Methods for treating disorders associated with hyperlipidemia in a mammal

• US 20070093468A1
• Filed: 10/18/2006
• Published: 04/26/2007
• Est. Priority Date: 10/18/2005
• Status: Abandoned Application

• Current Assignee: Aegerion Pharmaceuticals, Inc. (Valline Srl)
• Original Assignee: Aegerion Pharmaceuticals, Inc. (Valline Srl)
• Inventors: Wisler, Gerald
• Application Number:
  US11/582,835
• Publication Number:
  US 20070093468A1
• Time in Patent Office: Days
• US Class Current: 514/210.02
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• 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
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Abstract

The invention is directed to methods for treating hyperlipidemia in a mammal. The methods involve combination therapies using a microsomal triglyceride transfer protein (MTP) inhibitor (for example, BMS-201038 and implitade) and a cholesterol absorption inhibitor (CAI) (for example, ezetimibe). Co-administration of the MTP inhibitor with the CAI 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.

Claims

1. A method of reducing at least one of (i) the concentration of cholesterol and/or triglycerides in the blood of a mammal, and (ii) the amount of a marker of atherosclerosis in a mammal, the method comprising administering each day to the mammal a combination of ezetimibe and BMS-201038, wherein BMS 201038 initially is administered at a first dosage in the range of 2.5 to 7.5 mg/day for at least 4 weeks, is then administered at a second dosage in the range of 5 to 10 mg/day for at least 4 weeks, and is then administered at a third dosage in the range of 7.5 to 12.5 mg/day for at least 4 weeks.

2. The method of claim 1, wherein the first dosage is 5 mg/day.

3. The method of claim 1, wherein the first dosage is 2.5 mg/day

4. The method of claim 2, wherein the second dosage is 7.5 mg/day.

5. The method of claim 4, wherein the third dosage is 10 mg/day.

6. The method of claim 5, wherein the ezetimibe is administered at a dosage of 1 to 50 mg/day.

7. The method of claim 6, wherein the ezetimibe is administered at a dosage of 10 mg/day.

8. The method of claim 1, wherein the ezetimibe and BMS-201038 are administered together in the same dosage form.

9. The method of claim 1, wherein the ezetimibe and BMS-201038 are administered in separate dosage forms.

10. The method of claim 1, wherein the mammal is a human.

11. The method of claim 10, wherein the human is a patient resistant to statin monotherapy.

12. The method of claim 10, wherein the human is a statin-intolerant patient.

13. The method of claim 10, wherein the human has hyperlipidemia, hypercholesterolemia, hyperchylomicronemia, or a combination thereof.

14. The method of claim 13, wherein the hypercholesterolemia is homozygous or heterozygous familial hypercholesterolemia.

15. The method of claim 10, wherein the method reduces the concentration of at least one 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 during monotherapy.

16. The method of claim 10, wherein the method reduces the amount of arterial 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 during monotherapy.

17. The method of claim 15, wherein the adverse event is hepatic steatosis.

18. A method of reducing hepatic steatosis in a patient receiving BMS-201038, the method comprising co-administering BMS-201038 and ezetimibe to the patient.

19. The method of claim 18, wherein the BMS-201038 is administered at a dosage greater than 25 mg/day.

20. The method of claim 18, wherein the BMS-201038 is administered at a dosage of 1 to 25 mg/day.

21. The method of claim 18, wherein the ezetimibe and BMS-201038 are administered together in the same dosage form.

22. The method of claim 18, wherein the ezetimibe and BMS-201038 are administered in separate dosage forms.

23. The method of claim 22, wherein the ezetimibe is administered before, after, or simultaneously with BMS-201038.

24. A method of reducing at least one of (i) the concentration of cholesterol and/or triglycerides in the blood of a mammal, and (ii) the amount of a marker of atherosclerosis in a mammal, the method comprising administering each clay to the mammal a combination of ezetimibe and implitapide, wherein the implitapide is administered at a dosage in the range of 0.01 to 60 mg/day.

25. The method of claim 24, wherein the implitapide is administered at a dosage in the range of 20 to 40 mg/day.

26. The method of claim 24, wherein the ezetimibe is administered at a dosage of 1 to 25 mg/day.

27. The method of claim 26, wherein the ezetimibe is administered at a dosage of 10 mg/day.

28. The method of claim 24, wherein the implitapide and ezetimibe are administered together in the same dosage form.

29. The method of claim 24, wherein the implitapide and ezemitibe are administered in separate dosage forms.

30. The method of claim 24, wherein the mammal is a human.

31. The method of claim 30, wherein the human is a patient resistant 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, hyperlipidemidia, 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 24, wherein the method reduces the concentration of at least one of cholesterol 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 24, wherein the method reduces the amount of arterial 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.

38. A method of lowering the concentration of cholesterol and/or triglycerides in the blood of a mammal, the method comprising administering implitapide at a dosage of about 10 to 60 mg/day so as to reduce the concentration of the cholesterol and/or the triglycerides.

39. The method of claim 38, wherein the implitapide is administered at a dosage in the range of 20 to 40 mg/day.

40. The method of claim 38, further comprising administering a cholesterol lowering drug selected from the group consisting of a CAI, a HMG CoA reductase inhibitor, a bile acid sequestrant, a fibrate, niacin, and a squalene sythetase inhibitor.

41. The method of claim 38, wherein the mammal is a human.