KR20230003248A - 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 treatment {INTRAVENOUS ANTIVIRAL TREATMENTS}

<Related Applications>

This patent document relates to U.S. Application Serial No. 60/772,748, filed on February 13, 2006, and International Application No. PCT/US2006/013535, filed on April 12, 2006, both of which are incorporated herein by reference. included) claim priority advantage.

<Background Art>

Peramivir, an influenza virus neuraminidase inhibitor, has significant activity against influenza virus in vitro and experimentally infected mice (Govorkova et al., Antimicrobial Agents and Chemotherapy, 45(10), 2723-2732 ( 2001)] and [Smee el al., Antimicrobial Agents and Chemotherapy, 45(3), 743-748 (2001)]). Unfortunately, clinical trials using this drug have shown sub-optimal therapeutic effects against influenza infections 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 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 of the high efficacy of a single dose of the compound, but also because of the low doses of the compound that have been shown to provide effective treatment. The ability to obtain a therapeutically useful effect with a single administration is important because it minimizes patient compliance problems, especially when multiple administrations are required. In addition, administering low doses is important because it minimizes cost and potential for side effects. It has also surprisingly been found that intravenous and intramuscular injection of peramivir to humans provides high plasma concentrations of peramivir with an extended half-life.

Thus, in one embodiment, the present invention relates to an effective anti-viral amount of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, in a human, comprising administering to the human by the intravenous route. Methods of treating viral infections (eg, influenza infections) are 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 by an intravenous route an effective inhibitory amount of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof. to provide.

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

The present invention also provides a kit comprising a packaging material, 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 an intravenous route.

The present invention also relates to the administration of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, to a source of influenza virus by intravenous injection of a dose of the medicament each to members of a population exhibiting clinical signs of infection. Use in the manufacture of an intravenous injectable medicament for increasing life expectancy or reducing mortality in an exposed population of mammals is provided.

The present invention also relates to the administration of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, by intravenous injection to each member of a population of mammals exposed to a source of an influenza virus, a medicament of a predetermined dosage, thereby treating said mammal. Use in the manufacture of an intravenous injectable medicament for increasing life expectancy or reducing mortality in a population is provided.

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

It is already known that peramivir, an influenza virus neuraminidase inhibitor, has significant activity against influenza virus in vitro and experimentally in infected mice (Govorkova et al., (2001), supra); and [ Smee et al., (2001)]). Unfortunately, clinical trials using the drug showed inadequate suppressive effects on influenza in humans. This effect is because the drug is not well absorbed when administered orally once a day to a patient.

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

Accordingly, certain embodiments of the present invention relate to a virus in a human, comprising administering to the human by the intravenous route an effective anti-viral amount of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, Provides methods for treating infections.

<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 type A or type B infection. In certain embodiments, the viral infection is caused by a viral 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 amount is about 800 mg or less. In certain embodiments, the effective anti-viral amount is about 400 mg or less. In certain embodiments, the effective anti-viral amount is about 300 mg or less. In certain embodiments, the effective anti-viral amount is about 200 mg or less.

In certain embodiments, the entire effective dose is administered in a single intravenous administration. In certain embodiments, the total effective 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 plasma concentration of the compound is higher than the IC ₅₀ of the virus causing viral infection 12 hours after administration of the compound.

Certain embodiments of the present invention are directed to treating neuraminidase in a human, comprising administering to the human by an intravenous route an effective inhibitory amount of a compound of formula I, II, III or IV: or a pharmaceutically acceptable salt thereof. Provides a way to suppress.

<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 entire 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 may further comprise orally administering a neuraminidase inhibitor to the human.

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 10 days or less. In certain embodiments, the orally administered neuraminidase inhibitor is administered for 5 days or less.

Certain embodiments of the present invention provide a unit dosage form suitable for intravenous administration to humans 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, a unit dosage form contains about 400 mg or less of a compound or salt. In certain embodiments, a unit dosage form contains about 300 mg or less of a compound or salt. In certain embodiments, a unit dosage form contains about 200 mg or less of a compound or salt.

Certain embodiments of the present invention provide kits 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 an 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, a kit comprises about 800 mg or less of a compound or salt. In certain embodiments, a kit comprises about 400 mg or less of a compound or salt. In certain embodiments, a kit comprises about 300 mg or less of a compound or salt. In certain embodiments, a kit comprises about 200 mg or less of a compound or salt.

