Use of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]benzyl]-1,3-thiazolidine-2,4-dione and its salts

A method of treating a disease or disorder in a patient in need thereof, the method comprising administering 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, to the patient, wherein 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione is metabolized to 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in the patient, and:

• (a) the steady-state area under the curve (AUCss) of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in plasma from the patient is about 34 μg·h/mL to about 300 μg·h/mL;
• (b) the minimum steady-state plasma drug concentration (Cmin ss) of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in plasma from the patient is about 55 to about 9126 ng/mL;
• or
• (c) the AUCss of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in plasma from the patient is about 34 μg·h/mL to about 300 μg·h/mL, and the Cmin ss of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in plasma from the patient is about 55 to about 9126 ng/mL;
• and
• the AUCss of (i), the Cmin ss of (ii), or the AUCss and Cmin ss of (c) is measured after at least five days of orally administering 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, to the patient per day.

An oral dosage form, comprising an effective amount of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, wherein the effective amount provides the following:

• (a) the steady-state area under the curve (AUCss) of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in plasma from the patient of about 34 μg·h/mL to about 300 μg·h/mL;
• (b) the minimum steady-state plasma drug concentration (Cmin ss) of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in plasma from the patient of about 55 to about 9126 ng/mL;
• or
• (c) the AUCss of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in plasma from the patient of about 34 μg·h/mL to about 300 μg·h/mL, and the Cmin ss of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in plasma from the patient of about 55 to about 9126 ng/mL;
• and
• the AUCss of (i), the Cmin ss of (ii), or the AUCss and Cmin ss of (c) is measured after at least five days of orally administering 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, to the patient per day.

A method of administering a therapeutically effective amount of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione to a patient in need thereof, the method comprising determining the plasma concentration of a PPAR-γ engagement biomarker in a sample obtained from the patient to give a baseline concentration of the PPAR-γ engagement biomarker;

• and
• (a) administering an amount of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, to the patient per day;
• (b) obtaining a plasma sample from the patient after 5 days or more of administering according to (a);
• (c) determining the plasma concentration of the PPAR-γ engagement biomarker in the plasma sample obtained in (b);
• and
• (d) administering a recalculated amount of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, in milligrams, based on the concentration of the PPAR-γ engagement biomarker in the plasma sample obtained in (c), wherein:
• (i) an increase in the PPAR-γ engagement biomarker of about 200% or less in (c) relative to the baseline concentration of the PPAR-γ engagement biomarker comprises administering a greater amount of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, in mg per day, to the patient;
• (ii) an increase in the PPAR-γ engagement biomarker of about 600% or more in (c) relative to the baseline concentration of the PPAR-γ engagement biomarker comprises administering a lesser amount of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, in mg per day, to the patient;
• and
• (iii) an increase in the PPAR-γ engagement biomarker of about 200% to about 600% in (c) relative to the baseline concentration of the PPAR-γ engagement biomarker comprises administering the same amount of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, in mg per day, to the patient.

A method of administering a therapeutically effective amount of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione to a patient in need thereof, the method comprising:

• (i) administering an amount of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, to the patient per day;
• (ii) obtaining a plasma sample from the patient after at least 4 days of administering according to (i);
• (iii) determining the plasma concentration of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in the plasma sample obtained in (ii);
• and
• (iv) administering a recalculated amount of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, in milligrams, to the patient per day as determined according to the Equation 1:
• new
• ⁢
• ⁢
• amount
• ⁢
• ⁢
• in
• ⁢
• ⁢
• mg
• =
• SD
• ×
• (
• CMT
• PC
• )
• ,
• Equation
• ⁢
• ⁢
• 1
• wherein:
• SD is the amount of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, administered to the patient in (i) in mg;
• CMT is the Cmin target in ng/mL of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione;
• Cmin target=(target AUC in ng·h/mL×0.0341±20%)−1104±20%;
• and
• PC is the plasma concentration in ng/mL of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione determined in (iii).

A method of administering a therapeutically effective amount of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione to a patient in need thereof, the method comprising administering an initial dose of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, to the patient once per day for 5 days or more;

• and
• (a) administering a higher dose of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, to the patient once per day if the plasma concentration of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in the patient is less than 149 μg·h/mL;
• (b) administering a lower dose of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, to the patient once per day if the plasma concentration of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in the patient is more than 241 μg·h/mL;
• or
• (c) administering an unchanged dose of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, to the patient once per day if the plasma concentration of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in the patient is between 150 μg·h/mL and 240 μg·h/mL.