Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects

• US 9,861,622 B2
• Filed: 07/25/2016
• Issued: 01/09/2018
• 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.
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US15/218,670
• Publication Number:
  US 20160331739A1
• Time in Patent Office: 533 Days
• 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 hyperlipidemia or hypercholesterolemia, the method comprising orally administering to the subject an effective amount of an MTP inhibitor, wherein said administration comprises three step-wise, increasing dose levels of the MTP inhibitor, wherein each dose level is 50% of the immediately following dose level, wherein the third dose level is about 0.2 to about 0.59 mg/kg/day, and wherein the MTP inhibitor is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′

-(trifluoromethyl) [1,1′

-biphenyl]-2-yl] carbonyl] amino]-1-piperidinyl] butyl]-9H-fluorene-9-carboxamide, methanesulfonate;

wherein each dose level is administered for a period of about 7 to about 35 days; and

wherein the subject suffering from hyperlipidemia or hypercholesterolemia has homozygous familial hypercholesterolemia.

2. The method of claim 1, wherein the first dose level is administered for about 2 weeks and the second and third dose levels are each administered for about 4 weeks.

3. The method of claim 1, wherein administration further comprises a fourth dose level, wherein the third dose level is 50% of the fourth dose level.

4. The method of claim 3, upon administration, the LDL-cholesterol of the subject is reduced by at least 25% compared to pre-treatment levels.

5. The method of claim 1, wherein upon administration the subject has reduced symptoms of steatorrhea and/or hepatic fat as compared to a subject administered a starting dose of 25 mg/day of the MTP inhibitor.

6. A method of treating a subject suffering from hyperlipidemia or hypercholesterolemia the method comprising administering to the subject an effective amount of an MTP inhibitor, wherein said administration comprises at least three step-wise, increasing dose levels of the MTP inhibitor, wherein each dose level is 50% of the immediately following dose level, wherein the second dose level is about 0.06 mg/kg/day to about 0.19 mg/kg/day, wherein the MTP inhibitor is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′

-(trifluoromethyl) [1,1′

-biphenyl]-2-yl] carbonyl] amino]-1-piperidinyl] butyl]-9H-fluorene-9-carboxamide, methanesulfonate, wherein each dose level is administered for a period of about 7 to about 35 days, and wherein the subject suffering from hyperlipidemia or hypercholesterolemia has homozygous familial hypercholesterolemia.

7. The method of claim 6, wherein the first dose level is administered for about 2 weeks and the second and third dose levels are each administered for about 4 weeks.

8. The method of claim 6, wherein said increasing dose levels further comprise a fourth dose level, wherein the third dose level is 50% of the fourth dose level.

9. The method of claim 8, upon administration, the LDL-cholesterol of the subject is reduced by at least 25% compared to pre-treatment levels.

10. The method of claim 6, wherein upon administration the subject has reduced symptoms of steatorrhea and/or hepatic fat as compared to a subject administered a starting dose of 25 mg/day of the MTP inhibitor.

11. A method of treating a subject suffering from hyperlipidemia or hypercholesterolemia, the method comprising administering to the subject an effective amount of an MTP inhibitor, wherein said administration comprises three step-wise, increasing dose levels of the MTP inhibitor, wherein each dose level is no more than 50% of the immediately following dose level, and wherein the first dose level is about 0.02 to about 0.059 mg/kg/day, the second dose level is about 0.06 mg/kg/day to about 0.19 mg/kg/day, and the third dose level is about 0.2 to about 0.59 mg/kg/day;

wherein the MTP inhibitor is N-(2,2,2-trifluoroethyl) -9-[4-[4[[[4′

-(trifluoromethyl)[1,1′

-biphenyl]-2-yl] carbonyl] amino]-1-piperidinyl] butyl]-9H-fluorene-9-carboxamide, methanesulfonate;

wherein each dose level is administered for a period of about 7 to about 35 days; and

wherein the subject suffering from hyperlipidemia or hypercholesterolemia has homozygous familial hypercholesterolemia.

12. The method of claim 11, wherein said increasing dose levels further comprise a fourth dose level, wherein the fourth dose level is about 0.6 to about 2.0 mg/kg/day.

13. The method of claim 11, upon administration, the LDL-cholesterol of the subject is reduced by at least 25% compared to pre-treatment levels.

14. The method of claim 11, wherein upon administration the subject has reduced symptoms of steatorrhea and/or hepatic fat as compared to a subject administered a starting dose of 25 mg/day of the MTP inhibitor.