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
The present disclosure provides methods of treating a disease or disorder in a patient comprising administering 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (“Compound (1)”), or a pharmaceutically acceptable salt thereof, to the patient, wherein the patient achieves a threshold steady-state plasma concentration of Compound (1). The present disclosure also provides methods of administering a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof, to a patient. Compound (1) is a PPAR-γ agonist that is used to treat a variety of diseases and disorders including, but not limited to, nonalcoholic steatohepatitis and central nervous system diseases, e.g., X-linked adrenoleukodystrophy, Friedreich's Ataxia.
1 . 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 treat a disease or disorder in a patient in need thereof, wherein the disease or disorder is chronic granulomatous disorder, a polycystic ovary syndrome, a thyroid carcinoma, a thyroid autoimmune disorder, a pituitary adenoma, atherosclerosis, a skin disease, or an inflammatory respiratory disease, the method comprising:
(a) administering an amount of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-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 at least four days of administering according to (a);
(c) 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 (b); and
(d) administering a recalculated amount of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-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:
recalculated
amount
in
mg
=
SD
×
(
CMT
PC
)
,
Equation
1
wherein:
SD is the amount of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, administered to the patient in (a) in mg;
CMT is the C min target in ng/mL;
C min 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 (c), wherein the target AUC is about 100 μg h/mL to about 300 μg h/mL.
2 . The method of claim 1 , wherein the plasma sample is obtained from the patient after at least 7 days of administering according to (a).
3 . The method of claim 1 , wherein 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride is administered to the patient per day in (a) and (d).
4 . The method of claim 3 , wherein about 180 mg of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride is administered to the patient per day in (a) and the target AUC is about 200 ng·h/mL.
5 . The method of claim 3 , wherein a recalculated amount of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride is administered to the patient per day in (d).
6 . The method of claim 3 , wherein the 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride is administered to the patient in (a) and (d) as a suspension comprising about 15 mg of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride per mL.
7 . 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 treat a disease or disorder in a patient in need thereof, wherein the disease or disorder is chronic granulomatous disorder, a polycystic ovary syndrome, a thyroid carcinoma, a thyroid autoimmune disorder, a pituitary adenoma, atherosclerosis, a skin disease, or an inflammatory respiratory disease, the method comprising:
(a) administering 5 to 20 milliliters of an oral suspension of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride to the patient per day, wherein the oral suspension comprises 15 mg of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride per mL;
(b) obtaining a plasma sample from the patient following 5 days or more of administering according to (a);
(c) determining the C min ss 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 (b); and
(d) administering a recalculated amount, in milliliters, of the oral suspension to the patient per day as determined according to the Equation 4:
Dose
V
1
=
Dose
p
r
e
-
V
1
×
C
min
T
A
R
C
min
V
1
,
Equation
4
wherein:
Dose V1 is the recalculated amount, in milliliters, of the oral suspension administered to the patient per day in (d);
Dose pre-V1 is the amount, in milliliters, of the oral suspension administered to the patient in (a);
C min V1 is the C min ss , in ng/mL, of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione determined in (c) taken 22 hours to 26 hours after the last administration; and
C min TAR is the targeted concentration in ng/mL of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, wherein:
(A) C min TAR is calculated according to Equation 5A:
C min TAR =7700−(88.5×Dose pre-V1 ) Equation 5A
if the plasma sample in (b) was obtained 18 hours to 19.9 hours after the last administration of the oral suspension in (a);
(B) C min TAR is calculated according to Equation 5B:
C min TAR =7440−(103.4×Dose pre-V1 ) Equation 5B
if the plasma sample in (b) was obtained 20 hours to 21.9 hours after the last administration of the oral suspension in (a);
(C) C min TAR is 5716 if the plasma sample in (b) was obtained 22 hours to 25.9 hours after the last administration of the oral suspension in (a);
(D) C min TAR is calculated according to Equation 5D:
C min TAR =6740−(138.6×Dose pre-V1 ) Equation 5D
if the plasma sample in (b) was obtained 26 hours to 27.9 hours after the last administration of the oral suspension in (a); or
(E) C min TAR is calculated according to Equation 5E:
C min TAR =6520−(148.0×Dose pre-V1 ) Equation 5E
if the plasma sample in (b) was obtained 28 hours to 30 hours after the last administration of the oral suspension in (a).