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

A particular embodiment of the present invention relates to the treatment of influenza by intravenous injection of a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, each of a predetermined dose of the medicament to members of a population exhibiting clinical signs of infection. Use in the manufacture of an intravenous medicament for increasing life expectancy or reducing mortality in a population of mammals exposed to a source of a virus 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 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 _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 a H3N2, H1N1, H5N1, avian or seasonal influenza virus.

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

In certain embodiments, members of a population exhibiting clinical signs of infection 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, 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 relates to intravenous injection of a medicament of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, to each member of a mammalian population exposed to a source of influenza virus at a predetermined dose. thereby providing use in the manufacture of an intravenous injectable medicament for increasing life expectancy or reducing mortality in said mammalian population.

<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 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 type A or type B virus. In certain embodiments, the influenza virus is a 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, members of the population 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, 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 specific embodiment of the present invention relates to intravenous injection of a medicament of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, to a human at a given dose, thereby increasing plasma concentrations of the compound effective for the treatment of viruses in humans. It provides use in the manufacture of a medicament for intravenous injection to achieve.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

A specific embodiment of the present invention relates to intramuscular injection of a medicament of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, in a given dose to a human, thereby increasing the plasma concentration of the compound effective for the treatment of viruses in humans. It provides use in the manufacture of a medicament for intramuscular injection to achieve.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

In certain embodiments, the plasma concentration of the compound is higher 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, reduction of lung hardening and inhibition of lung viral titers. A dose of 3 mg/kg moderately suppressed lung parameters. This compound was shown to be well tolerated in toxicity controls tested concurrently. These data indicate that a single intravenous peramivir treatment is efficacious in influenza virus-infected mice.

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

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

A particular 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>

Certain compounds of formula I, II, III or IV are (1S,2S,3R,4R)-3-(1-acetamido-2-ethylbutyl)-4-guanidino-2-hydroxycyclopentane- carboxylic acids; (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.

A particular compound of Formula I is a compound of Formula Ia or a pharmaceutically acceptable salt thereof.

One skilled in the art will recognize that compounds having one or more chiral centers may exist or be isolated in optically active racemic forms. Some compounds may exhibit polymorphism. It should be understood that the present invention includes the use of any racemic, optically active, polymorphic or stereoisomeric form of a compound of formula I, II, III or IV which possesses the useful properties described herein; , methods for preparing the optically active form (e.g., resolution of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis or by chromatographic separation using a chiral stationary phase) and - Methods for determining viral (eg anti-influenza) activity (using standard tests described herein or other similar tests known in the art) are known in the art.

When the compound is sufficiently basic or acidic 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, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed including salts of the 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 (such as an amine) with a suitable acid that provides 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 can be formulated into pharmaceutical compositions and administered to mammalian hosts, such as human patients, 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 glycols, triacetin and mixtures thereof, and oils. Under normal conditions of storage and use, these formulations contain preservatives to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient(s) suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions (optionally encased in liposomes). there is. 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 can be a solvent or liquid dispersion medium, such as water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycols, etc.), vegetable oils, non-toxic glyceryl esters, and suitable contains a mixture Proper fluidity can be maintained, for example, by formation of liposomes, maintenance of the required particle size (in the case of dispersions) or use of surfactants. The action of microorganisms can be prevented using various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases it may be desirable to include an isotonic agent such as a sugar, buffer or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the composition of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound(s) in an appropriate solvent with any of the other ingredients enumerated above, optionally followed by filtered sterilization. In the case of sterile powders used in the preparation of sterile injectable solutions, 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 previously sterile-filtered solution. .

As used herein, the terms “treat,” “treating,” and “treatment” refer to after one or more clinical symptoms of a disease state/symptom have occurred 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 occurrence of clinical signs of the disease state/symptom to prevent the occurrence of any symptoms. Such treatment need not necessarily be useful. As explained 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 intravenous preparations containing a specified quantity of drug, all of which are administered as a single dose. This is to be distinguished from supplying medicines, for example, medicines in bottles, which are contained in inconstant amounts which must be measured and administered in divided doses.

