AU2016262644B2 - Intravenous antiviral treatments - Google Patents

Abstract

The invention provides unit dosage forms, kits and methods for treating viral infections.

Description

INTRAVENOUS ANTIVIRAL TREATMENTS

Related Applications

The present application is a divisional application from Australian patent application number 2013216632, which is in turn a divisional application from parent Australian patent application number 2007215156, the entire disclosures of which are incorporated herein by reference. The parent application claims the benefit of priority of U.S. Application No. 60/772,748, filed February, 13, 2006, and of International Application No.

PCT/US2006/013535, filed April 12, 2006, which applications are herein incorporated by reference.

Throughout the description and the claims of this specification the word comprise and variations of the word, such as comprising and comprises is not intended to exclude other additives, components, integers or steps.

A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that that document or matter was known or that the infonnation it contains was part of the common general knowledge as at the priority date of any of the claims.

Background

The influenza virus neuraminidase inhibitor peramivir has marked activity against the influenza virus in vitro and in experimentally infected mice (Govorkova et al., Antimicrobial Agents and Chemotherapy, 45(10), 2723-2732 (2001); and Smee et al., Antimicrobial Agents and Chemotherapy, 45(3), 743-748 (2001)). Unfortunately, clinical trials using this drug showed a suboptimal therapeutic effect on influenza infection in humans following oral administration over a period of days. Currently there is a need for methods and formulations that are useful for treating viral infections (e.g., influenza infections) in humans.

2016262644 21 Nov 2016

Summary of the Invention

It has unexpectedly been discovered that a single intravenous administration of peramivir to a mouse is effective to treat influenza. These findings are unexpected not only because of the high effectiveness of a single administration of the compound, but also because of the low dose of the compound that was found to provide effective treatment. The ability to obtain therapeutically useful effects with a single administration is important inter alia because it minimizes patient compliance issues resulting from the need for multiple administrations. Additionally, the administration of a low dose is important because it minimizes cost and the potential for side-effects. It has also been unexpectedly discovered that intravenous and intramuscular injections of peramivir to humans provides high plasma concentrations of peramivir with an extended half-life.

Accordingly, in one embodiment the invention provides a method for treating a viral infection (e.g., an influenza infection) in a human comprising la

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2016262644 21 Nov 2016 administering an effective anti-viral amount of a compound of formula I, II, III, or IV:

or a pharmaceutically acceptable salt thereof, to the human by an intravenous route.

The invention also provides a method for inhibiting a neuraminidase in a human comprising administering an effective inhibitory amount of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, to the human by an intravenous route.

The invention also provides a unit dosage form that is suitable for intravenous administration to a human comprising up to about 400 mg of a compound of formula I, II, III, or TV, or a pharmaceutically acceptable salt thereof.

The invention also provides a unit dosage form that is suitable for intravenous administration to a human comprising up to about 1,000 mg (e.g., up to about 800, 600, 500, 400, 300, 200, 150, 100, or 75 mg) of a compound of formula I, II, ΙΠ, or IV, or a pharmaceutically acceptable salt thereof.

The invention also provides a kit comprising packaging materials, a compound of· formula I, Π, ΠΙ, or IV, or a pharmaceutically acceptable salt

2016262644 21 Nov 2016 thereof, and instructions for administering the compound to a human by an intravenous route.

The invention also provides the use of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a group of mammals exposed 5 to a source of an influenza virus, by intravenous injection of a dose of the medicament into each member of the group presenting clinical symptoms of infection.

The invention also provides the use of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a group of mammals exposed 10 to a source of an influenza virus, by intravenous injection of a dose of the medicament into each member of the group.

According to a first aspect, the invention provides a method for treating an influenza infection in a human comprising administering an effective anti-viral amount of a compound of formula la:

or a pharmaceutically acceptable salt thereof, wherein the effective anti-viral amount is administered in a single intravenous administration per day.

According to a further aspect, the invention provides a kit, comprising packaging materials, a compound of formula la:

2016262644 21 Nov 2016

or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a human by an intravenous route via a single intravenous administration per day, wherein the compound is provided in a formulation suitable for a single intravenous administration per 5 day; when used for administration of the compound to a human via a single intravenous administration per day.

