KR102267754B1 - Intravenous antiviral treatments - Google Patents

Abstract

The present invention provides unit dosage forms, kits and methods useful for the treatment of viral infections.

Description

INTRAVENOUS ANTIVIRAL TREATMENTS

<Related Application>

This patent document is incorporated by reference in US Application Serial No. 60/772,748, filed on February 13, 2006, and International Application Serial No. PCT/US2006/013535, filed April 12, 2006, which applications are incorporated herein by reference. included as a ) claim the priority advantage.

<Background Technology>

Peramivir, an influenza virus neuraminidase inhibitor, has significant activity against influenza virus in mice infected both in vitro and experimentally (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 the drug have shown sub-optimal therapeutic effects against influenza infection in humans after oral administration over a period of time. Recently, there is a need for methods and formulations useful for treating viral infections (eg, influenza infections) in humans.

<Summary of the present invention>

Surprisingly, a single intravenous administration of peramivir to mice was found to be effective in the treatment of influenza. This finding was surprising not only because the effect of a single dose of the compound was high, but also because the dose of the compound, which was found to provide an effective treatment, was low. The ability to obtain a therapeutically useful effect with a single dose is important because it minimizes patient compliance problems, especially when multiple doses are required. In addition, administering low doses is important because it minimizes cost and the possibility of side effects. It has also surprisingly been found that intravenous and intramuscular injection of peramivir into humans provides high plasma concentrations of peramivir with an extended half-life.

Accordingly, in one embodiment, the present invention provides an effective anti-viral amount in a human, comprising administering to the human an effective anti-viral amount of a compound of formula (I), (II), (III) or (IV): A method of treating a viral infection (eg, influenza infection) is provided.

[ Formula I ]

[ Formula II ]

[ Formula III ]

[ Formula IV ]

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

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

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

The present invention also provides a kit comprising packaging materials, a compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a human by the intravenous route.

The present invention also relates to a source of influenza virus by intravenous injection of a compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, to a member of a population exhibiting clinical signs of infection, each of a prescribed dose of the medicament. Provided is a use in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a population of exposed mammals.

The present invention also relates to a mammal of a compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, by intravenously injecting a predetermined dose of a medicament to a member of a population of mammals exposed to a source of influenza virus, respectively. Provided is a use in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a population.

Figure 1. Figure 1 depicts the plasma peramivir concentration time curve 15 minutes after intravenous infusion of peramivir into healthy human volunteers.
Figure 2. Figure 2 depicts the plasma peramivir concentration time curve after intramuscular injection of peramivir into healthy human volunteers.

It is already known that the influenza virus neuraminidase inhibitor, peramivir, has significant activity against influenza virus in mice infected both in vitro and experimentally (Govorkova et al., (2001), supra; and [ Smee et al., (2001)]). Unfortunately, clinical trials using these drugs have shown inadequate inhibitory effects against human influenza. This effect is because the drug is poorly absorbed when orally administered to a patient once a day.

Peramivir is well absorbed when administered intravenously (i.v.) in mice, and the compound has been found to remain at relatively high levels in plasma for at least 6 hours. A series of experiments presented herein shows that a single intravenous treatment of peramivir will protect mice infected with influenza virus.

Accordingly, certain embodiments of the present invention provide 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 the intravenous route. A method of treating an infection is provided.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In certain embodiments, the compound of Formula I, II, III or IV is a compound of Formula Ia, IIa, IIIa, or IVa: or a pharmaceutically acceptable salt thereof.

[ Formula Ia ]

[ Formula IIa ]

[ Formula IIIa ]

[ Formula IVa ]

In certain embodiments, the viral infection is an influenza infection. In certain embodiments, the viral infection is an influenza A or B infection. In certain embodiments, the viral infection is _{caused by a virus strain represented by the formula H x} N _y , wherein X is an integer from 1 to 16 and Y is an integer from 1 to 9. In certain embodiments, the influenza is H3N2, H1N1, H5N1, avian or seasonal influenza.

