Use of compounds in the treatment of fungal infections
View Patent ↗Described herein is the use of compound 1, an antifungal agent with a novel mechanism of action, in the treatment of fungal infections.
1 . A method of treating a fungal infection in a human subject, the method comprising administering to a human subject with a fungal infection a therapeutically effective amount of compound 1:
or a pharmaceutically acceptable salt, solvate, or hydrate thereof;
wherein,
the fungal infection in the subject is caused by Aspergillus spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., Rhizopus spp., Mucor spp., Lichtheimia spp., Cunninghamella spp., Acremonium spp., Rasamsonia spp., Scedosporium spp., Schizophyllum spp., Trichoderma spp., Alternaria spp., Cladophialophora spp., Cladosporium spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scopulariopsis spp., Magnusiomyces ( Geotrichum ) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces ( Pichia ) spp., Emergomyces spp., Talaromyces spp., or Emmonsia-like fungi, or a combination thereof;
the therapeutically effective amount of compound 1 provides a steady state 24-hr Area Under the Concentration-Time Curve (AUC 0-24 ) of compound 1A in the subject that is greater than about 150 μg×hr/mL of compound 1A:
and
the administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to the subject comprises a treatment regimen comprising the daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for at least about 4 weeks;
wherein the treatment regimen comrises a loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a maintenance dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof
wherein the loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is 2000 mg, and
wherein the maintenance dose comprises once daily administration of 600 mg to 1500 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
2 . The method of claim 1 , wherein the therapeutically effective amount of compound 1 provides a steady state 24-hr Area Under the Concentration-Time Curve (AUC0-24) of at least about 200 μg×hr/mL of compound 1A.
3 . A method of treating a fungal disease or condition in a human subject, the method comprising administering to a human subject with a fungal disease or condition a therapeutically effective amount of compound 1:
or a pharmaceutically acceptable salt, solvate, or hydrate thereof;
wherein,
the fungal disease or condition in the subject is aspergillosis, fusariosis, scedosporiosis, or mucormycosis, or a combination thereof;
the therapeutically effective amount of compound 1 provides a steady state 24-hr Area Under the Concentration-Time Curve (AUC 0-24 ) of compound 1A in the subject that is greater than about 150 μg×hr/mL of compound 1A:
and
the administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to the subject comprises a treatment regimen comprising the daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for at least about 4 weeks;
wherein the treatment regimen comprises a loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a maintenance dose of compound 1, or a pharmaceutically acceptable salt, solvate , or hydrate thereof
wherein the loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is 2000 mg, and
wherein the maintenance dose comprises once daily administration of 600 mg to 1500 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
4 . The method of claim 3 , wherein the therapeutically effective amount of compound 1 provides a steady state 24-hr Area Under the Concentration-Time Curve (AUC0-24) of at least about 200 μg×hr/mL of the compound 1A.
5 . The method of claim 1 , wherein each loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered to the subject by intravenous (I.V.) infusion over about 30 minutes to about 4 hours.
6 . The method of claim 5 , wherein each dose of the loading dose comprises about 1000 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
7 . The method of claim 6 , wherein the loading dose comprises administration of about 1000 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to the subject by intravenous (I.V.) infusion followed by a second administration of about 1000 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to the subject by intravenous (I.V.) infusion within about 24 hours of the first infusion.
8 . The method of claim 1 , wherein the maintenance dose is administered once daily starting on the second day of treatment.
9 . The method of claim 8 , wherein the maintenance dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 4 hours by I.V. infusion starting on the second, third, or fourth day of treatment.
10 . The method of claim 8 , wherein the maintenance dose of about 600 mg to about 1200 mg compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 4 hours by I.V. infusion starting on the second, third, or fourth day of treatment.
11 . The method of claim 8 , wherein the maintenance dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally to the subject starting on the second, third, or fourth day of treatment.
12 . The method of claim 8 , wherein the maintenance dose of about 800 mg to about 1000 mg compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily to the subject starting on the second, third, or fourth day of treatment.