According to a further aspect, the invention provides use of a compound of formula la:

or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a single intravenous injection per day for increasing life expectancy or reducing mortality in a group of mammals exposed to a source of an influenza virus, by intravenous injection of a single dose of medicament per day into each member of the group.

According to a further aspect, the invention provides use of a compound of formula la:

3a

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or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a single intravenous injection per day for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intravenous injection of a single dose of the medicament per day into the human.

Brief Description of the Figures

Figure 1. Figure 1 depicts plasma peramivir concentration time curves after 15 minute intravenous infusions of peramivir to healthy human volunteers.

Figure 2. Figure 2 depicts plasma peramivir concentration time curves after intramuscular injections of peramivir to healthy human volunteers.

Detailed Description

The influenza virus neuraminidase inhibitor peramivir has been previously shown to have marked activity against influenza virus in vitro and in experimentally infected mice (Govorkova et al., (2001); and Smee et al., (2001)). Unfortunately, clinical trials using this drug showed an inadequate inhibitory effect on influenza in humans. This effect was attributed to a poor adsorption of the drug when administered once daily orally in patients.

It has been discovered that peramivir is well adsorbed when administered intravenously (i.v.) in mice and that the compound remains at relatively high levels in the plasma for at least 6 hours. A series of experiments presented herein indicates that a single treatment of peramivir given i.v. will protect mice infected with an influenza virus.

3b

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Accordingly, certain embodiments of the present invention provide a method for treating a viral infection in a human comprising administering an effective anti-viral amount of a compound of formula I, Π, III, or IV:

2016262644 21 Nov 2016

or a pharmaceutically acceptable salt thereof, to the human by an intravenous route.

In certain embodiments, the compound of formula I, II, ΙΠ, or IV is a compound of formula la, Ila, Illa, or IVa:

/ NHCOCH, OH (Ha)

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In certain embodiments, the viral infection is an influenza infection. In certain embodiments, the viral infection is an influenza type A or type B infection. In certain embodiments, the viral infection is caused by a strain of virus represented by the formula H_xN_y wherein X is an integer from 1-16 and Y is an integer from 1-9. In certain embodiments, the influenza is an H3N2, H1N1, H5N1, avian, or seasonal influenza.

In certain embodiments,· the effective anti-viral amount is up to about 800 mg. In certain embodiments, the effective anti-viral amount is up to about 400 mg. In certain embodiments, the effective anti-viral amount is up tp about 300

I mg. In certain embodiments, the effective anti-viral amount is up to about 200 mg.

In certain embodiments, the entire effective dose is administered in one intravenous administration. In certain embodiments, the entire effective dose is 15 administered in multiple intravenous administrations.

In certain embodiments, a compound or formula la, or a pharmaceutically acceptable salt thereof, is administered.

In certain embodiments, the plasma concentration of the compound is higher than the IC₅o of the virus causing the viral infection 12 hours following 20 administration of the compound.

Certain embodiments of the present invention provide a method for inhibiting a neuraminidase in a human comprising administering an effective inhibitory amount of a compound of formula I, Π, ΙΠ, or IV:

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or a pharmaceutically acceptable salt thereof, to the human by an intravenous 5 route.

In certain embodiments, the compound of formula I, II, ΠΙ, or IV is a compound of formula la, Ila, Illa, or IVa:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the effective inhibitory amount is up to about

800 mg. In certain embodiments, the effective inhibitory amount is up to about

400 mg. In certain embodiments, the effective inhibitory amount is up to about

300 mg. In certain embodiments, the effective inhibitory amount is up to about 20 200 mg.

In certain embodiments, the entire effective inhibitory dose is administered in one intravenous administration. In certain embodiments, the

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2016262644 21 Nov 2016 entire effective inhibitory dose is administered in multiple intravenous administrations.

In certain· embodiments, a compound of formula Ia, or a pharmaceutically acceptable salt thereof, is administered.

In certain embodiments, the methods may further comprise orally administering a neuraminidase inhibitor to the human.

In certain embodiments, the neuraminidase inhibitor that is administered orally is.oseltamivir carboxylate.

In certain embodiments, the neuraminidase inhibitor that is administered orally is a compound of formula I, Π, III, or IV:

nhcoch₃ (IV), or a pharmaceutically acceptable salt thereof.