In certain embodiments, the effective anti-viral dose is about 800 mg or less. In certain embodiments, the effective anti-viral dose is about 400 mg or less. In certain embodiments, the effective anti-viral dose is about 300 mg or less. In certain embodiments, the effective anti-viral dose is about 200 mg or less.

In certain embodiments, the total effective dosage is administered in a single intravenous administration. In certain embodiments, the total effective dosage 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 plasma concentration of the compound is greater than _{the IC 50} of the virus causing the viral infection 12 hours after administration of the compound.

A particular embodiment of the present invention provides an effective inhibitory amount of neuraminidase in a human, comprising administering to the human an effective inhibitory amount of a compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, to the human by the intravenous route. provide a way to suppress it.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In certain embodiments, the compound of Formula I, II, III or IV is a compound of Formula Ia, IIa, IIIa, or IVa: or a pharmaceutically acceptable salt thereof.

<Formula Ia>

<Formula IIa>

<Formula IIIa>

<Formula IVa>

In certain embodiments, the effective inhibitory amount is about 800 mg or less. In certain embodiments, the effective inhibitory amount is about 400 mg or less. In certain embodiments, the effective inhibitory amount is about 300 mg or less. In certain embodiments, the effective inhibitory amount is about 200 mg or less.

In certain embodiments, the total effective inhibitory dose is administered in a single intravenous administration. In certain embodiments, the total 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 method can further comprise orally administering to the human a neuraminidase inhibitor.

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

In certain embodiments, the orally administered neuraminidase inhibitor is a compound of Formula (I), (II), (III), or (IV): or a pharmaceutically acceptable salt thereof.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In certain embodiments, the orally administered neuraminidase inhibitor is a compound of Formula Ia, IIa, IIIa, or IVa: or a pharmaceutically acceptable salt thereof.

<Formula Ia>

<Formula IIa>

<Formula IIIa>

<Formula IVa>

In certain embodiments, the orally administered neuraminidase inhibitor is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof.

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

Certain embodiments of the present invention provide a unit dosage form suitable for intravenous administration to a human, comprising up to about 800 mg of a compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In certain embodiments, the compound of Formula I, II, III or IV is a compound of Formula Ia, IIa, IIIa, or IVa: or a pharmaceutically acceptable salt thereof.

<Formula Ia>

<Formula IIa>

<Formula IIIa>

<Formula IVa>

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), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a human by the intravenous route do.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

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

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

Certain embodiments of the present invention provide kits comprising packaging materials, the unit dosage forms described herein, and instructions for administering the compound to a human by the intravenous route.

A particular embodiment of the present invention provides an influenza vaccine by intravenous injection of a compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, to a member of a population exhibiting clinical signs of infection, respectively, a predetermined dose of a medicament. Provided is a use in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a population of mammals exposed to a source of virus.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In certain embodiments, the compound of Formula I, II, III or IV is a compound of Formula Ia, IIa, IIIa, or IVa: or a pharmaceutically acceptable salt thereof.

<Formula Ia>

<Formula IIa>

<Formula IIIa>

<Formula IVa>

In certain embodiments, the influenza virus is an avian influenza virus. In certain embodiments, the influenza virus is an influenza A or 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 the virus represented by the formula H _x N _y , wherein X is an integer from 1 to 16 and Y is an integer from 1 to 9. In certain embodiments, the influenza virus is an H3N2, H1N1, H5N1, avian or seasonal influenza virus.

In certain embodiments, only a single intravenous dose of the medicament is administered to each member of the population exhibiting signs of infection. In certain embodiments, multiple intravenous doses of each of the medicaments are administered to members of the population exhibiting signs of infection.

In certain embodiments, a member of the population exhibiting clinical signs of infection is orally treated 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), (III), or (IV): or a pharmaceutically acceptable salt thereof.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In certain embodiments, the neuraminidase inhibitor is a compound of Formula Ia, IIa, IIIa, or IVa: or a pharmaceutically acceptable salt thereof.

<Formula Ia>

<Formula IIa>

<Formula IIIa>

<Formula IVa>

In certain embodiments, the neuraminidase inhibitor is a compound of Formula Ia, or a pharmaceutically 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 exhibiting signs of infection.

