METHODS OF ADMINISTERING MONOMETHYL FUMARATE
Methods of therapeutic treatment using monomethyl fumarate are disclosed.
1 . A method of administering a therapeutically effective amount of monomethyl fumarate to treat multiple sclerosis in each patient of a population of patients in need of such treatment, comprising
administering the monomethyl fumarate to each patient to achieve
(i) a mean total area under a curve plotting average molar concentration of monomethyl fumarate-glutathione adducts in blood of the patients versus time; and
(ii) a mean total area under a curve plotting average molar concentration of monomethyl fumarate in the blood of the patients versus time; wherein a ratio of (i) to (ii) is from 20% to 50%.
2 . The method of claim 1 , wherein the ratio of (i) to (ii) is from 20% to 35%.
3 . The method of claim 1 , wherein the ratio of (i) to (ii) from 35% to 50%.
4 . The method of claim 1 , wherein the monomethyl fumarate-glutathione adducts are chosen from:
diastereomers thereof, ionic forms thereof, salt forms thereof, and combinations of the foregoing.
5 . The method of claim 1 , wherein the monomethyl fumarate is administered to the patient at a dose of from 300 to 600 mg monomethyl fumarate per day.
6 . The method of claim 1 , wherein the monomethyl fumarate is administered to the patient at a dosing frequency of from once per day to three times per day.
7 . A method of administering a therapeutically effective amount of monomethyl fumarate to treat multiple sclerosis in a patient in need of such treatment, comprising
administering the monomethyl fumarate to the patient at a monomethyl fumarate dose and dosing frequency that achieves
(i) a total area under a curve plotting average molar concentration of monomethyl fumarate-glutathione adducts in blood of the patient versus time; and
(ii) a total area under a curve plotting average molar concentration of monomethyl fumarate in the blood of the patient versus time; wherein a ratio of (i) to (ii) is from 20% to 50%.
8 . The method of claim 7 , wherein the ratio of (i) to (ii) is from 20% to 35%.
9 . The method of claim 7 , wherein the ratio of (i) to (ii) is from 35% to 50%.
10 . The method of claim 7 , wherein the monomethyl fumarate-glutathione adducts are chosen from:
diastereomers thereof, ionic forms thereof, salt forms thereof, and combinations of the foregoing.
11 . The method of claim 7 , wherein the monomethyl fumarate is administered to the patient at a dose of from 300 to 600 mg monomethyl fumarate per day.
12 . The method of claim 7 , wherein the monomethyl fumarate is administered to the patient at a dosing frequency of from once per day to three times per day.
13 . A method of administering a therapeutically effective amount of monomethyl fumarate to treat multiple sclerosis in each patient of a population of patients in need of such treatment, comprising administering the monomethyl fumarate to the patient at a monomethyl fumarate dose and dosing frequency that achieves formation of MMF-GA (monomethylfumarate-glutathione adducts) in blood; and wherein a mean maximum concentration of MMF-GA in the blood of the patients is from 5% to 35% of a mean maximum concentration of monomethyl fumarate in the blood of the patients.
14 . The method of claim 13 , wherein the mean maximum concentration of MMF-GA is from 5% to 20% of the mean maximum concentration of monomethyl fumarate.
15 . The method of claim 13 , wherein the mean maximum concentration of MMF-GA is from 20% to 35% of the mean maximum concentration of monomethyl fumarate.
16 . The method of claim 13 , wherein the monomethyl fumarate-glutathione adducts are chosen from:
diastereomers thereof, ionic forms thereof, salt forms thereof, and combinations of the foregoing.
17 . The method of claim 13 , wherein the monomethyl fumarate is administered to the patient at a dose of from 300 to 600 mg monomethyl fumarate per day.
18 . The method of claim 13 , wherein the monomethyl fumarate is administered to the patient at a dosing frequency of from once per day to three times per day.
19 . The method of claim 13 , wherein the MMF-GA concentration in the blood reaches the mean maximum concentration of MMF-GA value within a time period of 2 to 10 hours after the administration.
20 . A method of administering a therapeutically effective amount of monomethyl fumarate to treat multiple sclerosis in a patient in need of such treatment, comprising administering the monomethyl fumarate to the patient at a monomethyl fumarate dose and dosing frequency that achieves formation of MMF-GA (monomethylfumarate-glutathione adducts) in blood; and wherein maximum concentration of MMF-GA in the blood of the patient is from 5% to 35% of a maximum concentration of monomethyl fumarate in the blood of the patient.
21 . The method of claim 20 , wherein the maximum concentration of MMF-GA is from 5% to 20% of the maximum concentration of monomethyl fumarate.
22 . The method of claim 20 , wherein the maximum concentration of MMF-GA is from 20% to 35% of the maximum concentration of monomethyl fumarate.
23 . The method of claim 20 , wherein the monomethyl fumarate-glutathione adducts are chosen from:
diastereomers thereof, ionic forms thereof, salt forms thereof, and combinations of the foregoing.
24 . The method of claim 20 , wherein the monomethyl fumarate is administered to the patient at a dose of from 300 to 600 mg monomethyl fumarate per day.
25 . The method of claim 20 , wherein the monomethyl fumarate is administered to the patient at a dosing frequency of from once per day to three times per day.
26 . The method of claim 20 , wherein the MMF-GA concentration in the blood reaches the value within a time period of 2 to 10 hours after the administration.
27 . The method of claim 4 , wherein the monomethyl fumarate-glutathione adducts are chosen from
and diastereomers thereof, salt forms thereof, and combinations of the foregoing.
28 . The method of claim 4 , wherein the monomethyl fumarate-glutathione adducts are chosen from
and diastereomers thereof, salt forms thereof, and combinations of the foregoing.
29 . The method of claim 1 , wherein the administration is systemic administration.
30 . The method of claim 1 , wherein the administration is oral administration.