In certain embodiments, the neuraminidase inhibitor that is administered orally is a compound of formula Ia, Ila, Hla, or IVa:

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V	HN aJO'·-	UN.	Y°=H
/	nhcoch3 (Ma)	_ . NHCOCH3	(IVa),

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the neuraminidase inhibitor that is administered orally is a compound of formula la, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the neuraminidase inhibitor that is administered orally is administered for up to 20 days. In certain embodiments, the neuraminidase inhibitor that is administered orally is administered for up to 10 days. In certain embodiments, the neuraminidase inhibitor that is administered 10 orally is administered for up to 5 days.

Certain embodiments of the present invention provide a unit dosage form that is suitable for intravenous administration to a human, comprising up to about 800 mg of a compound of formula I, Π, III, or IV:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula la, Ila, Illa, or TVa:

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(Ha).

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the unit dosage form comprises up to about 400 mg of the compound or salt. In certain embodiments, the unit dosage form comprises up to about 300 mg of the compound or salt. In certain embodiments, the unit dosage form comprises up to about 200 mg of the compound or salt.

Certain embodiments of the present invention provide a kit, comprising packaging materials, a compound of formula I, Π, III, or IV:

HN

(II)

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2016262644 21 Nov 2016 or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a human by an intravenous route.

In certain embodiments, the compound is provided in a formulation suitable for intravenous administration.

In certain embodiments, the kit comprises up to about 800 mg of the compound or salt. In certain embodiments, the kit comprises up to about 400 mg of the compound or salt. In certain embodiments, the kit comprises up to about 300 mg of the compound or salt. In certain embodiments, the kit comprises up to about 200 mg of the compound or salt.

’ Certain embodiments of the present invention provide a kit comprising packaging materials, a unit dosage form as described herein, and instructions for administering the compound to a human by an intravenous route.

Certain embodiments of the present invention provide a use of a compound of formula I, II, III, or IV:

or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a group of mammals exposed to a sourbe of an influenza virus, by intravenous injection of a dose of the medicament into each member of the group presenting clinical symptoms of infection.

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In certain embodiments, the compound of formula I, II, HI, or IV is a compound of formula la, Ila, Illa, or IV a:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the influenza virus is an avian influenza virus.

In certain embodiments, the influenza virus is an influenza type A or type B ' virus. In certain embodiments, the influenza virus is H5N1, or a mutant strain thereof. In certain embodiments, the influenza virus is a strain of virus represented by the formula H_xN_y wherein X is an integer from 1-16 and Y is an integer from 1-9. In certain embodiments, the influenza virus is an H3N2, H1N1, H5N1, avian, or seasonal influenza virus.

In certain embodiments, each member of the group presenting symptoms of infection receives only one intravenous dose of the medicament. In certain embodiments, each member of the group presenting symptoms of infection receives multiple intravenous doses of the medicament.

In certain embodiments, the members of the group presenting clinical symptoms of infection are treated orally with a neuraminidase inhibitor. In certain embodiments, the neuraminidase inhibitor is oseltamivir carboxylate. In 25 certain embodiments, the neuraminidase inhibitor is a compound of formula I, Π, HI, or IV:

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NHCOCH3 (IV), or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula la, Ila, Hla, or IVa:

nhcoch3 (IVa), or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula la, or a pharmaceutically acceptable salt thereof.

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In certain embodiments, the source of the virus is an infected bird. In certain embodiments, the source of the virus is a mammal presenting symptoms of infection.

2016262644 21 Nov 2016

In certain embodiments, the use is for reducing mortality.

Certain embodiments of the present invention provide a use of a compound of formula I, Π, III, or IV:

or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a group of mammals exposed to a source of an influenza virus, by intravenous injection of a dose of the medicament into each member of the group.

In certain embodiments, the compound of formula I, II, HI, or IV is a compound of formula la, Ha, Illa, or IVa:

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or a pharmaceutically acceptable salt thereof.

In certain embodiments, the influenza virus is an avian influenza virus.

In certain embodiments, the avian influenza virus is H5N1, or a mutant strain thereof. In certain embodiments, the influenza virus is a strain of virus represented by the formula H_xN_y wherein X is an integer from 1-16 and Y is an 10 integer from 1-9. In certain embodiments, the influenza virus is an influenza type A or type B virus. In certain embodiments, the influenza virus is an H3N2, H1N1, H5N1, avian, or seasonal influenza virus.