In certain embodiments, said use is for reducing mortality.

A particular embodiment of the present invention provides an intravenous injection of a compound of formula (I), (II), (III) or (IV): thereby providing use in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a population of said mammals.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In certain embodiments, the compound of Formula I, II, III or IV is a compound of Formula Ia, IIa, IIIa, or IVa: or a pharmaceutically acceptable salt thereof.

<Formula Ia>

<Formula IIa>

<Formula IIIa>

<Formula IVa>

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 the virus represented by the formula H _x N _y , wherein X is an integer from 1 to 16 and Y is an integer from 1 to 9. In certain embodiments, the influenza virus is an influenza A or 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 population is administered only a single intravenous dose of the medicament. In certain embodiments, each member of the population is administered multiple intravenous doses of the medicament.

In certain embodiments, a member of the population is orally treated 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), (III), or (IV): or a pharmaceutically acceptable salt thereof.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In certain embodiments, the neuraminidase inhibitor is a compound of Formula Ia, IIa, IIIa, or IVa: or a pharmaceutically acceptable salt thereof.

<Formula Ia>

<Formula IIa>

<Formula IIIa>

<Formula IVa>

In certain embodiments, the neuraminidase inhibitor is a compound of Formula Ia, or a pharmaceutically 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 exhibiting signs of infection.

In certain embodiments, said use is for reducing mortality.

Certain embodiments of the present invention provide plasma concentrations of a compound effective for the treatment of a virus in a human by intravenously injecting into the human a predetermined dose of a medicament of a compound of formula (I), (II), (III) or (IV): Provided is a use in the manufacture of a medicament for intravenous injection for achieving

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

Certain embodiments of the present invention provide plasma concentrations of a compound effective for the treatment of a virus in a human by intramuscular injection into the human of a predetermined dose of a medicament of a compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof Provided is a use in the manufacture of a medicament for intramuscular injection for achieving

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In certain embodiments, the plasma concentration of the compound is greater than _{the IC 50 of the virus 12 hours after injection of the compound.}

Mice infected with influenza A/Duck/MN/1525/81 (H5N1) virus were treated with peramivir at doses of 20, 10 and 3 mg/kg (single intravenous 1 hour pre-virus exposure). Peramivir significantly protected mice at the two highest doses used, as shown by prevention of death, alleviation of lung consolidation and inhibition of pulmonary viral titers. A dose of 3 mg/kg moderately suppressed lung parameters. This compound has been shown to be well tolerated in the toxicity control tested concurrently. These data indicate that single intravenous peramivir treatment is efficacious in influenza virus-infected mice.

Compounds for use in the present invention are known in the art and can be synthesized by those skilled in the art using available methods (see, eg, US Pat. No. 6,562,861).

The specific values recited herein for radicals, substituents and ranges are for illustrative purposes only and do not exclude other values defined for radicals and substituents or other values within ranges defined therefor.

Certain compounds of formula I, II, III or IV are compounds of formula Ia, IIa, IIIa or IVa: or a pharmaceutically acceptable salt thereof.

<Formula Ia>

<Formula IIa>

<Formula IIIa>

<Formula IVa>

Certain compounds of formula I, II, III or IV are (1S,2S,3R,4R)-3-(1-acetamido-2-ethylbutyl)-4-guanidino-2-hydroxycyclopentane- carboxylic acid; (1S,2S,3R,4R)-3-(1-acetamido-2-propylpentyl)-4-guanidino-2-hydroxycyclopentanecarboxylic acid; (1S,3R,4R)-3-(1-acetamido-2-propylpentyl)-4-guanidinocyclopentanecarboxylic acid; or (1R,3R,4R)-3-(1-acetamido-2-ethylbutyl)-4-guanidinocyclopentanecarboxylic acid; or a pharmaceutically acceptable salt thereof.

Certain compounds of formula (I) are compounds of formula (Ia) or a pharmaceutically acceptable salt thereof.