8 . The method of claim 7 further comprising:
(i) obtaining a plasma sample from the patient following 5 days or more of administering the recalculated amount, in milliliters, of the oral suspension of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride to the patient per day in (d);
(ii) determining the C min calcd , in ng/mL, 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 (i) according to Equation 6:
C
min
c
a
l
c
d
=
Dose
V
1
×
C
min
V
2
Dose
last
taken
;
Equation
6
wherein Dose last taken is the amount, in milliliters, of the last administered dose of the oral suspension taken by the patient;
(iii) determining the AUC Calcd , in μg·h/mL, of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione based on the C min Calcd determined in (ii), wherein:
(A) the AUC Calcd is calculated according to Equation 7A:
A
U
C
Calcd
=
C
min
calcd
+
(
88.5
×
Dose
last
taken
)
3
8
.
5
,
Equation
7
A
if the plasma sample in (i) was obtained between 18 hours to 19.9 hours after the last administration of the oral suspension;
(B) the AUC Calcd is calculated according to Equation 7B:
A
U
C
C
a
l
c
d
=
C
min
c
a
l
c
d
+
(
103.4
×
Dose
last
taken
)
3
7
.
2
,
Equation
7
B
if the plasma sample in (i) was obtained 20 hours to 21.9 hours after the last administration of the oral suspension;
(C) the AUC Calcd is calculated according to Equation 7C:
A
U
C
C
a
l
c
d
=
C
min
c
a
l
c
d
+
1104.1
3
4
.
1
,
Equation
7
C
if the plasma sample in (i) was obtained 22 hours to 25.9 hours after the last administration of the oral suspension;
(D) the AUC Calcd is calculated according to Equation 7D:
A
U
C
Calcd
=
C
min
c
a
l
c
d
+
(
1
3
8.6
×
Dose
last
taken
)
3
3
.
7
,
Equation
7
D
if the plasma sample in (i) was obtained 26 hours to 27.9 hours after the last administration of the oral suspension; or
(E) the AUC Calcd is calculated according to Equation 7E:
A
U
C
C
a
l
c
d
=
C
min
c
a
l
c
d
+
(
148
×
Dose
last
taken
)
32.6
,
Equation
7
E
if the plasma sample in (i) was obtained 28 hours to 30 hours after the last administration of the oral suspension; and
(iv) administering the same recalculated amount, in milliliters, of the oral suspension to the patient per day as in (i) for 5 days or more if the AUC Calcd is 150 to 240 μg h/mL and, optionally, repeating (i)-(iii); or
(v) administering a new recalculated amount, in milliliters, of the oral suspension to the patient per day in (i) if the AUC Calcd is less than 150 or more than 240 μg h/mL.
9 . 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 treat a disease or disorder in a patient in need thereof, wherein the disease or disorder is chronic granulomatous disorder, a polycystic ovary syndrome, a thyroid carcinoma, a thyroid autoimmune disorder, a pituitary adenoma, atherosclerosis, a skin disease, or an inflammatory respiratory disease, the method comprising:
(a) administering an initial dose of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride to the patient once per day for 5 or more days; and
(b) administering a recalculated dose of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride according to:
(i) Equation 8a:
D recal =D initial *( AUC Tar /AUC _0 t ) Equation 8a
wherein:
D recal is recalculated dose of the 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride administered to the patient in milligrams;
D initial is the initial dose of the 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride administered to the patient in milligrams;
AUC Tar is the targeted exposure of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in the patient 24 hours after the last administration in (a) in ng h/ml; and
AUC_0t is the calculated exposure of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in the patient 24 hours after the last administration in (a) in ng h/ml; and
(ii) Equation 8b:
AUC _0 t =(28.31+0.472*Δ T )* C +(34410+2234*Δ T )* D initial /150 Equation 8b
wherein:
AUC_0t is the calculated exposure of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione in the patient 24 hours after the last administration in (a) in ng h/ml;
D initial is the initial dose of the 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride administered to the patient in milligrams;
C is 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 in ng/ml, wherein the plasma sample is taken from the patient 24±6 hours after the last administration in (a); and
ΔT is the difference between the time the plasma sample is taken from the patient and 24 hours after the last administration in (a) in hours;
wherein the targeted exposure is 50,000 ng h/mL to 250,000 ng h/mL.
10 . The method of claim 9 , the targeted exposure is 100,000 ng·h/mL to 200,000 ng·h/mL.
11 . The method of claim 9 , the targeted exposure is 50,000 ng·h/mL to 100,000 ng·h/mL.
12 . The use of claim 1 , wherein the target AUC is about 50 μgh/mL to about 100 μgh/mL.