In certain embodiments, each member of the group receives only one intravenous dose of the medicament. In certain embodiments, each member of 15 the group receives multiple intravenous doses of the medicament.

In certain embodiments, the members of the group are treated orally with a neuraminidase inhibitor. In certain embodiments, the neuraminidase inhibitor is oseltamivir carboxylate. In certain embodiments, the neuraminidase inhibitor is a compound of formula I, II, ΙΠ, or IV:

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or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula la, Ha, Illa, or IVa:

(Ha)

(IVa), or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula la, or a pharmaceutically 15 acceptable salt thereof.

In certain embodiments, the source of the virus is an infected bird. In certain embodiments, the source of the virus is a mammal presenting symptoms of infection.

In certain embodiments, the use is for reducing mortality.

Certain embodiments of the present invention provide a use of a compound of formula I, II, III, or IV:

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or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intravenous injection 10 of a dose of the medicament into the human.

Certain embodiments of the present invention provide a use of a compound of formula I, II, ΙΠ, or IV:

nhcoch₃ (IV),

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2016262644 21 Nov 2016 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intramuscular injection for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intramuscular injection of a dose of the medicament into the human.

In certain embodiments, the plasma concentration of the compound is higher than the IC50 of the virus 12 hours following injection of the compound.

Mice infected with influenza A/Duck/MN/1525/81 (H5N1) virus were treated a single time i.v. 1 hour pre-virus exposure with peramivir at doses of 20, 10 10 and 3 mg/kg. Peramivir was significantly protective to the mice at the two highest dosages used, as seen by prevention of deaths, lessening of lung consolidation, and inhibition of lung virus titers. The 3 mg/kg dose was moderately inhibitory to lung parameters. The compound appeared well tolerated in concomitantly run toxicity controls. These data indicate that a single

i.v. peramivir treatment is efficacious in influenza virus-infected mice.

The compounds used in the invention are known in the art and can be synthesized by the art worker using available methods (see, e.g., U.S. Patent No. 6,562,861).

Specific values listed herein for radicals, substituents, and ranges, are for 20 illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents

A specific compound of formula I, Π, HI, or IV is a compound of formula la, Ila, BHa, or IVa:

NHCOCH, OH

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or a pharmaceutically acceptable salt thereof.

A specific compound of formula I, II, IH, or IV is (15,25,322,422)-3-(1Acetamido-2-ethylbutyl)-4-guanidino-2-hydroxycyclopentane-carboxylic acid; (15,25,322,422)-3-(l-Acetamido-2-propylpentyl)-4-guanidino-2hydroxycyclopentanecarboxylic acid; (122,322,422)-3-( l-Acetamido-2propylpentyl)-4-guanidinocyclopentanecarboxylic acid; or (122,322,422)-3-(1 10 Acetamido-2-ethylbutyl)-4-guanidinocyclopentanecarboxylic acid; or a pharmaceutically acceptable salt thereof.

A specific compound of formula I is a compound of formula la, or a pharmaceutically acceptable salt thereof.

It will be appreciated by those skilled in the art that compounds having one or more chiral centers may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses the use of any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of formula I, H, ΙΠ, or IV, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine anti-viral (e.g. anti-influenza) activity using the standard tests described herein, or using other similar tests which are well known in the art.

In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for

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2016262644 21 Nov 2016 example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate,· α-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, phosphate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic • compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

The compounds of formula I, II, HI, and IV can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, by intravenous routes. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.

Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient(s) which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal,

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2016262644 21 Nov 2016 ’ and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound(s) into an appropriate solvent with the other optional ingredients enumerated above, optionally followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

As used herein the terms “treat”, treating and “treatment” include administering a compound prior to the onset of clinical symptoms of a disease state/condition so as to prevent the development of any symptom, as well as 15 administering a compound after the onset of one or more clinical symptoms of a disease state/condition so as to reduce or eliminate any such symptom, aspect or characteristic of the disease state/condition. Such treating need not be absolute to be useful. As illustrated hereinbelow, the active compounds can be administered prior to exposure to the virus. The agents can also be administered subsequent 20 (e.g., within 1, 2, 3, 4, or 5 days) to exposure to the virus.