One of ordinary skill in the art will recognize that compounds having one or more chiral centers may exist or be isolated in an optically active racemic form. 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 of a compound of Formula I, II, III or IV that possesses the useful properties described herein and , methods for preparing the optically active form (e.g., by resolution of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis or chromatographic separation using a chiral stationary phase) and anti Methods for determining viral (eg anti-influenza) activity (using the standard tests described herein or other similar tests known in the art) are known in the art.

When a compound is basic or acidic enough to form a stable, non-toxic acid or base salt, it may be appropriate to administer the compound as a salt. Examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids forming physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed, including salts of hydrochloride, sulfate, nitrate, phosphate, bicarbonate and carbonate salts.

Pharmaceutically acceptable salts can be obtained using standard procedures known in the art, for example, by reaction of a sufficiently basic compound (eg, an amine) with a suitable acid to provide a physiologically acceptable anion. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids may also be prepared.

The compounds of formulas I, II, III and IV may be formulated into pharmaceutical compositions and administered to a mammalian host, such as a human patient, by the intravenous route. Solutions of the active compounds or salts thereof can be prepared using water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared using glycerol, liquid polyethylene glycol, triacetin and mixtures thereof, and oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient(s) (optionally in liposomes) suitable for the extemporaneous preparation of sterile injectable or infusion solutions or dispersions. have. In all cases, the final dosage form must be sterile, flowable, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle may be a solvent or liquid dispersion medium, for example, water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters and suitable mixtures. Proper fluidity can be maintained, for example, by the formation of liposomes, maintenance of the required particle size (in the case of dispersions) or the use of surfactants. The action of microorganisms can be prevented by using various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it may be desirable to include isotonic agents, for example, sugars, buffers or sodium chloride. Absorption delaying agents, such as aluminum monostearate and gelatin, may be used in the compositions to prolong absorption of the injectable compositions.

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

As used herein, the terms “treat,” “treating,” and “treatment” refer to after one or more clinical signs of a disease state/symptom have arisen in order to reduce or eliminate any sign, aspect or characteristic of the disease state/symptom. as well as administering the compound prior to the onset of clinical signs of the disease state/symptom to prevent the occurrence of any signs. Such treatment need not necessarily be useful. As described below, the active compound may be administered prior to exposure to the virus. These agents may also be administered after exposure to the virus (eg, within 1, 2, 3, 4 or 5 days).

As used herein, the term "unit dosage form" refers to an intravenous preparation containing a specified amount of a drug, all administered in a single dose. This is distinct from the supply of a medicine contained in an indefinite amount, for example, a medicine in a bottle, which must be administered in divided doses by measuring the dose.

In one embodiment, the present invention provides a method of treating a viral infection in a human, comprising administering to the human an effective amount of a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, by intravenous administration. to provide. Typically, an effective amount is administered in a single intravenous administration. In some embodiments, the effective amount is administered in multiple doses. Thus, the method of the present invention provides high patient compliance and requires low doses of the active agent.

In one embodiment of the present invention, the effective inhibitory amount of the compound of formula (I), (II), (III) or (IV) is about 1,000 mg or less.

In one embodiment of the present invention, the effective inhibitory amount of the compound of formula (I), (II), (III) or (IV) is about 800 mg or less.

In one embodiment of the present invention, the effective inhibitory amount of a compound of formula (I), (II), (III) or (IV) is about 600 mg or less.

In one embodiment of the present invention, the effective inhibitory amount of a compound of formula (I), (II), (III) or (IV) is about 500 mg or less.

In one embodiment of the present invention, the effective inhibitory amount of the compound of formula (I), (II), (III) or (IV) is about 400 mg or less.

In one embodiment of the present invention, the effective inhibitory amount of the compound of formula (I), (II), (III) or (IV) is about 300 mg or less.

In one embodiment of the present invention, the effective inhibitory amount of the compound of formula (I), (II), (III) or (IV) is about 200 mg or less.

In one embodiment of the invention, the effective inhibitory amount of a compound of formula (I), (II), (III) or (IV) is about 150 mg or less.

In one embodiment of the invention, the effective inhibitory amount of a compound of formula (I), (II), (III) or (IV) is about 75 mg or less.