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

In one embodiment of the 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 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 the 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 the 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 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 the compound of formula I, II, III or IV is about 150 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 75 mg or less.

According to the method of the present invention, a compound of formula I, II, III or IV is administered to a human by the intravenous route. In one embodiment of the invention, the compound of Formula I, II, III or IV is administered once to a human by the intravenous route. In another embodiment of the present invention, a neuraminidase inhibitor is also administered orally to a 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 present 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, may also be used in one or more additional therapeutic agents, such as anti-viral agents (eg agents active against influenza) or antibiotics. can be administered together with

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

Thus, intravenous administration of peramivir to treat viral infections is described herein. Intramuscular administration of peramivir to treat viral infections is also described herein (see, eg, Example 2), International Application No. PCT/US2006/013535, filed on Apr. 12, 2006. (the disclosure of which is incorporated herein by reference by reference above) further illustrates the intramuscular administration of peramivir to treat a viral infection. Also surprisingly, as described herein, intravenous and intramuscular injection of peramivir to humans has been found to provide high plasma concentrations of peramivir with an extended plasma half-life.

As described herein, the compounds described herein can be used to treat viruses, such as influenza viruses. For example, the compound can be used to treat any one or a combination of strains below. In the table below, “H” represents the hemagglutinin type and “N” represents 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) can also be used to describe the combinations shown in the table.

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.

A specific embodiment of the present invention relates to intravenous injection of a medicament of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, to a human at a given dose, thereby increasing plasma concentrations of the compound effective for the treatment of viruses in humans. It provides use in the manufacture of a medicament for intravenous injection to achieve.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

Certain embodiments of the present invention also relate to intramuscular injection of a medicament of a predetermined dosage of a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, to a human, thereby increasing the plasma concentration of the compound effective for the treatment of viruses in humans. It provides a use in the manufacture of a medicament for intramuscular injection to achieve.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

Certain embodiments of the present invention also provide compositions comprising peramivir formulated for intravenous administration to humans. 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 to treat the virus in a human.

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

In certain embodiments of the invention, the plasma concentration of the compound is higher 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 higher 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 higher 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 higher 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 higher 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 higher 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 mutant strains thereof.

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

[ Example ]

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

Experimental Design: Mice were infected (i.n.) using a dose considered to be the 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-virus exposure). In parallel, placebo (sterile saline) was administered intravenously to 20 infected mice. Death of drug-treated infected mice and placebo-treated controls was observed daily for 21 days. As a toxicity control, three uninfected mice were treated with the highest dose of compound at the same time as the infected animals. Death of all toxic control groups was observed for 21 days, and body weights were recorded immediately before the first treatment and 18 hours after the last treatment. Body weights of 5 normal controls were recorded.

^b Mean number of days to death for mice that were dying prior to day 21

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

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

These data indicate that peramivir is a significant inhibitor of influenza 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 conducting 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 the plasma concentration of the drug. Curves over time for intravenous and intramuscular administration are shown in FIGS. 1 and 2 , respectively.

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

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

The long plasma half-life and high levels of peramivir shown 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. Although the foregoing description has described the invention in connection with its specific embodiments, and numerous details are set forth for explanatory purposes, it will be apparent to those skilled in the art that the invention may include additional embodiments and the details set forth herein. It will be apparent that some of these may be varied considerably without departing from the basic principles of the invention.

The terms "a" and "an" and definite articles ("the") and similar referents used herein in the context of the present invention refer to the singular and the singular unless otherwise indicated herein or otherwise clearly contradicted by context. It is interpreted as encompassing all plurals. The terms “comprising,” “having,” “including,” and “including” are to be interpreted as open-ended terms (ie, meaning “including but not limited to”) unless otherwise stated. Ranges of values recited herein are merely used as a shorthand method of referring individually to each individual value falling within the range, unless otherwise indicated herein, and each individual value is not disclosed in 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 exemplary language (eg, “such as”) provided herein is merely to more clearly explain the invention and does not limit the scope of the invention unless otherwise claimed.

Claims (1)

A method of treating a viral infection in a human comprising administering to the human by an intravenous route an effective anti-viral amount of a compound of Formula II: or a pharmaceutically acceptable salt thereof.
<Formula II>

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