As used herein the term “unit dosage form” relates to an intravenous formulation containing a specific amount of a drug, the whole of which is intended to be administered as a single dose. It is distinguished from a supply of an indefinite amount of a medicament, e.g., a bottle of medicine, from which a 25 dose has to be measured out.

In one embodiment the invention provides a method for treating a viral infection in a human comprising administering an effective amount of a compound of formula I, II, IH, or IV, or a pharmaceutically acceptable salt thereof, to the human by intravenous administration. Typically, the effective 30 amount is administered in a single intravenous administration. In some embodiments, the effective amount is administered in multiple administrations.

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Accordingly, the methods of the invention provide for high patient compliance and they require a low dose of the effective agent.

In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, Π, ΙΠ, or IV is up to about 1,000 mg.

· In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, Π, III, or IV is up to about 800 mg.

In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, III, or IV is up to about 600 mg.

In one embodiment of the invention, the effective inhibitory, amount of the compound of formula I, Π, ΠΙ, or IV is up to about 500 mg.

In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, IH, or IV is up to about 400 mg.

In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, III, or IV is up to about 300 mg.

In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, Π, ΠΙ, or IV is up to about 200 mg.

' In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, IH, or IV is up to about 150 mg.

In one embodiment of the invention, the effective inhibitory amount of 20 the compound of formula I, II, ΙΠ, or IV is up to about 75 mg.

According to the methods of the invention a compound of formula I, II, • ΠΙ, or IV is administered to a human intravenously. In one embodiment of the invention, the compound of formula I, Π, III, or IV is administered once to a human intravenously. In another embodiment of the invention, a neuraminidase 25 inhibitor is also administered to the human orally. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is oseltamivir carboxylate. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is a compound of formula I, II, III, or IV:

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nhcoch₃ (IV), or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is a. compound of formula Ia, Ha, Illa, or IVa:

or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is a compound of formula la, or a pharmaceutically acceptable salt thereof.

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According to the methods of the invention, the compound of formula I, · •Π, ΙΠ, or IV, or a pharmaceutically acceptable salt thereof, can also be administered in combination with one or more additional therapeutic agents, such as anti-viral agents (e.g., agents active against influenza) or antibiotics.

The intravenous formulations of the invention can also comprise one or more additional therapeutic agents, such as anti-viral agents (e.g., agents active against influenza) and antibiotics.

.Thus, intravenous administration of peramivir to treat a viral infection is described herein.. Intramuscular administration of peramivir to treat a viral infection is also described herein (see, e.g., Example 2), which further exemplifies intramuscular administration of peramivir. to treat a viral infection, as is described in International Application No. PCT/US2006/013535, filed April 12, 2006, the disclosure of which is incorporated by reference. Further, as described herein, it has been unexpectedly discovered that intravenous and intramuscular injections of peramivir to humans provides high plasma concentrations of peramivir with an extended plasma half-life.

As described herein, the compounds described herein can be used to treat a virus, e.g., an influenza virus. For example₅ the compounds can be used to treat any one or combination of the following strains. In the table below, the “H” stands for a type of hemagglutinin, and the “N” stands for a type of neuraminidase. The formula H_xN_y wherein X is an integer from 1-16 and Y is an integer from 1-9, can also be used to describe the combinations presented in the table.

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Table 1

	N1	N2	N3	N4	N5	N6	N7	N8	N9
Hl	H1N1	H1N2	H1N3	H1N4	H1N5	H1N6	HIN7	H1N8	H1N9
H2	H2N1	H2N2	H2N3	H2N4	H2N5	H2N6	H2N7	H2N8	H2N9
H3	H3N1	H3N2	H3N3	H3N4.	H3N5	H3N6	H3N7	H3N8	H3N9 .
H4	H4N1	H4N2	H4N3	H4N4	. H4N5	H4N6.	H4N7	H4N8	H4N9
H5	H5N1	H5N2	H5N3	H5N4	H5N5	H5N6	H5N7	H5N8	H5N9
H6	H6N1	H6N2	H6N3	H6N4	H6N5	H6N6	H6N7	H6N8	H6N9
H7	H7N1	H7N2	H7N3	H7N4	H7N5	H7N6	H7N7	H7N8	H7N9
H8	H8N1	H8N2	H8N3	H8N4	H8N5	H8N6	H8N7	H8N8	H8N9
H9	H9N1	H9N2	H9N3	H9N4	H9N5	H9N6	H9N7	H9N8	H9N9
H10	Hl 0N1	H10N2	H10N3	H10N4	H10N5	H10N6	H10N7	H10N8	H10N9
Hll	HllNl	H11N2	H11N3	H11N4	H11N5	H11N6	H11N7	H11N8	H11N9
H12	H12N1	H12N2	H12N3	H12N4	H12N5	. H12N6	H12N7	H12N8	H12N9
H13	H13N1	H13N2	H13N3	H13N4	H13N5	H13N6	H13N7	H13N8	H13N9
H14	H14N1	H14N2	H14N3	H14N4	H14N5	H14N6	H14N7	H14N8	H14N9
HIS	H15N1	H15N2	H15N3	H15N4	H15N5	H15N6	H15N7	H15N8	H15N9
H16	H16N1	H16N2	H16N3	H16N4	H16N5	H16N6	H16N7	H16N8	H16N9