According to the method of the present invention, the compound of formula (I), (II), (III) or (IV) is administered to a human by intravenous route. In one embodiment of the invention, the compound of formula (I), (II), (III) or (IV) is administered to the human once by intravenous route. In another embodiment of the invention, the neuraminidase inhibitor is also administered orally to the human. In one embodiment of the invention, the orally administered neuraminidase inhibitor is oseltamivir carboxylate. In one embodiment of the present invention, the orally administered neuraminidase inhibitor is a compound of formula (I), (II), (III) or (IV): or a pharmaceutically acceptable salt thereof.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In one embodiment of the present invention, the orally administered neuraminidase inhibitor is a compound of formula Ia, IIa, IIIa or IVa, or a pharmaceutically acceptable salt thereof.

<Formula Ia>

<Formula IIa>

<Formula IIIa>

<Formula IVa>

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

According to the method of the present invention, the compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, also contains one or more additional therapeutic agents, such as anti-viral agents (eg agents active against influenza) or antibiotics. may be administered together with

The intravenous formulations of the invention may also include one or more additional therapeutic agents, such as anti-viral agents (eg, agents active against influenza) and antibiotics.

Accordingly, the intravenous administration of peramivir to treat a viral infection is described herein. The intramuscular administration of peramivir to treat viral infections is also described herein (see, eg, Example 2), International Application No. PCT/US2006/013535, filed April 12, 2006 It further exemplifies intramuscular administration of peramivir to treat viral infection as described in (the disclosure of which is incorporated herein by reference by reference above). Also surprisingly, as described herein, it has been found that intravenous and intramuscular injection of peramivir into 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 viruses, eg, influenza viruses. For example, the compound can be used to treat any one of the following strains or a combination thereof. In the table below, "H" indicates the hemagglutinin type, and "N" indicates the neuraminidase type. The formula H _x N _y (wherein X is an integer from 1 to 16 and Y is an integer from 1 to 9) may also be used to describe the combinations shown in the tables.

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

Certain embodiments of the present invention provide plasma concentrations of a compound effective for the treatment of a virus in a human by intravenously injecting into the human a predetermined dose of a medicament of a compound of formula (I), (II), (III) or (IV): Provided is a use in the manufacture of a medicament for intravenous injection for achieving

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

Certain embodiments of the present invention also provide a plasma concentration of a compound effective for the treatment of a virus in a human by intramuscular injection of a compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, of a medicament in a predetermined dose to the human. Provided is a use in the manufacture of a medicament for intramuscular injection for achieving

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

Certain embodiments of the present invention also provide compositions comprising peramivir formulated for intravenous administration to a human. Certain embodiments of the present invention also provide a composition comprising peramivir formulated for intravenous administration for use in treating a virus by achieving a plasma concentration of peramivir effective for treating the virus in a human.

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

In certain embodiments of the invention, the plasma concentration of the compound is greater than _{the IC 50 of the virus at least about 12 hours after injection.}

In certain embodiments of the invention, the plasma concentration of the compound is greater than _{the IC 50 of the virus at least about 24 hours after injection.}

In certain embodiments of the invention, the plasma concentration of the compound is greater than _{the IC 50 of the virus at least about 36 hours after injection.}

In certain embodiments of the invention, the plasma concentration of the compound is greater than _{the IC 50 of the virus at least about 48 hours after injection.}

In certain embodiments of the invention, the plasma concentration of the compound is greater than _{the IC 50 of the virus at least about 60 hours after injection.}

In certain embodiments of the invention, the plasma concentration of the compound is greater than _{the IC 50 of the virus at least about 72 hours after 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 certain embodiments of the invention, the virus is H5N1 or a mutant strain thereof.

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

[ Example ]

Example 1. Effect of intravenous treatment of peramivir on influenza A virus infection

Experimental design: Mice were infected (i.n.) using a dose believed to be LD100 of influenza virus. Cohorts of 10 mice were treated intravenously with peramivir at doses of 20, 10 and 3 mg/kg (single 1 hour pre-viral exposure). At the same time, placebo (sterile saline) was administered intravenously to 20 infected mice. The mortality of drug-treated infected mice and placebo-treated controls was observed daily for 21 days. As a virulence control, three uninfected mice were treated with the highest dose of compound concurrently with the infected animals. All toxic controls were observed for death for 21 days, and body weights were recorded just before the first treatment and 18 hours after the last treatment. The body weights of 5 normal controls were recorded.