13 . The method of claim 8 , wherein, starting on the second, third, or fourth day of treatment:
a) about 600 mg to about 900 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 3 hours by I.V. infusion; or
b) about 800 mg to about 1000 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily.
14 . The method of claim 8 , wherein:
starting on the second day of treatment, about 600 mg to about 900 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 3 hours by I.V. infusion; and
starting on the fourth day of treatment:
a) about 600 mg to about 900 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 3 hours by I.V. infusion; or
b) about 800 mg to about 1000 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily.
15 . The method of claim 3 , wherein:
the treatment regimen comprises the daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for about 4 weeks to about 12 weeks.
16 . The method of claim 3 , wherein:
the treatment regimen increases the chances of survival for the subject, decreases galactomannan levels in the subject, decreases β-d-glucan levels in the subject, or a combination thereof.
17 . The method of claim 1 , wherein the fungal infection is a mold infection.
18 . The method of claim 17 , wherein the mold infection is caused by Aspergillus spp., Scedosporium spp., Fusarium spp., Lomentospora spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., or Mucorales fungi, or a combination thereof.
19 . The method of claim 17 , wherein the mold infection is caused by Aspergillus spp., Scedosporium spp., Fusarium spp., Lomentospora spp., or Mucorales fungi.
20 . The method of claim 17 , wherein the mold infection is caused by Aspergillus spp., Scedosporium spp., Fusarium spp., or Mucorales fungi.
21 . The method of claim 17 , wherein the mold infection is caused by Aspergillus spp.
22 . The method of claim 17 , wherein the mold infection is caused by A. fumigatus.
23 . The method of claim 17 , wherein the mold infection is caused by Lomentospora spp.
24 . The method of claim 17 , wherein the mold infection is caused by Scedosporium spp.
25 . The method of claim 17 , wherein the mold infection is caused by Fusarium spp.
26 . The method of claim 17 , wherein the mold infection is caused by Mucorales fungi.
27 . The method of claim 17 , wherein the mold infection is caused by an azole-resistant mold.
28 . The method of claim 17 , wherein the mold infection is caused by azole-resistant Aspergillus spp.
29 . The method of claim 17 , wherein the mold infection is caused by azole-resistant A. fumigatus.
30 . The method of claim 17 , wherein the mold infection is an echinocandin-resistant mold.
31 . The method of claim 17 , wherein the mold infection is an invasive mold infection.
32 . The method of claim 17 , wherein the mold infection is invasive aspergillosis.
33 . The method of claim 17 , wherein the mold infection is an invasive infection of the eye and/or central nervous system.
34 . The method of claim 17 , wherein:
the loading dose comprises administration of about 1000 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to the subject by intravenous (I.V.) infusion followed by a second administration of about 1000 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to the subject by intravenous (I.V.) infusion within about 24 hours of the first infusion; and wherein starting on the second day of treatment, about 600 mg to about 900 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 3 hours by I. V. infusion; and
starting on the fourth day of treatment:
a) about 600 mg to about 900 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 3 hours by I. V. infusion; or
b) about 800 mg to about 1000 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily.
35 . The method of claim 34 , wherein the mold infection is caused by Aspergillus spp., Scedosporium spp., Fusarium spp., or Mucorales fungi.
36 . The method of claim 35 , wherein the therapeutically effective amount of compound 1 provides a steady state 24-hr Area Under the Concentration-Time Curve (AUC 0-24 ) of at least 200 μg×hr/mL of compound 1A.
37 . The method of claim 1 , wherein the compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered in combination with an additional antifungal agent.
38 . The method of claim 37 , wherein the additional antifungal agent is an azole antifungal agent or an echinocandin antifungal agent.
39 . The method of claim 10 , wherein the maintenance dose of about 600 mg to about 1200 mg compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 4 hours by I.V. infusion starting on the second day of treatment.
40 . The method of claim 12 , wherein the maintenance dose of about 800 mg to about 1000 mg compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily to the subject starting on the fourth day of treatment.