The virus may be, for example, an avian virus or a humanized avian virus. Thus, the term “avian virus” includes both avian forms of the virus and humanized forms of the avian virus.

Certain embodiments of the present invention provide the use of a compound of formula I, Π, ΙΠ, or IV:

(Π)

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or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intravenous injection of a dose of the medicament into the human.

Certain embodiments of the present invention also provide the use of a compound of formula I, Π, ΠΙ, or IV:

or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intramuscular injection for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intramuscular injection of a dose of the medicament into the human.

Certain embodiments of the invention also provide compositions comprising peramivir formulated for intravenous administration to a human. Certain embodiments of the invention also provide compositions comprising

WO 2007/095218

PCT/US2007/003755

2016262644 21 Nov 2016 peramivir formulated for intravenous administration for use in treating a virus by achieving a plasma concentration in a human of peramivir that is effective to treat the virus.

Certain embodiments of the invention also provide compositions comprising peramivir formulated for intramuscular administration to a human.

Certain embodiments of the invention also provide compositions comprising peramivir formulated for intramuscular administration for use in treating a virus by achieving a plasma concentration in a human of peramivir that is effective to treat the virus.

In certain embodiments of the invention, the plasma concentration of the compound is higher than the IC50 of the virus at least about 12 hours following the injection.

In certain embodiments of the invention, the plasma concentration of the compound is higher than the IC50 of the virus at least about 24 hours following 15 the injection.

In certain embodiments of the invention, the plasma concentration of the compound is higher than the IC₅₀ of the virus at least about 36 hours following the injection.

In certain embodiments of the invention, the plasma concentration of the 20 compound is higher than the IC₅₀ of the virus at least about 48 hours following the injection.

In certain embodiments of the invention, the plasma concentration of the compound is higher than the IC50 of the virus at least about 60 hours following the injection.

In certain embodiments of the invention, the plasma concentration of the compound is higher than the IC50 of the virus at least about 72 hours.following the injection.

In certain embodiments of the invention, the virus is an influenza virus.

In certain embodiments of the invention, the virus is an avian influenza virus. In 30 certain embodiments of the invention, the virus is H5N1, or a mutant strain thereof.

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The invention will now be illustrated by the following non-limiting Examples.

Example 1. Effect of IV Treatment with Peramivir on Influenza A Virus.

Infection

Experiment Design: Mice were infected i.h. with a dose thought to be the LD100 of influenza virus. Groups of 10 mice were treated i.v. with peramivir at dosages of 20,10 and 3 mg/kg a single time 1 hour pre-virus exposure. Placebo (sterile saline) was administered i.v. in parallel with the above to 20 infected 10 mice. Drug-treated infected mice and placebo-treated controls were observed daily for death through 21 days. As toxicity controls, 3 uninfected mice were treated with the highest dose of the compounds in parallel to the infected animals. All toxicity controls were observed for death through 21 days and were weighed immediately prior to the initial treatment and 18 h after the final treatment. Five normal controls were weighed.

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Table 2. Effect of Single I.V. Treatment with Peramivir on an Influenza A Virus Infection in Mice.

