Methods for treating disorders associated with hyperlipidemia in a mammal
The invention is directed to methods for treating disorders associated with hyperlipidemia in a mammal. The methods involve combination therapies using a microsomal triglyceride transfer protein (MTP) inhibitor (for example, BMS-201038 and implitapide) and a fibrate (for example, fenofibrate). Co-administration of the MTP inhibitor with the fibrate produces a therapeutic benefit, for example, a reduction in the concentration of cholesterol and/or triglycerides in the blood stream, but with fewer or reduced side effects than when higher dosages of the MTP inhibitor are used during monotherapy to provide the same or similar therapeutic benefit.
1 . A method of reducing the concentration of cholesterol and/or triglycerides in the blood of a mammal, and/or the amount of a marker of atherosclerosis in a mammal, the method comprising adminstering each day to the mammal a combination of a fibrate and BMS-201038, wherein BMS-201038 initially is administered at a first dosage in the range of 1 to 5 mg/day for at least 4 weeks, is then administered at a second dosage in the range of 3 to 7 mg/day for at least 4 weeks, and is then administered at a third dosage in the range of 6 to 9 mg/day for at least 4 weeks.
2 . The method of claim 1 , further comprising administering a fourth dosage of BMS-201038 in the range of 9 to 12 mg/day for at least 4 weeks.
3 . The method of claim 1 , wherein the first dosage is 2.5 mg/day.
4 . The method of claim 1 , wherein the second dosage is 5 mg/day.
5 . The method of claim 1 , wherein the third dosage is 7.5 mg/day.
6 . The method of claim 2 , wherein the fourth dosage is 10 mg/day.
7 . The method of claim 1 , wherein the fibrate is administered at a dosage of 25 to 500 mg/day.
8 . The method of claim 7 , wherein the fibrate is administered at a dosage of 25 to 250 mg/day.
9 . The method of claim 8 , wherein the fibrate is administered at a dosage of 100-200 mg/day.
10 . The method of claim 9 , wherein the fibrate is administered at a dosage of 160 mg/day.
11 . The method of claim 1 , wherein the fibrate and BMS-201038 are administered together in the same dosage form.
12 . The method of claim 1 , wherein the fibrate and BMS-201038 are administered in separate dosage forms.
13 . The method of claim 1 , wherein the fibrate is fenofibrate.
14 . The method of claim 1 , wherein the mammal is a human.
15 . The method of claim 14 , wherein the human is a patient resistant to statin monotherapy.
16 . The method of claim 14 , wherein the human is a statin-intolerant patient.
17 . The method of claim 14 , wherein the human has hyperlipidemia, hypercholesterolemia, hyperchylomicronemia, or a combination thereof.
18 . The method of claim 14 , wherein the hypercholesterolemia is homozygous or heterozygous familial hypercholesterolemia.
19 . The method of claim 14 , wherein the method reduces the concentration of cholesterol or triglycerides in the blood but with a reduced incidence of an adverse event as compared to administration of a dosage of 25 mg/day of BMS-201038 in monotherapy.
20 . The method of claim 14 , wherein the method reduces the number or amount of plaques on a wall of a blood vessel of the mammal but with a reduced incidence of an adverse event as compared to administration of a dosage of 25 mg/day of BMS-201038 in monotherapy.
21 . The method of claim 19 , wherein the adverse event is hepatic steatosis.
22 . A method of reducing the concentration of cholesterol and/or triglycerides in the blood of a mammal, and/or the amount of a marker of atherosclerosis in a mammal, the method comprising administering each day to the mammal a combination of a fibrate and implitapide, wherein the implitapide is administered at a dosage in the range of 0.01 to 60 mg/day.
23 . The method of claim 22 , wherein the implitapide is administered at a dosage in the range of 20 to 40 mg/day.
24 . The method of claim 22 , wherein the fibrate is administered at a dosage of 25 to 500 mg/day.
25 . The method of claim 24 , wherein the fibrate is administered at a dosage of 25 to 250 mg/day.
26 . The method of claim 25 , wherein the fibrate is administered as a dosage of 100 to 200 mg/day.
27 . The method of claim 25 , wherein the fibrate is administered at a dosage of 160 mg/day.
28 . The method of claim 22 , wherein the implitapide and fibrate are administered together in the same dosage form.
29 . The method of claim 22 , wherein the implitapide and fibrate are administered in different dosage forms.
30 . The method of claim 22 , wherein the mammal is a human.
31 . The method of claim 30 , wherein the human is a patient resistait to statin monotherapy.
32 . The method of claim 30 , wherein the human is a statin-intolerant patient.
33 . The method of claim 30 , wherein the human has hypercholesterolemia, hyperlipidemia, hyperchylomicronemia, or a combination thereof.
34 . The method of claim 33 , wherein the hypercholesterolemia is homozygous or heterozygous familial hypercholesterolemia.
35 . The method of claim 22 , wherein the method reduces the concentration of cholesterol and/or triglycerides in the blood but with a reduced incidence of an adverse event as compared to administration of a dosage of 80 mg/day of implitapide during monotherapy.
36 . The method of claim 22 , wherein the method reduces the number and/or amount of plaques on a wall of a blood vessel of the mammal but with a reduced incidence of an adverse event as compared to administration of a dosage of 80 mg/day of implitapide during monotherapy.
37 . The method of claim 35 , wherein the adverse event is hepatic steatosis.