POSOLOGY AND ADMINISTRATION OF GLUCOCORTICOID BASED COMPOSITIONS
The present invention relates to an improved method of administration of glucocorticoid based composition in glucocorticoid replacement therapies enabling an objectively based regimen for administration enabling correct individual dosing of glucocorticoids resulting in an optimized individual replacement therapy and thus an improved long-term outcome for patients with temporary or chronic adrenal insufficiency.
1 . An improved method of treating glucocorticoid deficiency, the method comprising administering to a subject in need thereof once daily in the morning a composition in a dose equivalence to hydrocortisone according to the nomograms selected from a weight nomogram;
Dose (mg)
Body weight (kg)
15
55-59
20
60-69
25
70-79
30
80-84
35
85-89
40
90-100
and wherein the dose is the total daily dose of hydrocortisone to be administered and the body weight is the bodyweight of the subject, and/or
a pharmacokinetic nomogram;
C cortisol
C 0 h ≦ 150 nM
150 < C 0 h ≦ 250 nM
250 < C 0 h ≦ 350 nM
(nM)
Dose (mg)
Dose (mg)
Dose (mg)
≧198
15
10
5
197-161
20
10
5
160-141
25
15
10
140-115
30
15
10
114-97
35
15
10
<97
40
15
10
and wherein the dose is the total daily dose of hydrocortisone to be administered and wherein the C cortisol (nM) is the difference in serum cortisol concentration between 6 hours post-dose and pre-dose as defined herein.
2 . A method according to claim 1 , wherein the composition is a dual composition which comprises an immediate release part and an extended release part.
3 . A method according to claim 1 , wherein the ratio of the glucocorticoids in the composition between the immediate release part and the extended release part is in range from about 1:1 to about 0.01:1.
4 . A method according to claim 1 , wherein the composition is administered in form of an oral dosage, wherein from about 15 to about 35% w/w of the total amount of the glucocorticoids is immediate released upon administration and the remaining part of the glucocorticoids is modified released during a time period of at least about 8 hours such as at least about 12 hours.
5 . A method according to claim 1 , wherein the one or more glucocorticoids is/are administered in form of a single-unit dosage form comprising a core containing the extended release part of the glucocorticoids and the core being coated with the remaining part of the glucocorticoid and wherein the coating is the immediate release part.
6 . A method according to claim 1 , wherein the administration of the once daily dose is supplemented with one or more further doses of glucocorticoids administered from twice daily to 6 times daily.
7 . A method according to claim 6 , wherein the supplemental administration is oral or parenteral.
8 . A method according to claim 6 , wherein the time interval between any consecutive administrations is from about 2 hours or more to about 12 hours or more independently of each other.
9 . A method according to any claim 6 , wherein the total daily dose of glucocorticoids is from about 15 mg to about 200 mg.
10 . A method according to any claim 1 , wherein the administration can be a combination of different unit dosages including dosage forms containing from a 5 mg dose to a 20 mg dose.
11 . A method according to claim 1 , wherein the composition is in form of a solid dosage form including a tablet or a capsule.
12 . A method according to claim 1 wherein the composition is according to the table below
Quantity
Quantity
(5 mg tablet),
(20 mg tablet),
Ingredient
mg/unit
mg/unit
Standard
Hydrocortisone
5.0
20.0
Ph. Eur.
Hypromellose K 100 cP
47.05
41.2
Ph. Eur.
(Methocel K 100)
Hypromellose K 4000 cP
20.0
24.6
Ph. Eur.
(Methocel K4M)
Cellulose, microcrystalline
100.8
100.8
Ph. Eur.
(Avicel PH-102)
Starch, pregelatinized
16.4
16.4
Ph. Eur.
(Starch 1500)
Silica colloidal anhydrous
1.0
1.0
Ph. Eur.
(Aerosil 200)
Magnesium stearate
1.0
1.0
Ph. Eur.
Opadry II
about 13.75
about 11.0
Colorcon
Water, purified[*]
about 102
about 107
Ph. Eur.
and in the case of a 5 mg tablet an amount of 1.25 mg of hydrocortisone is in the coating and 3.75 mg of hydrocortisone is in the core, and in the case of a 20 mg tablet the coating has an amount of 5 mg of hydrocortisone and an amount of 15 mg of hydrocortisone in the core, said water being caused to evaporate during the manufacturing process.
13 . A method for deriving an individualized dosing of glucocorticoids, the method comprising:
i) taking a first blood sample from the subject at fasted state prior to administering a dose of a glucocorticoid;
ii) administering an oral test dose of 20 mg hydrocortisone or hydrocortisone equivalent to the subject, the oral test dose being a first dose of hydrocortisone or hydrocortisone equivalent administered during a day in which said individualized dosing occurs;
iii) taking a second blood sample from the subject exactly 6 hours post-dose;
iv) determining the serum cortisol concentration in said first and second blood samples by an immunoassay method;
v) establishing the difference in serum cortisol concentration (C cortisol =C 6 h −C 0 h ) between 6 hours post-dose (C 6 h ) and pre-dose (C 0 h ); and
vi) deriving individual once daily hydrocortisone or hydrocortisone equivalent dose based on the established C cortisol and C 0 h values and the PK nomogram according to the table below
C cortisol
C 0 h ≦ 150 nM
150 < C 0 h ≦ 250 nM
250 < C 0 h ≦ 350 nM
(nM)
Dose (mg)
Dose (mg)
Dose (mg)
≧198
15
10
5
197-161
20
10
5
160-141
25
15
10
140-115
30
15
10
114-97
35
15
10
<97
40
15
10
14 . A method according to claim 13 , wherein the oral test dose is according to the table below
Quantity
Quantity
(5 mg tablet),
(20 mg tablet),
Ingredient
mg/unit
mg/unit
Standard
Hydrocortisone
5.0
20.0
Ph. Eur.
Hypromellose K 100 cP
47.05
41.2
Ph. Eur.
(Methocel K 100)
Hypromellose K 4000 cP
20.0
24.6
Ph. Eur.
(Methocel K4M)
Cellulose, microcrystalline
100.8
100.8
Ph. Eur.
(Avicel PH-102)
Starch, pregelatinized
16.4
16.4
Ph. Eur.
(Starch 1500)
Silica colloidal anhydrous
1.0
1.0
Ph. Eur.
(Aerosil 200)
Magnesium stearate
1.0
1.0
Ph. Eur.
Opadry II
about 13.75
about 11.0
Colorcon
Water, purified[*]
about 102
about 107
Ph. Eur.
and in the case of a 5 mg tablet an amount of 1.25 mg of hydrocortisone is in the coating and 3.75 mg of hydrocortisone is in the core, and in the case of a 20 mg tablet the coating has an amount of 5 mg of hydrocortisone and an amount of 15 mg of hydrocortisone in the core, said water being caused to evaporate during the manufacturing process.