Animals·. Female 18-21 gram BALB/c mice	Treatment schedule·. Peramivir,: Single treatment 1 hour pre-virus exposure
Virus'. Influenza A/Duck/MN/152518 (H5N1)	Treatment route·. Peramivir i.v.;
Drug diluent·. Sterile Saline	Expt, duration·. 21 days

		Tox Controls	Infected, Treated Mice
Treatment	Dose (mg/kg)	Surv/ Total	Surv/ Total	Mean Day to Death15 ± SD
Peramivir	20	3/3	10/10**	>21.0 ± . ο θ***
	10	3/3	10/10**	>21.0 ± · Q Q***
	•3	3/3	5/10	9.6 ± 1.3
Saline	—	—	9/20	9.1 ± 1.4
Normal Controls	—	5/5	—	—

^bMean day to death of mice dying prior to day 21.

**P<0.01; ***P<0.001 compared to saline-treated controls.

The infection induced in this experiment was lethal to 55% of the mice (Table

1), with a mean day to death of 9.1 days. The single i.v. injection with peramivir at 20 and 10 mg/kg was highly protective to the infected animals, with 100% surviving the infection (P<0.01). Toxicity controls run in parallel all survived and gained weight, indicating compound was well tolerated in this experiment.

These data indicate that peramivir is a significant influenza inhibitor when used in a single i.v. injection.

Example 2. Effects of IV and IM Treatment with Peramivir in Humans

Peramivir was studied in a placebo-controlled phase 1 clinical study in healthy human volunteers to evaluate safety and pharmacokinetic parameters using intravenous and intramuscular administrations. Blood samples were ·

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2016262644 21 Nov 2016 collected from the subjects at different time points after drug administration to determine the concentration of the drug in plasma. The time course plots are shown in Figure 1 and Figure 2 for intravenous and intramuscular administrations respectively.

In the intravenous study, peramivir concentrations followed linear kinetics with an unusually extended plasma half life of greater than 12 hours. At doses of 2 mg/kg and above, the level of peramivir in plasma at 48 hours postdose is greater than the IC50 for all strains of influenza virus tested, including H5 virus types. For doses greater than 4 mg/kg, even at 72 hours, the levels of the drug are greater than the IC50 values.

In the intramuscular study, peramivir concentrations also followed linear kinetics with an unusually extended plasma half life. Even at 72 hours postdosing, the levels of peramivir are higher than the IC50 values for all the influenza virus strains tested.

The long plasma half-life and the high levels of peramivir in human volunteers are unusual and unexpected findings and indicate that intravenous and intramuscular administrations of peramivir are beneficial in the treatment of influenza in humans.

All publications, patents and patent applications cited herein are incorporated herein by reference. While in the foregoing specification this invention has been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein may be varied considerably without departing from the basic principles of the invention.

The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to 30 be construed as open-ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate

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2016262644 21 Nov 2016 value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

Claims (43)

1. The claims defining the invention are as follows:

   1. A method for treating an influenza infection in a human comprising administering an effective anti-viral amount of a compound of formula la: or a pharmaceutically acceptable salt thereof, wherein the effective anti-viral amount is administered in a single intravenous administration per day.
2. 2. The method of claim 1, wherein the influenza infection is an influenza type A or type B infection.
3. 3. The method of claim 1, wherein the influenza infection is caused by a strain of virus represented by the formula HxNy, wherein X is an integer from 1-16 and Y is an integer from 1-9.
4. 4. The method of claim 1, wherein the influenza is H3N2, H1N1, H5N1, avian or seasonal influenza.
5. 5.

   The method of any about 800 mg.

   one of claims

   1-4, wherein the effective anti-viral amount is up to
6. 6.

   The method of any one of claims

   1-4, wherein the effective anti-viral amount is up to about 600 mg.
7. 7.

   The method of any one of claims

   1-4, wherein the effective anti-viral amount is up to about 300 mg.
8. 8.

   The method of any one of claims

   1-4, wherein the effective anti-viral amount is 600 mg.

