. Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this disclosure pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present 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 from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims

1 ) Fosnetupitant for use in a method of safe administration to a human subject in need thereof, wherein a liquid solution of fosnetupitant is administered to the subject over a duration of 2-15 minutes via an intravenous bolus.

2) Fosnetupitant for use in a method of treating or preventing emesis in a human subject in need thereof, wherein a therapeutically effective amount of solubilized fosnetupitant is administered to the subject over a duration of 2-15 minutes via an intravenous bolus.

3) Fosnetupitant for use in a method of treating or preventing nausea or vomiting in a human subject in need thereof, wherein a therapeutically effective amount of solubilized fosnetupitant is administered to the subject over a duration of 2-15 minutes via an intravenous bolus.

4) Fosnetupitant for use in a method of treating or preventing chemotherapy induced nausea and vomiting in a human subject in need thereof, wherein 235 mg of fosnetupitant, based on the weight of the free base, equivalent to 260 mg fosnetupitant chloride hydrochloride, in a ready to use solution for intravenous administration, are administered to the subject over a duration of 2-15 minutes via an intravenous bolus.

5) Fosnetupitant for the use of any of claims 1-4, undertaken without causing injection site adverse reactions.

6) Fosnetupitant for the use of any of claims 1-5, wherein the duration is about 2, 5, 10, or 15 minutes.

7) Fosnetupitant for the use of any of claims 1, 2, 3, 5, or 6, wherein the fosnetupitant is administered as the chloride hydrochloride salt.

8) Fosnetupitant for the use of any of claims 1, 2, 3, 5, or 6, wherein about 235 mg of the fosnetupitant, based on the weight of the free base, equivalent to 260 mg fosnetupitant chloride hydrochloride, is administered.

9) Fosnetupitant for the use of any of claims 1-8, wherein the fosnetupitant is solubilized in about 10-30 mL or 20 mL of water.

10) Fosnetupitant for the use of any of claims 1-9, wherein the fosnetupitant is solubilized at a pH of 6-11, 7-10, or 8.5-9.5.

11) Fosnetupitant for the use of any of claims 1 -10, wherein the fosnetupitant is administered in an aqueous solution comprising a chelating agent. 12) Fosnetupitant for the use of any of claims 1-11, wherein the fosnetupitant is administered in an aqueous solution comprising disodium edetate.

13) Fosnetupitant for the use of any of claims 1-12, wherein the fosnetupitant is administered as an aqueous isotonic solution having a tonicity of 270-330 mOsm/kg.

14) Fosnetupitant for the use of any of claims 1-13, wherein the fosnetupitant is administered in an aqueous solution comprising a tonicity agent, preferably mannitol.

15) Fosnetupitant for the use of any of claims 1 -14, wherein the fosnetupitant is administered in an aqueous solution comprising mannitol.

16) Fosnetupitant for the use of any of claims 1-15, wherein the fosnetupitant is solubilized in about 10-30 mL of 20 mL of water at a pH of from 6 to 11 , in the absence of any surfactants, antioxidants, or preservatives.

17) Fosnetupitant for the use of any of claims 1-16, wherein the fosnetupitant is administered in an aqueous solution as a single agent free of any other active ingredients.

18) Fosnetupitant for the use of any of claims 1 -16, wherein the fosnetupitant is administered in an aqueous solution in combination with one or more additional active ingredients.

19) Fosnetupitant for the use of any of claims 1-18, comprising administering about 20 mL of a liquid solution comprising: a) about 235 mg of the fosnetupitant, based on the weight of the free base, equivalent to 260 mg fosnetupitant chloride hydrochloride; b) about 3.2 mg disodium edetate; c) about 760 mg mannitol; d) sodium hydroxide and optionally hydrochloric acid to a pH of about 8.5-9.5; and e) water q.s. to 20 mL.

20) Fosnetupitant for the use of any 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 initiating or completing intravenous bolus.

21) Fosnetupitant for the use of any of claims 1-20, further comprising intravenous chemotherapy less than or equal to about 30 minutes after initiating or completing intravenous bolus. 22) Fosnetupitant for the use of any of claims 1 -21 , wherein the fosnetupitant is administered at an 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 initiating or completing intravenous bolus.

23) Fosnetupitant for the use of any of claims 1-22, wherein the administration is free of clinically significant adverse reactions selected from thrombophlebitis, necrosis and vasculitis.

24) Fosnetupitant for the use of any of claims 1-22, wherein the administration is free of clinically significant adverse reactions selected from administration-site erythema, bruising, edema, pain, papule, paresthesia, swelling, and dyspnea.

25) Fosnetupitant for the use of any of claims 1-24, wherein the fosnetupitant is administered as a ready to use solution.

26) Fosnetupitant for the use of any of claims 1 -25, wherein the fosnetupitant is administered in undiluted form.

27) Fosnetupitant for the use of any of claims 1-26, wherein fosnetupitant is administered as a ready to use solution for intravenous bolus administration.

28) Fosnetupitant for the use of any of claims 27, for treating or preventing of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.

29) Fosnetupitant for the use of any of claims 1 -28, wherein the fosnetupitant is administered via a peripheral line without dilution.