Methods for Treating Disorders or Diseases Associated with Hyperlipidemia and Hypercholesterolemia While Minimizing Side Effects

• US 20090042941A1
• Filed: 03/07/2005
• Published: 02/12/2009
• Est. Priority Date: 03/05/2004
• Status: Active Grant

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Rader, Daniel J.
• Granted Patent: US 7,932,268 B2
• Time in Patent Office: Days
• US Class Current: 514/325
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention provides methods and compositions for treating hyperlipidemia and/or hypercholesterolemia comprising administering to the subject an effective amount of an MTP inhibitor to inhibit hyperlipidemia and/or hypercholesterolemia in said subject, wherein said administration comprises an escalating series of doses of the MTP inhibitor. In some embodiments the method comprises administering at least three step-wise, increasing dosages of the MTP inhibitor to the subject. In some embodiments, the method further comprises the administration of one or more other lipid modifying compounds.

Claims

1. A method of treating a subject suffering from a disorder associated with hyperlipidemia and/or hypercholesterolemia, the method comprising administering to the subject an amount of an MTP inhibitor effective to ameliorate the disorder, wherein said administration comprises at least three step-wise, increasing dosages of the MTP inhibitor.

2. The method of claim 1 wherein the disorder is severe hypercholesterolemia.

3. The method of claim 1 wherein one or more of Total Cholesterol, LDL, fasting triglycerides (TG), VLDL, lipoprotein (a) (Lp(a)), and apolipoproteins A-I, A-II, B, and E are reduced by at least 15%, compared to control levels.

4. The method of claim 1 wherein one or more of Total Cholesterol, LDL, fasting triglycerides (TG), VLDL, lipoprotein (a) (Lp(a)), and apolipoproteins A-I, A-II, B, and E are reduced by at least 25%, compared to control levels.

5. The method of claim 1 wherein said MTP inhibitor has the structure:

or a pharmaceutically acceptable salt thereof or the piperidine N-oxide thereof.

6. The method of claim 1 wherein the MTP inhibitor is administered orally.

7. The method of claim 1 wherein said escalating doses comprise at least a first dose level, a second dose level, and a third dose level.

8. The method of claim 7 wherein said escalating doses further comprise a fourth dose level.

9. The method of claim 7 wherein said escalating doses further comprise a fourth and a fifth dose level.

10. The method of claim 9 wherein the first dose level is 6.25 mg/day, the second dose level is 12.5 mg/day, the third dose level is 25 mg/day, the fourth dose level is 37.5 mg/day, and the fifth dose level is 50 mg/day.

11. The method of claim 1 wherein each of said escalating dose levels is no more than 50% of the immediately following dose level.

12. The method of claim 1 wherein each of said escalating dose levels is no more than 20% of the immediately following dose level.

13. The method of claim 9 wherein said first dose level is from about 2 to about 13 mg/day, said second dose level is from about 5 to about 30 mg/day, and said third dose level is from about 10 to about 50 mg/day, said fourth dose level is from about 20 to about 60 mg/day, and said fifth dose level is from about 30 to about 75 mg/day.

14. The method of claim 8 wherein the first dose level is 12.5 mg/day, the second dose level is 25 mg/day, the third dose level is 37.5 mg/day, and the fourth dose level is 50 mg/day.

15. The method of claim 7 wherein the first dose level is 6.25 mg/day, the second dose level is 12.5 mg/day, and the third dose level is 50 mg/day.

16. The method of claim 1 wherein said MTP inhibitor is administered to said subject in combination with a further lipid modifying compound.

17. The method of claim 1 wherein each dose level is administered to the subject for from about 1 to 4 weeks.

18. The method of claim 16 wherein the MTP inhibitor and the lipid modifying compounds are present in the same dosage unit.

20. The method of claim 17 wherein said MTP inhibitor is administered to said subject in combination with a further lipid modifying compound.

21. The method of claim 17 wherein the MTP inhibitor has the structure:

or a pharmaceutically acceptable salt thereof or the piperidine N-oxide thereof.

23. The method of claim 20 wherein the lipid modifying compounds are selected from the group consisting of HMG CoA reductase inhibitors, cholesterol absorption inhibitors, ezetimide, squalene synthetase inhibitors, fibrates, bile acid sequestrants, statins, probucol and derivatives, niacin, niacin derivatives, PPAR alpha agonists, fibrates, PPAR gamma agonists, thiazolidinediones, and cholesterol ester transfer protein (CETP) inhibitors.

19. A method for inhibiting MTP in a subject in need thereof comprising administering to the subject an amount of an MTP inhibitor effective to inhibit MTP, wherein said administration comprises at least three step-wise, increasing dosages of the MTP inhibitor.

22. The method of claim 19 wherein one or more of Total Cholesterol, LDL, fasting triglycerides (TG), VLDL, lipoprotein (a) (Lp(a)), and apolipoproteins A-I, A-II, B, and E are reduced by at least 15%, compared to control levels.

24. A kit for treating a disorder associated with hyperlipidemia and/or hypercholesterolemia in a subject, comprising:

a) at least four sets of pharmaceutical dosage units, wherein a first set of dosage units provides 6.25 mg/day for a first interval, a second set of dosage units provides 12.5 mg/day for a second interval, a third set of dosage units provides 37.5 mg/day for a third interval, a fourth set of dosage units provides 50 mg/day for a third interval; and

b) instructions for use.

25. The kit of claim 24 further comprising a fourth set of dosage units, said fourth set providing 75 mg/day for a fourth interval.