   2016262644 07 Dec 2018
9. 9. The method of any one of claims 1-4, wherein the effective anti-viral amount is 300 mg.
10. 10. The method of any one of claims 1-9, wherein the plasma concentration of the compound is higher than the 1C50 of the virus causing the viral infection 12 hours following the administration of the compound.
11. 11. The method of any one of claims 1-9, wherein the plasma concentration of the compound is higher than the 1C50 of the virus causing the viral infection 72 hours following the administration of the compound.
12. 12. A method for inhibiting an influenza neuraminidase in a human comprising administering an effective inhibitory amount of a compound of formula la:

    H,N

    NH

    HN

    NHCOCH3 ^OH (la) or a pharmaceutically acceptable salt thereof, wherein the effective inhibitory amount is administered in a single intravenous administration per day.
13. 13. The method of claim 12, wherein the effective inhibitory amount is up to about 800 mg.
14. 14. The method of claim 12, wherein the effective inhibitory amount is up to about 600 mg.
15. 15. The method of claim 12, wherein the effective inhibitory amount is up to about 300 mg.
16. 16. The method of claim 12, wherein the effective inhibitory amount is 600 mg.
17. 17. The method of claim 12, wherein the effective inhibitory amount is 300 mg.
18. 18. The method of claim 12, wherein the influenza neuraminidase is from a type A or type B virus.

    2016262644 07 Dec 2018
19. 19. The method of claim 12, wherein the influenza neuraminidase is from a strain of virus represented by the formula HxNy, wherein X is an integer from 1-16 and Y is an integer from 1-9.
20. 20. The method of claim 12, wherein the influenza neuraminidase is from a H3N2, H1N1, H5N1, avian or seasonal influenza virus.
21. 21. The method of any one of claims 1-20, further comprising orally administering a neuraminidase inhibitor to the human.
22. 22. The method of claim 21, wherein the neuraminidase inhibitor that is administered orally is oseltamivir carboxylate.
23. 23. The method of claim 21, wherein the neuraminidase inhibitor that is administered orally is a compound of formula I, II, III, or IV:
24. 24. The method of claim 21, wherein the neuraminidase inhibitor that is administered orally is a compound of formula la, Ila, Illa, or IVa

    2016262644 07 Dec 2018 or a pharmaceutically acceptable salt thereof.
25. 25. The method of claim 24, wherein· the neuraminidase inhibitor that is administered orally is a compound of formula la, or a pharmaceutically acceptable salt thereof.
26. 26. The method of any one of claims 21-25, wherein the neuraminidase inhibitor that is administered orally is administered for up to 20 days.
27. 27. The method of claim 26, wherein the neuraminidase inhibitor that is administered orally is administered for up to 10 days.
28. 28. The method of claim 27, wherein the neuraminidase inhibitor that is administered orally is administered for up to 5 days.
29. 29. A kit, comprising packaging materials, a compound of formula la:

    2016262644 07 Dec 2018 or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a human by an intravenous route via a single intravenous administration per day, wherein the compound is provided in a formulation suitable for a single intravenous administration per day; when used for administration of the compound to a human via a single intravenous administration per day to treat an influenza infection in the human.
30. 30. The kit of claim 29 that comprises up to about 800 mg of the compound or salt.
31. 31. The kit of claim 29 that comprises up to about 600 mg of the compound or salt.
32. 32. The kit of claim 29 that comprises up to about 300 mg of the compound or salt.
33. 33. The kit of claim 29 that comprises 600 mg of the compound or salt.
34. 34. The kit of claim 29 that comprises 300 mg of the compound or salt.
35. 35. The kit of any one of claims 29-34 wherein the compound of formula la, or a pharmaceutically acceptable salt thereof, is present in a unit dosage form.
36. 36. Use of a compound of formula la:

    2016262644 07 Dec 2018 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a single intravenous injection per day for increasing life expectancy or reducing mortality in a group of mammals exposed to a source of an influenza virus, by intravenous injection of a single dose of medicament per day into each member of the group.
37. 37. Use as claimed in claim 36, in which the source of the virus is an infected bird.
38. 38. Use as claimed in claim 36, in which the source of the virus is a mammal presenting symptoms of infection.
39. 39. Use as claimed in claim 36, in which each member of the group presents clinical symptoms of infection.
40. 40. Use as claimed in any one of claims 36-39, which is for reducing mortality.
41. 41. Use of a compound of formula la:

    or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a single intravenous injection per day for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intravenous injection of a single dose of the medicament per day into the human.
42. 42. The use of claim 41, wherein the plasma concentration of the compound is higher than the 1C50 of the virus 12 hours following the injection of the compound.
43. 43. The use of claim 41, wherein the plasma concentration of the compound is higher than the 1C50 of the virus 72 hours following injection of the compound.