^b Mean number of days that mice dying before day 21 reached death

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

The infection induced in this experiment was lethal in 55% of mice (Table 1), and the average number of days to death was 9.1 days. Single intravenous injections of 20 and 10 mg/kg of peramivir resulted in significant protection (P<0.01) of infected animals with 100% survival. All of the toxicity controls also survived and gained body weight, indicating that the compound is highly tolerated in this experiment.

These data indicate that peramivir is a significant influenza inhibitor when used as a single intravenous injection.

Example 2. Effect of Intravenous and Intramuscular Treatment of Peramivir in Humans

The safety and pharmacokinetic parameters of peramivir were evaluated by performing a placebo-controlled Phase I clinical study in healthy human volunteers using intravenous and intramuscular administration of peramivir. Blood samples were collected from subjects at different time points after drug administration to determine plasma concentrations of the drug. The curves over time for intravenous and intramuscular administration are shown in Figures 1 and 2, respectively.

In intravenous studies, peramivir has a significantly extended plasma half-life of >12 hours, and its concentrations have been shown to follow linear kinetics. At doses above 2 mg/kg, plasma levels of peramivir 48 hours after dosing were higher than _{the IC 50 for all influenza virus strains tested, including the H5 virus type.} For doses greater than 4 mg/kg, the level of the drug was higher than the _{IC 50 value, even after 72 hours.}

In intramuscular studies, peramivir also has a significantly extended plasma half-life, and its concentration has been shown to follow a linear kinetics. Even 72 hours after administration, the levels of peramivir were higher than _{the IC 50 values for all influenza virus strains tested.}

The long plasma half-life and high levels of peramivir in human volunteers are a remarkably surprising finding, indicating that intravenous and intramuscular administration of peramivir is beneficial for the treatment of influenza in humans.

All publications, patents and patent applications cited herein are hereby incorporated by reference by reference. While the foregoing specification has described the invention in connection with specific embodiments thereof, and numerous details are set forth for purposes of explanation, those skilled in the art may recognize that the invention includes additional embodiments and the details set forth herein It will be apparent that certain contents may vary considerably without departing from the basic principles of the invention.

As used in the context of the present invention, the terms indefinite ("a" and "an") and definite articles ("the"), and similar referents, refer to the singular and the singular and unless otherwise indicated herein or otherwise clearly contradicted by context. It is interpreted as encompassing all plurals. The terms "comprising", "having", "including" and "comprising" are to be construed as open-ended terms (ie, meaning "including but not limited to") unless otherwise stated. Ranges of values recited herein, unless otherwise indicated herein, are merely used as a simplified method to refer to each individual value falling within that range, each individual value being incorporated into the specification as if it were individually recited herein. Included. 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 illustrative language (eg, “such as”) provided herein is merely to better illuminate the invention and does not limit the scope of the invention unless otherwise claimed.

Claims (6)

A pharmaceutical composition for intravenous administration in humans for the treatment of avian influenza infection in humans by a single intravenous administration to humans, comprising 300 mg to 400 mg of a compound of formula Ia: or a pharmaceutically acceptable salt thereof.
<Formula Ia>

The pharmaceutical composition of claim 1 , wherein the single intravenous administration comprises 300 mg of the compound or a salt thereof. The pharmaceutical composition of claim 1 , wherein the single intravenous administration comprises 400 mg of the compound or a salt thereof. The pharmaceutical composition of claim 1 , wherein the avian influenza infection is a H5N1 infection. The pharmaceutical composition according to claim 1, wherein the plasma concentration of the compound is higher than _{the IC 50} of the virus causing avian influenza infection 48 hours after a single intravenous administration of the compound or a salt thereof. The pharmaceutical composition according to claim 1, wherein the plasma concentration of the compound is higher than _{the IC 50} of the virus causing avian influenza infection 72 hours after a single intravenous administration of the compound or a salt thereof.

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